NO751055L - - Google Patents

Description

After the introduction of reserpine and chlorpromazine into psychotherapeutic medicine in the early 1950s, great efforts have been made to find other sedatives that

have improved biological profiles.

It has now been shown that certain indoles, and one in particular

series of. 2-substituted-5-aryl-1,2,3,4-tetrahydro-γ-carbolines and 2-substituted-4-aryl-1,2,3,4-tetrahydropyrrolo[3,4-b]indoles are very effective as sedatives.

γ-carbolines are not new to the chemical and patent literature;

the antihistamine effect is indicated in British patent no. 721,171,

the antidepressant action in US Patents Nos. 3,419,568, 3, 68.7, 960, 3,705,902 and 3,718,657, the anti-trypanosomal action in German Patents 2,117,286 and 2,115,738, the sedative and analgesic action in US Patent No. 3,466,293 and the sedative action in US -patents no. 3,687,961 and 3,755,584.

The fused pyrrolo[3,4-b]indole ring system is

relatively new in the chemical literature, the first successful preparation is reported by Southwich, et al., J. Org. Chem. 25,

1133 (1960). The simple 2-substituted-1,2,3,4-tetrahydropyrrolo[3,4-b]indoles prepared and tested had no anti-tumor activity.

The tranquilizers according to the present invention

is of the formula:

and pharmaceutically acceptable acid addition salts thereof, wherein X is fluorine, chlorine, bromine, methyl or hydrogen, Z is fluorine, chlorine, methoxy or hydrogen, n is 1 or 2 and R is alkyl containing 1-6 carbon atoms, benzyl or substituted alkylene of the formula:

where A is the alkylene containing 1-5 carbon atoms,

0 OR, OR,

II I 1 .1 1

M is -CH=CH-, -CH2~, -C-, -CH- or -C(CH3)- where R± is hydrogen or alkanoyl containing 2-5 carbon atoms and Y is fluorine, chlorine, methyl or hydrogen under provided that when Z is hydrogen and n is 2, X is equal to fluorine, chlorine, bromine or methyl.

The compounds according to the present invention of the formula:

where X, Z and n have the previously indicated meaning, are useful intermediates leading to tranquilizers according to the present invention.

A preferred group of chemotherapeutic compounds according to the present invention are compounds of formula I where Z is fluorine, X is fluorine, chlorine, bromine, hydrogen or methyl, n is 2 and R is substituted alkylene of the formula:

where A is the alkylene containing 1-5 carbon atoms, M is -CH=CH-, -CH2~,

where is

hydrogen or alkanoyl containing 2-5 carbon atoms and Y is fluorine, chlorine, methyl or hydrogen.

Another preferred class are compounds of the formula I where Z is methoxy, X is fluorine, n is 2 and R is substituted alkylene of the formula:

where A is the alkylene containing 1-5 carbon atoms, M is -CH=CH-, -CH2-,

where R^ is

hydrogen or alkanoyl containing 2-5 carbon atoms and Y is fluorine, chlorine, methyl or hydrogen.

A third class of preferred compounds are compounds of formula I where Z is fluorine, X is fluorine, chlorine, bromine, hydrogen or methyl, n is 2 and R is benzyl or alkyl containing 1-6 carbon atoms.

A fourth class of preferred compounds are compounds of formula I where Z is hydrogen, X is fluorine, chlorine, bromine or methyl, n is 2 and R is alkyl containing 1-6 carbon atoms or substituted alkylene of the formula:

where A is the alkylene containing 1 to 5 carbon atoms, M is -CH=CH-,"CH2-,

where R^ is hydrogen

or alkanoyl containing 2-5 carbon atoms and Y is fluorine, chlorine, methyl or hydrogen.

A fifth class of preferred compounds are compounds of formula I where Z is chlorine, X is fluorine, chlorine, bromine or methyl, n is 2 and R is substituted alkylene of the formula:

where A is the alkylene containing 1-5 carbon atoms,

OH

IN

M is -CH-

and Y is fluorine, chlorine, methyl or hydrogen.

A sixth class of preferred compounds are compounds of formula I' where X is fluorine, Z is fluorine, chlorine, hydrogen or methoxy, n is 1 and R is the substituted alkylene of the formula:

where A is the alkylene containing 1-5 carbon atoms, M is

where R 1 is hydrogen or alkanoyl

which contains 2-5 carbon atoms and Y is fluorine, chlorine, methyl or hydrogen.

A preferred class of intermediates leading to the chemotherapeutic agents of the present invention are compounds of the formula:

where X is fluorine, n is 1 or 2 and Z is fluorine, chlorine, methoxy or hydrogen.

Compounds of the following formula are also covered by the present invention:

where X, Y, Z, n, M and A. are as previously indicated and p is an integer of 1 or 2.

Compounds according to the present invention show a marked, and unexpectedly, superior sedative effect to the most closely related known compounds, namely 5-phenyl-2-methyl-1,2,3,4-tetrahydro-γ-carboline in British Patent No. 721,171 and 5-phenyl-2-benzyl-1,2,3,4-tetrahydro-γ-carboline described by Spickett, J. Med. Chem, 9, 436 (1966).

The following scheme illustrates the synthesis of compounds according to the present invention:

where X, Z and n are as previously indicated, Hal is halogen or sulfonate ester and R is hydrogen, benzyl, alkyl of 1-6 carbon atoms or substituted alkylene of the formula: where A is the alkylene containing 1-5 carbon atoms, M is -CH -- or

Y is as previously stated.

The compounds of formula II are suitably prepared from commercially available 1-carbethoxy-4-piperidone and from 1-carbethoxy-3-pyrrolidinone, and necessary phenylhydrazines according to the classical Fischer indole synthesis which comprises heating approx. equimolar amounts of the appropriate phenylhydrazine hydrogen chloride with piperidone in a reaction inert solvent, such as absolute ethanol.

Arylation of II is carried out by reacting II with a suitably substituted p-bromobenzene derivative, and using a 2-3 times molar excess of bromobenzene derivative for optimal yield of the product, III. In addition to equimolar amounts, plus as much as 100% excess, cuprous bromide and sodium carbonate are used in the reaction, the reaction being carried out in a reaction-inert solvent, such as nitrobenzene, hexamethylphosphoramide or N-methyl-2-pyrrolidione at a temperature of 125-225° C, preferred range 175-200°C.

The hydrolysis of compounds related to III is carried out by heating an ethanolic solution of the appropriate 2-carbethoxy-5-aryl-1,2,3,4-tetrahydrocarboline with at least two molar equivalents of potassium hydroxide.

This reaction sequence is preferred for the production of the useful intermediates according to the present invention of formula I, where R means hydrogen.

Compounds of formula I where X and Z are as previously indicated and R is alkyl, benzyl or substituted alkylene of the formula: where A is alkylene, M is -CH2~ or

and Y is as before

indicated, is synthesized by alkylation of I where R is hydrogen.

The reaction is carried out experimentally with an equimolar amount, plus as much as a 10-20% excess of the alkylating agent in a reaction-inert, aprotic, polar solvent such as tetramethylene sulfone, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide or a dialkyl ketone at elevated temperatures. To facilitate completion of the reaction, a catalytic amount of potassium iodide is added to the reaction mixture, and in situ reactive amounts of iodoalkylating agent are formed.

In addition, an excess of 5-6 mol of sodium carbonate is added

to remove hydrogen halide which is produced as a by-product during the alkylation.

A number of further synthetic routes can be used for the preparation of compounds of formula I, where R is alkyl. The first alternative route first employs the reaction of a phenylhydrazine derivative with a 1-alkyl-4-piperidone, followed by

of arylation of the 5-position; the reaction scheme is as follows:

The conditions for Fischer's indole synthesis leading to IV and the subsequent arylation reaction of IV leading to I are similar to those previously described.

Another alternative synthetic route leading to 2-alkyl-5-aryl-1,2,3,4-tetrahydro-γ-carbolines and 2-alkyl-4-aryl-1,2,3,4-tetrahydropyrrolo[3, 4-b] indoles employ acylation of compounds of formula I, where R is hydrogen with a suitable acid halide, anhydride or mixed anhydride, followed by metal hydride reduction of the formed amide by the following route:

where X, Z and n are as previously indicated and R<1> is alkyl containing 1-5 carbon atoms.

In practice, the acylation of compounds of formula I (R = H) is carried out as shown above, with an acid halide, anhydride or mixed anhydride and using equimolar amounts of the acylating agent plus as much as 20% excess in a reaction inert solvent, such as a chlorinated hydrocarbon. An equimolar amount, plus as much as a 2-fold excess, of a tertiary amine, such as triethylamine, is added to facilitate termination of the reaction, which can be carried out at ambient temperature.

Reduction of compounds of formula V is conveniently carried out with a metal hydride, such as lithium aluminum hydride or aluminum hydride in a reaction inert solvent, such as dialkyl or cycloalkyl ethers.

In a similar manner, the acylation can be carried out with the corresponding acid halide or anhydride of an arylalkanoic acid of the formula:

where Y is as previously indicated and R" is the alkylene with 1-5 carbon atoms.

The reduction of the amides formed, corresponding to V, is carried out using lithium aluminum hydride or aluminum hydride and gives compounds where the 2-substituent is aralkyl of the formula:

where Y, M and A are as indicated above.

A third synthetic route to compounds of formula I, wherein R is methyl, involves the reduction with lithium aluminum hydride or aluminum hydride of compounds of formula III as follows:

The person skilled in the art will easily understand that any carbo alkoxy can be used and this leads to 2-methyl compounds. An alternative preparative route leads to compounds of formula I wherein R is where A and X are as previously indicated and M is shown in the following diagram:

Alkylation of compounds of formula I (R = H) with

etGj-haloalkylnitrile is carried out under the same alkylation conditions as previously indicated.

Further reaction of the nitrile, VI, with the necessary Grignard reagent leads to the desired ketones. It is preferred to use 4 mol of Grignard reagent per moles of nitrile, although the desired product can be prepared with a smaller excess. As with Grignard reactions, it is preferred that the reaction be carried out in a reaction-inert solvent, such as diethyl ether.

The synthesis of compounds of formula I, where R is

where A and Y are as previously indicated is carried out by reduction of the corresponding ketone using sodium borohydride as indicated in the following scheme:

Experimentally, 1 mole of ketone is brought into contact with

about. 4 moles of hydride in a reaction-inert solvent, such as ethanol, at from room temperature to elevated temperatures. The addition of tetrahydrofuran facilitates the reaction by promoting the solubility of the reactants.

The tertiary alcohols according to the present invention are prepared by reacting the appropriate ketone with methyl magnesium iodide, as follows:

where X, Z, n, A and Y are as previously indicated.

As with the previously stated Grignard reaction is

it is preferred, even if the starting materials react in equimolar amounts, to use as much as 100% excess methylmagnesium iodide. In addition, it is also preferred that the reaction is carried out in a reaction-inert solvent such as diethyl ether

ambient temperatures.

The alcohols according to the present invention are easily converted into esters by acylation with an acid halide, anhydride or mixed anhydride. These acylation reactions can be carried out in such solvents as chlorinated hydrocarbons using a tertiary amine, such as pyridine or triethylamine, to ensure completion of the reaction.

■ The secondary alcohols according to the present invention are transferred by treatment with 6N hydrochloric acid at elevated temperatures by dehydration to compounds where M is -CH=CH-. It is often preferred to use a co-solvent such as ethanol to promote the solubility of carboline and pyrrolo[3,4-b]-indole.

With regard to the necessary starting materials leading to the synthesis of the compounds according to the present invention,

they are either commercially available, the preparation is indicated in chemical literature or they can be prepared according to methods known to the person skilled in the field. Phenylhydrazines are e.g. commercially available or can be synthesized by reduction of phenyldiazonium salt as indicated by Wagner and Zook in "Synthetic Organic Chemistry", John Wiley&Sons, New York, N.Y., 1956, Chapter 26; 1-Substituted 4-piperidones are commercial reagents or prepared according to the method of McElvain and Rorig, J. Am. Chem. Soc., 70, 1826 (1948), o-haloalkylaryl ketones are synthesized according to the method set forth in US Patent No. 2, 997, 472 (CA. 5-6, 11603 (1962)), and 1-alkyl-3-pyrrolidinones are synthesized according to Casy et al.,

J. Pharm. Pharmacol. 17(3), 157 (1965).

As previously mentioned, the compounds according to the present invention can form acid addition salts. The basic compounds are converted to their acid addition salts by reacting the base with an acid either in an aqueous or non-aqueous medium. Similarly, treatment of the acid addition salts with an equivalent amount of an aqueous base solution, e.g. alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates.or with an equivalent amount of a metal cation which leads to an insoluble scavenging with the acid anion, to regenerate the free base form. The bases can thus be regenerated by transfer to the same or to a different acid addition salt.

When using the chemotherapeutic effect of the compounds according to the present invention, it is of course preferred to use pharmaceutically acceptable salts. Although water insolubility, high toxicity or lack of crystalline nature may render some of the salts undesirable or less desirable for use in a given pharmaceutical application, the water insoluble or toxic salts may be transferred to the corresponding pharmaceutically acceptable bases by cleavage of the salt as indicated above , or alternatively they can be transferred to any pharmaceutically acceptable acid addition salt.

Examples of acids which give pharmaceutically acceptable anions are hydrogen chloride, hydrogen bromide, hydrogen iodide, nitric acid, sulfuric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and gluconic acid.

As previously stated, the γ-carbolines and pyrrolo[3,4-b]-indoles of the present invention, except for compounds of formula I where R is hydrogen which are useful as intermediates, are useful for therapeutic use as tranquilizers in mammals. The following agents are excellent in this respect: 8-fluoro-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)-propyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p -fluorophenyl)-2-(4-phenyl-4-hydroxybutyl)-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-fluorophenyl)-2-[4-(p- chloro-phenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-tolyl)-4-hydroxybutyl ]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluoro-phenyl)-4-acetoxybutyl]-1,2, 3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-fluorophenyl-2-[3-(p-fluorophenyl)-3-hydroxypropyl]-1,2,3,4-tetrahydro-γ-carboline , 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluoro-phenyl)-5-hydroxypentyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5 - (p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxypentyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-fluorophenyl)-2 -[4-(p-fluoro-phenyl-3-butenyl]-1,2,3,4-tetrahydro-γ-carboline, 8-chloro-5-(p-fluorophenyl)-2-[3-(p- fluorobenzoyl)propyl]-1,2,3,4-tetrahydro-γ-carboline, 8-chloro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxy-butyl]-! ,2,3,4-tetrahydro-γ-carboline, 8-chloro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxypentyl]-1,2,3,4-tetrahydro -γ-carboline, 8-bromo-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydro-γ-carboline, 8-bromo-5- (p-fluorophenyl)-2-

[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-methyl-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl) propyl]-1,2,3,4-tetrahydro-γ-carboline, 8-methyl-5-(p-fluorophenyl)-2-[4-(p-fluoro-phenyl)-4-hydroxybutyl]-1,2 ,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-methoxyphenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ -carboline, 8-fluoro-5-(p-methoxyphenyl)-2-[4-(p-tolyl)-4- hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5 -(p-methoxyphenyl)-2-[4-(p-chlorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-fluorophenyl)-1 ,2,3,4-tetrahydro-γ-carboline , 8-fluoro-5-(p-fluorophenyl)-2-benzyl-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-( p-fluorophenyl)-2-methyl-1,2,3,4-tetrahydro-y-carboline, 8-fluoro-5-(p-fluorophenyl)-2-ethyl-1,2,3,4-tetrahydro-y -carboline, 8-fluoro-5-(p-fluorophenyl)-2-n-propyl-1,2,3,4-tetrahydro-y-carboline, 8-fluoro-5-(p-fluorophenyl)-2-( 3,3-dimethyl-n-butyl)-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-methoxyphenyl)-1,2,3,4-tetrahydro- γ-carboline, 8-fluoro-5-(p- chlorophenyl)-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-phenyl-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-phenyl1-2-[ 4-(p-tolyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-chloro-5-phenyl-2-[4-(p-tolyl)-4-hydroxybutyl] -1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-phenyl-2-[3-(p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-phenyl-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-phenyl-2-[4 -(p-fluoro-phenyl)-4-hydroxypentyl]-1,2,3,4-tetrahydro-γ-carboline, 8-chloro-5-phenyl-2-[4-,(p-fluorophenyl)-4- hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-phenyl-2-methyl-1,2,3,4-tetrahydro-γ-carboline , 8-chloro-5-phenyl -2-methyl-1,2,3,4-tetrahydro-γ-carboline, 8-chloro-5-phenyl-2-ethyl-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5 -(p-chlorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-chlorophenyl)-2 -[4-(p-chlorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5-(p-chlorophenyl)-2-(4-phenyl-4- hydroxybutyl)-1,2,3,4-tetrahydro-γ-ka rboline, 7-fluoro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 7- fluoro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-acetoxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 7-fluoro-4- (p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxypentyl]-1,2,3,4-tetrahydropyrrolo [3,4-b]indole and 7-fluoro-4-(p-fluorophenyl) )-2-[4-(p-fluorophenyl)-4-acetoxypentyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole. A preferred intermediate according to the present invention is

7-fluoro-4-(p-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole.

The tranquilizers according to the present invention

are characterized by alleviating such schizophrenic manifestations in humans as hallucinations, hostility, suspiciousness, emotional or social withdrawal, anxiety, excitement and tension. Standard methods for demonstrating and comparing the sedative action of compounds in this series and for which there is an excellent correlation with action in humans are the antagonism of amphetamine-induced symptoms in rat experiments, as indicated by A. Weissman, et al., J. Pharmacol. Exp. Ther., 151, 339 (1966) and Quinton, et al., Nature, 200, 178 (1963).

γ-carbolines and pyrrolo[3,4-b]indoles and pharmaceutically acceptable salts thereof, which are useful as sedative agents, may either be administered as individual therapeutic agents or as mixtures of therapeutic agents. They can be administered alone, but are usually administered together with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. They can e.g. administered orally in the form of tablets.or.capsules containing such excipients as starch, milk sugar or certain types of clay etc.

They can be administered in the form of elixirs or oral suspensions together with the active ingredients combined with emulsifying and/or suspending agents. They can be injected parenterally and for this use they, or suitable derivatives, can be prepared,

in the form of sterile aqueous solutions. Such aqueous solutions should, if necessary, be suitably buffered and should contain other solvents such as saline or glucose solutions

to make them isotonic.

Although the application according to the present invention is directed to the treatment of mammals in general, it is preferably directed to humans. When determining an effective dose for therapy in connection with humans, the results of animal experiments are often extrapolated and a correlation is assumed between the animal experiments and the proposed dose for humans. When there is a commercially available standard, the dose level for humans is often determined clinically by comparing the effect with the standard in animal experiments. If a standard sedative

e.g. is effectively administered in humans at a dose of

10-400 mg daily, it is believed that the compounds according to the present

invention has a comparable effect in relation to this standard and that similar doses will give a comparable response in humans.

The physician will ultimately determine the appropriate dose for a particular individual, and it will vary with the age, weight, and response of the particular patient, as well as the nature and degree of symptoms and the pharmacodynamic properties of the particular agent being administered. Usually, small doses will be administered at first, with a gradual increase in the dose until the optimal level is determined. It will often be found that when the preparation is administered orally, larger amounts of the active ingredient will be required to give the same level as with a smaller amount administered parenterally.

When it comes to the above mentioned factors one will

daily dose of the compounds according to the present invention for humans of approx. 1-100 mg, with a preferred range of

1-50 mg have an effective sedative effect. In individuals where the compounds according to the present invention have a prolonged effect and the dose can be 5-150 mg per week, it can be administered in one or two divided doses. These values are given only as examples and there may of course be individual cases where higher or lower doses are necessary.

The following examples are given to illustrate the invention.

Example 1 8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-y-carboline

( I: X = F, Z = F, n = 2 and R = H)

A. 8- fluoro- 2-carbethoxyl, 2, 3, 4- tetrahydro- y- carboline

(II: X = F)

A mixture of 15.9 g (0.093 mol) of N-carbethoxy-4-piperidone and 15.1 g (0.093 mol) of p-fluorophenylhydrazine hydrogen chloride in 150 ml of ethanol is heated under reflux for 2 hours. The reddish reaction mixture is cooled and filtered and the collected solid is washed with a small amount of cold 95% ethanol, 21.3 g (88% yield), m.p. 169-170°C The analytical sample is recrystallized from ethanol-water, m.p. 169-170°C. Analysis:

Calculated for C14H15<0>2N2F: c 641 H 5.8, N 10.7

Found: C 63.8, H 5.8, N 10.6.

B. 8-fluoro-5-(p-fluorophenyl)-2-carbethoxy-1,2,3,4-tetrahydro-y-carboline (III: X and Z = F)

3.45 g is added to 30 ml of N-methyl-2-pyrrolidione

(0.013 mol) 8-fluoro-2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline, 7.8 g (0.045 mol) p-fluorobromobenzene, 4.14 g (0.014 mol) cuprobromide and 1, 5 g (0.014 mol) of sodium carbonate and the resulting mixture is heated in an oil bath at 200°C for 6 hours. The mixture is allowed to cool to room temperature overnight and is then decanted into 300 ml of water containing 60 ml of ethylenediamine. Benzene (200 ml) is added and the two-phase system is filtered through a pad of "super-cel". The filtrate is then extracted a number of times with a total of 700 ml of benzene. The extracts are combined, washed one after the other with water and a saturated salt solution and dried over anhydrous sodium sulfate. The removal of the solvent leaves the impure product as a dark, residual oil.

The crude product in benzene is chromatographed on a silica gel column using 10% ethyl acetate-benzene as eluent. Fractions 1 to 16, consisting of 10-25 ml each, and containing p-fluorobromobenzene, are collected and discarded. Fractions 16 to 38 are combined and concentrated in vacuo to an oil which solidifies on standing at 5°C overnight. The product, 3.5 g (76% yield), is triturated with pentane and filtered. The analytical sample is recrystallized from pentane, m.p. 118-120°C. Analysis: Calculated for c2o<H>l8°2<N>2<F>2<:>C 67 ' 4' H 5 1, 1' N 7'9>

Found: C 67.4,. H 5.2, N 7.8.

c• 8- fluoro- 5-( p- fluorophenyl)- 1, 2, 3, 4- tetrahydro- y- carboline

( I: X and Z = F, and R = H)

A suspension of 3.56 g (0.01 mol) of 8-fluoro-5-(p-fluorophenyl)-2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline and 8.2 g (0.146 mol ) potassium hydroxide in 53 ml of ethanol containing 5 ml of water is heated to reflux overnight. A further 3.0 g of potassium hydroxide is added and heating is continued for 2 3 hours. The brown solution is cooled, concentrated in vacuo to dryness and partitioned between water and diethyl ether. The aqueous layer is further extracted with ether, the ether layers are combined, washed with saturated brine and dried over magnesium sulfate. Removal of the solvent gives the desired product as a

orange-yellow solid, 2.6 g, m.p. 125-127°C. The analytical sample is recrystallized from pentane, m.p. 127-128°C

Analysis:

Calculated for C17<H>14<N>2<F>2: C 71'8'H 5'0'N 9'9

Found: C 71.6, ■ H 5.1, N 10.2.

The hydrogen chloride salt is prepared by bubbling hydrogen chloride into a solution of the free base in diethyl ether,

sm.p. 270-272°C.

Example 2

Starting from the appropriate phenylhydrazine and applying the procedure in Example 1, the following 5-aryl-1,2,3,4-tetrahydro-γ-carbolines are prepared as free bases and hydrogen chloride salts: 8-chloro-5-( p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 269-271°C; 8-bromo-5-phenyl-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 280-282°C; 8-methyl-5-phenyl 1-1,2,3,4-tetrahydro-γ-carboline', m.p. 288-289°C, ,8-fluoro-5-(p-chlorophenyl)-1,2,3,4-tetrahydro-γ-carboline-. bydrogen chloride, m.p. 283-285°C and 8-chloro-5-phenyl-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 276-278°C, and as free base: 8-fluoro-5-(p-methoxyphenyl)-1,2,3,4-tetrahydro-γ-carboline, m.p. 119-122°C, 8-chloro-5-(p-chlorophenyl)-1,2,3,4-tetrahydro-γ-carboline , 8-bromo-5-(p-fluorophenyl)-1,2,3, 4-tetrahydro-γ-carboline, 8-methyl-5-(p-chlorophenyl)-1,2,3,4-tetrahydro-γ-carboline, 5-(p-fluorophenyl)-1,2,3,4- tetrahydro-γ-carboline and 5-(p-chlorophenyl)-1,2,3,4-tetrahydro-γ-carboline.

Example 3

8- fluoro- 5- ( p- fluorophenyl)- 2-( 3- phenethyl)- 1, 2, 3, 4- tetrahydro- y- carboline- hydrogen chloride ( I: XogZ=F, n=2, A= - CH ^-,

M = - CH2- and Y = H)

To a stirred suspension of 1.4 g (4.9 mmol) of 8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline and 1.02 g (7.4 mmol ) potassium carbonate in 10 ml of dimethylformamide heated to 60°C, 1.09 g (5.9 mmol) of 3-phenethyl bromide in 10 ml of the same solvent is added dropwise. After heating for 3.5 hours, the reaction mixture is decanted into 200 ml of an aqueous 2% potassium carbonate solution and the resulting solution is then extracted (3 x 200 ml) with benzene. The combined extracts are washed successively with water and a saturated salt solution and dried over magnesium sulfate. The solvent is removed in vacuo

and the remaining oil, which crystallizes on standing, is triturated with hexane and filtered, 1.6 g, m.p. 115-121°C.

The crude product is chromatographed on a silica gel column using 25% ethyl acetate-75% benzene as eluent. Fractions 12-32, which consist of 5-7 ml per fraction, is collected and evaporated to dryness. The remaining crystalline product is dissolved in diethyl ether-methylene chloride and transferred to the hydrogen chloride salt using gaseous hydrogen chloride, 1.13 g (54% yield), m.p. 275-276°C.

Analysis

Calculated for<C>25<H>22N2F2'HCl: C 70.7'H 5'5'N 6.6

Found: C 70.4, H5.5, N6.5.

Example 4

The procedure in the example. 3 is repeated starting from the appropriate alkylating agent and the necessary 5-aryl-1,2,3,4-tetrahydro-γ-carboline and the following analogues are obtained as hydrogen chloride salts<r>:

Example 5

8- fluoro- 5-( p- fluorophenyl- 2-[ 3-( p- fluorobenzoyl) propyl]- 1, 2, 3, 4- tetrahydro- T- carboline- hydrogen chloride

0

II

(I: X and Z = F, n = 2, A = -(CH2)3~, M = -C- and Y = F)

In a similar manner to Example 3, 2.84 g (0.01 mol) of 8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline gave 2.8 g (0 .01 mol) co-chloro-p-fluorobutyrophenone, 3.15 g (0.03 mol) sodium carbonate and traces of (50 mg) potassium iodide in 50 ml 4-methyl-2-pentan-one, after heating to reflux for 15 hours, followed by work-up, 2.6 g of the desired product as free base,

sm.p. 150<1>155°C.

The crude base in diethyl ether is transferred to the hydrogen chloride using hydrogen chloride gas, 2.72 g,

sm.p. 235°C, split Recrystallization from ethanol containing a small amount of diethyl ether gives the pure product, 2.2 g, m.p. 237-238°C.

Analysis

Calculated for C27H23<O>N2F3•HC1•1/4 H20: C 66.3, H 4.9, N 5.7 Found: C 66.3, H 5.2, N5.6

Example 6

Using a similar alkylation method as in Examples 3, 4 and 5, and starting from the appropriate alkylating agent and 1,2,3,4-tetrahydro-γ-carboline, the following analogues are prepared: 8-fluoro-5- (p-fluorophenyl)-2-[2-(p-fluorobenzoyl)ethyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 19-5-198 oC.

Analysis

Calculated for C2gH21ON2F3•HC1•1/3 H2O: C 65.5, H 4.7, N 5.9 Found: C 65.6, H 4., 7, N 5.9.

8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorobenzoyl)butyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 242-244°C. Analysis: Calculated for c28H25ON2F3"HCl'1//4 H20: C 66'8'H 5'3'N 5.6 Found: C 66.8, H 5.3, N 5.5,

8-fluoro-5-(p-fluorophenyl)-2-(3-benzoylpropyl)-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 208-211°C.

Analysis:

Calculated for C27H24ON2F2•HCl•H20: C 66.9, H 5.6, N 5.8 Found: C 67.2, H 5.4, K 5.8.

8-fluoro-5-(p-fluorophenyl-2-[3-(p-tolubyl)propyl]-1,2,3,4-tetrahydro-γ-carboline, mp 125-127°C.

Analysis:

Calculated for C„QH„,0NoF_* 1/4 Ho0: C 74.9, H 5.8, N 6.2

Zo Zo Z 5 Z

Found: C 74.6, H 6.0, N 6.0.

8-fluoro-5-(p-fluorophenyl)-2-[3-(p-chlorobenzoyl)-propyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 20l-203°C. Analysis: Calculated for C27H230N2C1F (free base): C 69.7, H 5.0, N 6.0 Found: C 69.4, H 5.0, -N 5.9

8-fluoro-5-. (p-trifluoromethylphenyl)-2-[3-(p-fluorobenzoyl)-propyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, srt.p. 245-247°C

Analysis:

Calculated for c28H23<O>N2F5"HCl: c62'9'H 4.5, N5.5

Found: C 62.5, H 4.5, N 5.2

8-fluoro-5-(m-trifluoromethylphenyl)-2-[3-(p-fluorobenzoyl)-propyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride,

sm.p. 247-248°C.

Analysis:

Calculated for C2gH23ON2F5•HCl'1/3 H20: C 62.2, H 4.6, N 5.2 Found: C 62.2, H 4.5, N 5.2,

8-fluoro-5-(p-methoxyphenyl)-2-[3-(p-fluorobenzoyl)-propyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 209-211°C.

Analysis

Calculated for C2 8H26°2N2F2"HC1'1/'4H20: C 67.1, H 5'5, N 5.6 Found: C 67.3, H 5.3, N 5.5.

8-chloro-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)-propyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 233-235°C. Analysis:

Calculated for C27H23ON2ClF2•HCl: C, 64.7, H 4.8, N 5.6

Found: C 64.3, H 4.8, N 5.7.

Example 7

By again repeating the alkylation method in examples 3, 4, 5 and 6 and starting from the required reagents, the following compounds are obtained:

Example 8

8- chloro- 5-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 4- hydroxybutyl]-1, 2, 3, 4- tetrahydro- y- carboline- hydrogen chloride

OH

IN

(I- X = Cl, Z = F, n = 2, A = -( CH-Jg-, M = - CH- and Y = F)

To 575 mg (15.2 mmol) of sodium borohydride in 25 ml of ethanol, 1.8 g (3.8 mmol) of 8-chloro-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl] are added dropwise -1,2,3,4-tetrahydro-γ-carboline in a hot solution of 40 ml of ethanol and 10 ml of tetrahydrofuran at such a rate that a slight reflux is obtained. After the addition is finished, the reaction mixture is heated under reflux for a further 1 hour and then cooled to room temperature. The overlying liquid is decanted into 200 ml of water and organic solvents are removed from the aqueous solution in vacuo. The remaining water is extracted (3 x 75 ml) with methylene chloride, and the organic layers are combined, backwashed with a saturated salt solution and dried over magnesium sulfate. The solvent is removed under reduced pressure and the remaining product is dissolved in diethyl ether-methylene chloride. Hydrogen chloride gas is carefully bubbled into the solution until the precipitation stops. The desired product is filtered and dried, 1.9 g, m.p. 245-246°C.

Analysis:

Calculated for C27H25ON2ClF2•HCl•H20: C 62.2, H 5.4, N 5.4 Found: C 62.3, H 5.1, N 5.3.

Example 9

The reduction in example 8 is repeated starting from the appropriate ketone and the following γ-carbolines are obtained: 8-fluoro-5-(p-methoxyphenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]- 1,2,3,4-tetrahydro-γ-carboline hydrogen chloride,

sirt.p. 235-236°C.

Analysis:

Calculated for C28H28°2N2<F>2"<H>C1: C 67'4'H 5.9/N 5.6 Found: . C 67.7, H 5.8, N 5.6.

8-fluoro-5-(m-trifluoromethylphenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 243-245°C.

Analysis:

Calculated for C2gH25ON2F5•HCl•1/2H20: C 61.6, H 5.0, N 5.1 Found: C 61.6, H 4.8, N 5.1.

8-fluoro-5-(p-fluorophenyl)-2-[4-(p-tolyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 236-237°C.

Analysis:

Calculated for C2gH28ON2F2•HCl'1.2 H20: C 68.3, H 6.1, N 5.7

.Found: C 68.7, H 6.3, N 5.6. 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-chlorophenyl)-4-hydroxy-butyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride,

sm.p. 242-244°C.

Analysis:

Calculated for C2?H250N2F2C1•HCl'3/4 H2O: C 62.7, H 5.1, N 5.4 Found: C 62.7, H 5.1, N 5.3.

8-fluoro-5-(p-fluorophenyl)-2-[4-m-trifluoromethylphenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 225-227°C.

Analysis:

Calculated for C2gH95ON2F5•HCl•1/4 H2O: C 62.2, H 4.7, N5.2 Found: C 62.2, H 4.9, N 5.2.

8-fluoro-5-(p-fluorophenyl)-2-[3-(p-fluorophenyl)-4-hydroxy-propyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride,

sm.p. 237-239°C.

Analysis:

Calculated for C2gH23ON2F3•HCl: C 66.0, H 5.1, N 5.9

Found: C 65.8, H 5.1, N 5.9.

8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 249-250°C.

Analysis:

Calculated for C27H25ON2F3-HGl'1/2 H2O: C 65.4, H 5.5, N5.6 Found: C 65.6, H 5.4, N 5.6.

8-fluoro-5-(p-fluorophenyl)-2-(4-phenyl-4-hydroxybutyl)-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, m.p. 236-238°C.

Analysis:

Calculated for C27H2gON2F2•HCl•1/2 H2O: C 68.0, H 5.7, N 5.9 Found: C 67.7, H 5.8, N 5.8.

8-fluoro-5-(p-fluorophenyl)-2-[4-(4-chloro-3-trifluoromethyl-phenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride, sm.p. 216-217°C.

Analysis:

Calculated for C2gH240N2F5C1'HCl: C 58.9, H 4.4, N 5.0 Found: C 58.7, H 4.3, N 5.0.

8-fluoro-5-(p-fluorophenyl)-2-[5-(p-fluorophenyl)-5-hydroxy-pentyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride,

sm.p. 207-208°C.

Analysis:

Calculated for C2g<H>27ON2F3•HCl'3/4 H20: C 65.4, H 5.8, N 5.4 Found: C 6 5.2, H 5.6, N 5.4.

Example 10

Example 11

8- fluoro- 5-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 4- hydroxypentyl]-1, 2, 3, 4- tetrahydro- Y- carboline hydrochloride

OH

IN

(I: X and Z = F, n = 2, A - -(CH^-, M = -C(CH3)- and Y = F)

A solution of 3.3 g (7.3 mmol) of 8-fluoro-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydro-γ- carboline in 15 ml of tetrahydrofuran is added dropwise to a cooled solution of methyl magnesium iodide in 30 ml of diethyl ether, prepared from 4.56 g

(32.2 mmol) of methyl iodide and 788 mg (32.2 mmol) of magnesium metal and the resulting reaction mixture is allowed to stir overnight at room temperature. The mixture is decanted into 150 ml of ice water and the organic solvent is removed from the solution in vacuo. The aqueous solution is extracted

(3 x 75 ml) with methylene chloride and the organic extracts are beaten. together, dried over magnesium sulfate and concentrated under reduced pressure to a pale yellow oil. The remaining product in diethyl ether is transferred to hydrogen chloride using hydrogen chloride gas. The resulting precipitate is filtered and dried, 1.35 g, m.p. 216-217°C.

Analysis:

Calculated for C2gH27ON2F3•HCl•1/3 H20: C 66.3, H 5.6, N 5.5 Found-: C66.6,H5.7,N5.6.

Example 12

Starting from methylmagnesium iodide and 5-aryl-2-benzoylalkyl-1,2,3,4-tetrahydro-y-carbolines in examples 6 and 7 and applying the method in example 11, the following compounds are obtained:

Example 13

8- fluoro- 5-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 4- acetoxybutyl]-1, 2, 3, 4- tetrahydro- y- carboline

OR.

) 1

(I:XogZ=F, n=2, A= -(CH2)3~, M = -CH- where Rx = COCH3

and Y = F)

Acetyl chloride (260 mg, 3.3 mmol) in 10 ml of methylene chloride is added dropwise to a cold solution of 1.0 g (2.2 mmol) of 8-fluoro-5-(p-fluorophenyl)-2-[4-(p -fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline in 30 ml of methylene chloride containing 350 mg (4.4 mmol) of pyridine. After the addition, the reaction mixture is allowed to warm to room temperature and allowed to stand overnight with stirring. The mixture is decanted into a cold saturated aqueous sodium bicarbonate solution and the crude product is extracted (3 x 50 mL) with methylene chloride. The combined organic extracts are dried over magnesium sulfate and concentrated to an oil which, after chromatography on a silica gel column using 1:1 benzene-ethyl acetate as eluent, gives purified product in fractions 4-7 as a yellow oil, 392 mg.

Analysis

Calculated for<c>2<gH>27°2<N>2<F>3<:>C 70'7'H 5'5'N 5.9

C 70.6, H 5.4, N 5.8

Example 14

By starting from the appropriate carbinol from examples 8-12, and the necessary acid chloride or anhydride and by applying the procedure in example 13, the following esters are obtained:

Example 15

8-fluoro-5-(p-fluorophenyl)-2-ethyl-1,2,3,4-tetrahydro-Y-carboline hydrogen chloride (I: X and Z=F, n - 2 and R = C2H5^

A. 8-fluoro-5-(p-fluorophenyl)-2-acetyl-1,2,3,4-tetrahydro-y-carboline (V: X and Z = F and R' = CHQ

To a solution of 1.4 g (4.9 mmol) of 8-fluoro-5-(p-fluoro-phenyl)-1,2,3,4-tetrahydro-γ-carboline in 10 ml of methylene chloride which is cooled in a 1.49 g (5.4 mmol) of triethylamine is added to an ice bath and the solution is stirred for 5 minutes. 423 mg (5.4 mmol) of acetyl chloride dissolved in 5 ml of methylene chloride is added to the stirred solution and the reaction mixture is allowed to stand under stirring at room temperature for 1 hour. The mixture is decanted

to 75 mL of cold saturated sodium bicarbonate and then extracted (3 x 50 mL) with methylene chloride. The combined extracts are backwashed with a saturated salt solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives the product as a glassy solid which on trituration with hexane crystallizes to a white powder, 1.55 g, m.p. 150-152°C.

Analysis

Calculated for c19H16ON2F2: C 69.9, H4.9, N8.6

Found: C 69.9, H5.3,. N8.4.

B. 8-fluoro-5-(p-fluorophenyl)-2-ethyl-1,2,3,4-tetrahydro-y-carboline hydrogen chloride

A suspension of 24 3 mg (6.4 mmol) of lithium aluminum hydride in 20 ml of diethyl ether and 10 ml of tetrahydrofuran cooled to 0-5°C is treated with 283 mg (2.1 mmol) of aluminum chloride and the mixture is left to stir in the cold for 30 minutes . During continued cooling, 871 mg is added dropwise over 20 minutes

(2.6 mmol) of 8-fluoro-5-(p-fluorophenyl)-2-acetyl-1,2,3,4-tetrahydro-γ-carboline in 15 mL of tetrahydrofuran to the metal hydride mixture. When the addition is finished, stir the reaction mixture for a further 2 hours and the reaction is stopped with water. The ether is separated and the aqueous phase is further extracted with the same solvent. The combined ether extracts are dried and concentrated to dryness to give crude base as a semi-crystalline oil, 868 mg.

Crude base (818 mg), dissolved in diethyl ether, is transferred to the hydrogen chloride salt using hydrogen chloride gas,

848 mg, m.p. 250-253°C.

Analysis:

Calculated for C19H13N2<F>2•<H>Cl•1/2H20: C 63.8, H 5.6, N 7.8 Found: C 63.7, H 5.5, N 8.1.

Example 16

8- fluoro- 5-( p- fluorophenyl)- 2- methyl- 1, 2, 3, 4- tetrahydro- y- carboline hydrogen chloride

To 316 mg (8.3 mmol) of lithium aluminum hydride in 30 ml of tetrahydrofuran, 2.7 g (7.58 mmol) of 8-fluoro-5-(p-fluorophenyl)-2-carbethoxy-1,2,3,4- tetrahydro-γ-carboline in 65 ml of the same solvent, and the reaction mixture is stirred at room temperature for 2 hours. Water (5 ml) is added to stop the reaction and the mixture is filtered. The filtrate is concentrated in vacuo and the remaining oil is distributed between benzene and water. The organic layer is separated, dried over magnesium sulfate, concentrated under reduced pressure to 2.6 g of a yellow oil. The impure product is chromatographed on a silica gel column using methanol as eluent, 5-10 ml are collected per faction. Fractions 24-39 are combined and concentrated in vacuo to give a yellow solid which, on treatment with hydrogen chloride gas in diethyl ether, gives the hydrogen chloride salt, 1.06 g, m.p. 295-2'97°C.

Analysis

Calculated for C18<H>16N2F2'HCl: C 64'6'H 5>1'N 8'4

Found: C 64.3, H 5.2, N 8.4.

Example 17

By applying the specified procedure and proceeding from them

. suitable reagents the following 2-alkyl-1,2,3,4-tetrahydro-γ-carboline hydrogen chlorides are obtained:

Example 18

The procedure in examples 15 or 16 is repeated again starting from the appropriate amide or ester, and the following 2-alkyl-1,2,3,4-tetrahydro-γ-carbolines are obtained: 8-fluoro-5-(p -methoxyphenyl)-2-methyl-1,2,3,4-tetrahydro-γ-carboline (method in Example 16); 8-Chloro-5-(p-methoxy-phenyl)-2-methyl-1,2,3,4-tetrahydro-γ-carboline (Procedure in Example 16), 8-methyl-5-(p-methoxyphenyl) -2-methyl-1,2,3,4-tetrahydro-γ-carboline (method in Example 16), 8-fluoro-5-(p-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro -γ-carboline (Procedure in Example 16), 8-chloro-5-(p-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-γ-carboline (Procedure in Example 16), 8-methyl -5-(p-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-γ-carboline (Procedure in Example 16), 8-fluoro-5-(p-fluorophenyl)-2-n-butyl -1,2,3,4-tetrahydro-γ-carboline (Procedure in Example 15), 8-fluoro-5-(p-fluorophenyl)-2-i-butyl-1,2,3,4-tetrahydro-γ -carboline (Procedure in Example 15), 8-fluoro-5-(p-methoxyphenyl)-2-n-hexyl-1,2,3,4-tetrahydro-γ-carboline (Procedure in Example 15), 8-fluoro -5-(p-chlorophenyl)-2-neopentyl-1,2,3,4-tetrahydro-y-

carboline (Procedure in Example 15), 8-chloro-5-(p-fluorophenyl)-2-ethyl-1,2,3,4-tetrahydro-γ-carboline (Procedure in Example 15), 8-methyl-5- phenyl-2-n-pentyl-1,2,3,4-tetrahydro-γ-carboline (procedure in Example 15) and 5-p-methoxyphenyl-2-n-propyl-1,2,3,4-tetrahydro- γ-carboline (method in Example 15).

Example 19

8- chloro- 5- phenyl- 2- methyl- 1, 2, 3, 4- tetrahydro- y- carboline- hydrogen chloride ( I: X = Cl, Z = H, n- 2 and R = CH,)

A. 8- Chloro- 2- methyl- 1, 2, 3, 4- tetrahydro- y- carboline

To 35.6 g (0.2 mol) of p-chlorophenylhydrazine hydrogen chloride, 22.6 g (0.2 mol) of 1-methyl-4-piperidone in 400 ml of ethanol saturated with hydrogen chloride gas are added while cooling in an ice bath. When the addition is finished, the ice bath is removed and the mixture is heated under reflux for 2 hours and then allowed to stand cold overnight. Ethanol (100 ml) is added and the precipitate is allowed to stand at 5°C

for 3 hours. The solid is filtered off and dried at 50°C

at a pressure of 25 mm for a few days, 11.0 g. The free base is released by treating the hydrogen chloride with 40% sodium hydroxide solution, the base is extracted with diethyl ether. The removal of ether gives the product as a golden brown solid,

sm.p. 194-196°C.

B. 8- chloro- 5- phenyl- 2- methyl- 1, 2, 3, 4- tetrahydro- y- carboline hydrogen chloride

A mixture of 7.3 g (33.2 mmol) 8-chloro-2-methyl-1,2,3,4-tetrahydro-γ-carboline, 18.2 3 g (0.116 mol) bromobenzene, 10.4 g (0.0364 mol) of cuprous bromide and 4.51 g (0.0364 mol) of sodium carbonate

in 12 5 ml of N-methyl-2-pyrrolidinone is heated in a nitrogen atmosphere

at an internal temperature of 184°C for 9 hours. The mixture is cooled, decanted into 300 ml of water containing 30 ml of ethylene-hydramine and sodium chloride and extracted with benzene. The combined extracts are backwashed with a saturated salt solution, dried over magnesium sulfate and concentrated in vacuo.

The crude product is chromatographed on a silica gel column using methanol as eluent and fractions of 5 ml each. Elution of the product is followed by thin layer chromatography and the fractions containing the desired material are pooled and concentrated under reduced pressure to dryness. The remaining material is crystallized by trituration with cold ethyl acetate, 945 mg, m.p. 124-126°C.

The hydrogen chloride salt is prepared by treating a methanol solution of the free base with hydrogen chloride gas to the saturation point, followed by the addition of an equal volume of diethyl ether, m.p. 281-283°C.

Analysis

Calculated for C18H18<N>2<C>12•HCl: C 64.9, H. 5.4, N8.4

Found: C 64.6, H 5.5, N 8.4.

Example 20

Starting from the suitably substituted phenylhydrazine and the necessary 1-alkyl-4-piperidone and halobenzene and applying the procedure in example 19, one obtains the following 5-aryl-2-alkyl-1,2,3,4-tetrahydro- y-carbolines:

Example 21

8- fluoro- 5-( p- fluorophenyl)- 2-( 3- benzoylpropyl)- 1 , 2 , 3 , 4- tetrahydro-y-carboline

f

(I: X and Z = F, n = 2 , A = -(CH2)3~, M = -C- and. Y = H)

A. 8- fluoro- 5-( p- fluorophenyl)- 2-( 3- cyanopropyl)- 1, 2, 3, 4- tetrahydro-y-carboline

A mixture of 25.0 g (0.088 mol) of 8-fluoro-5-(p-fluoro-phenyl)-1,2,3,4-tetrahydro-γ-carboline,- 18.3 g (0.1232 mol ) bromo-butyronitrile, 27.7 g (0.264 mol) of sodium carbonate and 100 mg of potassium iodide in 250 ml of 4-methyl-2-pentanone are heated under reflux for 2 hours. The reaction mixture is then cooled and decanted into a corresponding volume of water. The organic layer is separated, concentrated in vacuo and the remaining oil is taken up in methylene chloride and washed successively with water and a saturated salt solution. The methylene chloride layer is dried over magnesium sulfate and concentrated under reduced pressure to 30 g of a reddish oil. A small sample of the product in diethyl ether gives on treatment with hydrogen chloride gas. the hydrogen chloride salt, m.p. 234-236°C.

B. 8- fluoro- 5-( p- fluorophenyl)- 2-( 3- benzoylpropyl)- 1, 2, 3, 4-tetrahydro- y-carboline- hydrogen chloride

Phenyl magnesium bromide, prepared below standard

Grignard reaction conditions from 4.8 ml bromobenzene and 1.1 g magnesium powder, in 80 ml diethyl ether are added dropwise to 4.0 g (0.114 mol) 8-fluoro-5-(p-fluorophenyl)-2-(3-cyanopropyl)- 1,2,3,4-tetrahydro-γ-carboline within 30 min. The reaction mixture is heated under reflux for 1 hour, then cooled and the ether decanted from the precipitate. The residue is washed several times with ether and then added to 80 ml of 12N hydrochloric acid in ice. The acid mixture is then heated under reflux for 1.5 hours, cooled to room temperature and treated with sufficient 1.0N aqueous sodium hydroxide to make the solution basic. The product, which separates as an oil, is extracted with ether. Removal of the solvent gives 3.8 g of the product as the free base. A small sample is transferred to the hydrogen chloride salt, m.p. 208-211°C.

Using a similar series of reactions and starting from the appropriate 5-aryl-2-cyanoalkyl-1,2,3,4-tetrahydro-α-carboline and Grignard reagent, the ketones in examples 5, 6 are prepared and 7.

Example 2 2

8- fluoro- 5-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 3- butenyl]- 1, 2, 3, 4-tetrahydro-γ-carboline (I: X and Z = F, n = 2, A = -(CH2)2~,

M = - CH=CH- and Y = F)

A solution of 2.0 g (4.1 mmol) of 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro -y-carboline in 20 ml of ethanol and 50 ml of 6N hydrochloric acid is heated under reflux for 4 hours and then stirred at room temperature for a few days. The precipitated product is filtered and dried, 1.8 g. Further purification is carried out by recrystallization from ethanol, m.p. 258-259°C

Example 2 3

Starting from the carbinol in examples 8, 9 and 10 and using the method in example 22, the following y-carbolines are obtained:

Example 24

7- fluoro- 4-( p- fluorophenyl)- 1, 2, 3, 4- tetrahydropyrrolo[ 3, 4- b ]- indole hydrogen chloride ( I: X and Z = F, n = 1 and R = H

A- 7- fluoro- 2- carbethoxy-l, 2, 3, 4- tetrahydropyrrolo[ 3, 4-b] indole

(II: X = F)

5.5 g (0.035 mol) l-carbethoxy-3 -pyrrolidinone in 50 ml of the same solvent. After stirring for 20 minutes, the precipitated hydrazone is filtered, washed with water and dried, 9.0 g. The analytical sample is recrystallized from methylene chloride-hexane, m.p. 157-160°C.

To 3.9 g (14.7 mmol) of the above hydrazone is added

25 ml 85% phosphoric acid, heat is generated as the solid dissolves. Within 30 minutes, a half solid, which is treated with a further 10 ml of phosphoric acid and stirred until a smooth, brown suspension is obtained. The reaction mixture is quenched with 200 ml of cold water and the resulting precipitate is filtered and dried, 2.19 g. Recrystallization from ethanol-water gives 1.4 g of the desired product, m.p. 248-249°C.

Analysis:

Calculated for C13H1302<N>2<F:>C 62'9'H 5'2'N H'3-

Found: C 62.9, H 5.3, N 11.5.

B. 7-fluoro-4-(p-fluorophenyl)-2-carbethoxy-l,2,3,4-tetrahydropyrrolo[3,4-b]indole (III: X and Z = F)

A mixture of 6.6 g (0.028 mol) 7-fluoro-2-carbethoxy-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 8.86 g (0.031 mol) cuprobromide, 3.28 g (0.031 mol) of sodium carbonate and 17.2 g (0.098 mol) of p-bromofluorobenzene in 75 ml of N-methyl-2-pyrrolidione are heated under reflux for 4 hours. The reaction mixture is cooled and poured onto ice and water containing 40 ml of ethylenediamine. The mixture is extracted with benzene, the benzene extractant is then backwashed with water and a saturated salt solution and dried over magnesium sulfate. Removal of the solvent in vacuo gives a gum which on trituration with hexane gives 5.8 g of product as a brown solid, m.p. 143-145°C.

C. 7-fluoro-4-(p-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]-indole- hydrogen chloride (I: X and Z = F and R = H)

7-Fluoro-4-(p-fluorophenyl)-2-carbethoxy-1,2,3,4-tetrahydropyrrolo[3,4-b]indole (342 mg, 0.001 mol) and 1.12 g (0.02 mol ) of potassium hydroxide in 20 ml of ethanol and 2 ml of water is heated under reflux for 24 hours, followed by evaporation of the solution to a brown gum. The residue is distributed between methylene chloride and water, the organic phase is separated, washed with water and dried over magnesium sulphate. Removal of the solvent gives the product as a golden brown solid, which on dissolution in diethyl ether and treatment with an ethereal solution of hydrogen chloride gives 193 mg of the hydrogen chloride salt, m.p. 145-150°C.

Example 2 5

Starting from the appropriate,-,phenylhydrazines and applying the procedure in example 25, the following 4-aryl-1,2,3,4-tetrahydropyrrolo[3,4-b]indoles are obtained as free bases and hydrogen chloride salts: 7 -chloro-4-(p-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]-indole, 7-bromo-4-phenyl1-1,2,3,4-tetrahydropyrrolo[3, 4-b]indole, 7-methoxy-4-(p-fluorophenyl).-1,2,3,4-tetrahydropyrrolo[3,4-b]indole,7-fluoro-4-(p-methoxyphenyl)-1 ,2,3,4-tetrahydropyrrolo[3,4-b]indole, 7-methyl-4-phenyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 7-fluoro- 4-( p-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 7-Fluoro-4-phenyl1-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 7 -chloro-4-phenyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole,7-chloro-4-(p-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[3 ,4-b]indole, 7-bromo-4-(p-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 7-methyl-4-(p-chlorophenyl)-1 ,2,3,4-tetrahydropyrrolo[3,4-b]indole, 4-phenyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 4-(p-fluorophenyl)-1,2 ,3,4-tetrahydropyrrolo [ 3,4-b]indole, 4-(p-cl orphenyl)-1,2,3,4-tetrahydropyrrolo-[3,4-b]indole and 7-chloro-4-(p-methoxyphenyl)-1,2,3,4-tetrahydropyrrolo-[3,4-b ]indole.

Example 2 6

7-fluoro-4-(p-fluorophenyl)-2-methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]-indole (I: X and Z = F, n = 1 and R = CH ^)

To a mixture of 244 mg (6.4 mmol) of lithium aluminum hydride in 20 ml of dry tetrahydrofuran in a nitrogen atmosphere and cooled to -10°C is added 284 mg (2.1 mmol) of aluminum chloride and the resulting reaction mixture is stirred for 30 minutes. 7-Fluoro-4-(p-fluorophenyl)-2-carbethoxy-1,2,3,4-tetrahydropyrrolo-[3,4-b]indole (2.9 mmol) in 10 ml of the same solvent is added dropwise to the cold solution while stirring. After a reaction time of 1 hour, the reaction is stopped with 5 ml of water added dropwise and the mixture is heated to room temperature. The mixture is filtered and the solid material is washed with hot tetrahydrofuran. The combined filtrate and washings are concentrated to a brown solid which, on dissolution in diethyl ether followed by treatment with ether saturated with hydrogen chloride, gives 448 mg of the desired product, m.p. 160-165°C.

Example 27

By applying the procedure in Example 26, and exit

from the required 4-aryl-2-carbethoxy-1,2,3,4-tetrahydropyrrolo[3,4-b]indole the following analogues are obtained:

Example 28 7-fluoro-4-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole hydrochloride

0

II

( I: X and Z = F, n = 1, A = -( CH2)3-, M = - C- and Y =F)

7-Fluoro-4-(p-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]-indole (6.02 g, 22.2 mmol), 6.7 g (33.3 mmol) of γ-chloro-p-fluorobutyrophenone, 4.28 g (23.4 mmol) of potassium iodide and 7.05 g (66.6 mmol) of sodium carbonate in 175 ml of dimethylformamide are heated at 90°C for 8 hours and then stirred at room temperature overnight. The mixture is heated again to 90°C, treated with 1 g of decolorizing charcoal, filtered and the filtrate is poured onto ice and water. The suspension is extracted with chloroform and the combined extracts are dried and evaporated to 10.5 g of crude product. The residue is chromatographed on 200 g of silica gel using 3:1 diethyl ether-ethanol as eluent, each fraction consists of 30-40 ml.

The desired product, which is isolated from fractions 6-14, is added to the hydrogen chloride salt, 1.76 g, and then recrystallized from acetonitrile-methanol, 850 mg, m.p. 175-179°C.

Analysis:

Calculated for C26<H>21ON2F3•HCl: C 66.3, H 4.7, N 6.0.

Found: C 65.3, H 4.7, N 5.8.

Mass spectra calculated M+ (free base): 434

Found: 4 34.

Example 2 9

The procedure in example 28 is repeated starting from the necessary co-halogenary ketone and 4-aryl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole from examples 24 or 25, and the following compounds are obtained :

Example 30

7- fluoro- 4-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 4- hydroxybutyl]-1, 2, 3, 4- tetrahydropyrrolo[ 3, 4-b] indole- hydrogen chloride

OH

IN

(I: X and Z = F, n = 1, A = -(CH2>3~, M = -CH- and Y = F)

To a solution of 2.4 g (5.5 mmol) of 7-fluoro-4-(p-fluoro-phenyl)-2-[3-(p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydropyrrolo -[3,4-b]indole in 85 ml of dry tetrahydrofuran containing 12 ml of ethanol is added portionwise to 1.2 g of sodium borohydride over the course of 2 hours. The brown solution is then evaporated to dryness and partitioned between water and diethyl ether. The organic layer is separated, dried over magnesium sulfate and concentrated in vacuo to dryness. The resulting product, after it has been transferred to the hydrogen chloride salt, is recrystallized from acetonitrile, and 430 mg of pure product is obtained, m.p. 210-211.5°C. Another portion is isolated from the filtrate, 290 mg, m.p. 203-205°C.

Example 31

The reduction in example 30 is repeated starting from the appropriate ketones from examples 28 or 29, and the following carbinols are obtained:

Example 12

7- fluoro- 4-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 4- hydroxypentyl]-1, 2, 3, 4- tetrahydropyrrolo[ 3, 4-b] indole- hydrogen chloride

OH

IN

(I: X and Z = F, n = 1, A = -(CH^-, M = -C(CH3)- and Y = F)

A methyl Grignard reagent prepared from 852 mg (6 mmol) methyl iodide and 144 mg (6 mmol) magnesium in 40 ml diethyl ether is divided into equal portions. 500 mg (1.1 mmol) of 7-fluoro-4-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)-propyl]-1,2,3,4-tetrahydropyrrolo[3 ,4-b]indole hydrogen chloride i

20 ml of tetrahydrofuran and the mixture is stirred for 1 hour. To

the mixture is then added to the other half of the Grignard solution and stirring is continued for 30 minutes. The mixture

poured onto ice and water and extracted with ether. The combined ether extracts are dried over magnesium sulfate, concentrated to dryness and the residue chromatographed on 20 g of silica gel using 3:1 diethyl ether-ethanol as eluent, each fraction being 3 ml. Fractions 10-27 are combined and transferred to the hydrogen chloride salt, 180 mg.

Mass spectra M+: 450

Found: '4 50.

Example 33

By starting from methylmagnesium iodide and 4-aryl-2-benzoyl-1-alkyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indoles in examples 28 and 29 and by applying the procedure in example 32, we get one the following connections:

X_ Z_ A_ Y_

F- F- -'(CH2)5- F-F- F- -(CH2)4- CH3-F- F- -(CH2)4- Cl-F- Cl- -(CH2)3- F-F- Cl- - (CH 2 ) 3 ~ . Cl-F- Cl- -(CH2)3- CH3-F- CH3°"~(CH2)2~F"

F- CH3°~"(CH2)5~H~

Example 3. 4

7- fluoro- 4-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 4- acetoxybutyl]-1 ,* 2 , 3 , 4- tetrahydropyrrolo [ 3 , 4- b ] indole

OR,

IN 1

( I: X and Z = F, n = 1, A = -( CH,,).,-, M - CH- where R±= COCU ^ and

Y = F)

Acetyl chloride (260 mg, 3.3 mmol) in 10 ml of methylene chloride is added dropwise to a cold solution of 959 mg (2.2 mmol) of 7-fluoro-4-(p-fluorophenyl)-2-[4-(p- fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole in 30 ml of methylene chloride containing 350 mg (4.4 mmol) of pyridine. After the addition, the reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is decanted into a cold saturated aqueous sodium bicarbonate solution and the crude product is extracted (3 x 50 mL) with methylene chloride. The combined organic extracts are dried over magnesium sulfate and concentrated to an oil which, after chromatography on a silica gel column using 1:1 benzene-ethyl acetate as eluent, gives the purified product.

Example 35

Starting from the appropriate carbinol from examples 30-33 and the necessary acid chloride or anhydride and applying the procedure in example 34, the following esters are obtained:

Example 36

7- fluoro- 4-( p- fluorophenyl)- 2-(3,3- dimethyl-1- propyl)- 1, 2, 3, 4-tetrahydropyrrolo[ 3, 4-b] indole- hydrogen chloride

( I: X and Z = F, n = 1, and R = - ( CH2 ) 2 C ( CH3 ) 3 ).

A. 7-fluoro-4-(p-fluorophenyl)-2-t-butylacetyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole (V: X and Z = F and R' = - CH2C(CH3)3).

To a suspension of 1.0 g (3.7 mmol) 7-fluoro-4-(p-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole in 10 ml methylene chloride is added t- butyl acetyl chloride, prepared from 860 mg of t-butylacetic acid and 10 ml of thionyl chloride (CA. 45, 1050 g) in 10 ml of the same solvent and the mixture is heated at steam bath temperatures for 30 minutes. The reaction mixture is treated with decolorizing charcoal, filtered and the filtrate is concentrated under reduced pressure to 5 ml. The material which precipitates on cooling and scraping, mainly the starting material, is filtered and dried, 231 mg, m.p. 159-174°C. Dilution of the filtrate with ether precipitates the crude product, 277 mg, m.p. 163-174°C. Additional product is obtained by concentrating the ether filtrate

to dryness, 403 mg, m.p. 170-174°C.

The raw products are combined and used in the following turnovers without further purification.

B. 7-fluoro-4-(p-fluorophenyl)-2-(3,3-dimethyl-1-propyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole hydrogen chloride

( I: X and Z = F and R = - ( CH,,) 2 C ( CH,) 3 .

To a suspension of 133 mg (3.7 mmol) of lithium aluminum hydride in 5 ml of dry tetrahydrofuran in a nitrogen atmosphere, slowly add 680 mg (1.85 mmol) of 7-fluoro-4-(p-fluorophenyl)-2-t-butylacetyl-1 ,2,3,4-tetrahydropyrrolo[3,4-b]indole in 5 ml of the same solvent. After stirring for 2 hours at room temperature, the mixture is cooled in an ice bath and the reaction is stopped by the dropwise addition of water. Tetrahydrofuran is removed in vacuo and the residue is partitioned between water (25 ml)

and methylene chloride. The organic phase is separated, backwashed with water and a saturated salt solution and dried over sodium sulphate. The remaining residue, after removal of solvent under reduced pressure, is dissolved in ether, anything insoluble is filtered off and diethyl ether saturated with hydrogen chloride is carefully added to the ether. The precipitated hydrogen chloride is filtered and dried, 441 mg, m.p. 200-208°C. Recrystallization from benzene-methylene chloride gives 166 mg of the desired product, m.p. 222-223°C.

Mass spectra calculated M+ (free base): 355

Found: 355

Example 37

The procedure in example 36 is repeated by starting from the necessary 4-aryl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole and acid chloride, and you get:

Example 38

7- fluoro- 4-( p- fluorophenyl)- 2- benzyl- 1, 2, 3, 4- tetrahydropyrrolo[ 3, 4- b]-indole hydrogen chloride ( I: X and Z = F, n=logR= C ^ H^ CH^-)

A solution of 500 mg (1.63 mmol) 7-fluoro-4-(p-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 418 mg (2.44 mmol) a -bromotoluene and 526 mg (4.08 mmol) of N,N-diisopropylethylamine in 5 ml of toluene are heated under reflux for 30 minutes. After treatment with decolorizing charcoal, the solvent is removed in vacuo and the residue is suspended in 25 ml of ether. The ether solution is filtered and sufficient ether saturated with hydrogen chloride is added to completely precipitate the product as a hydrogen chloride salt (pH 2-3). The crude product is filtered and dried, 658 mg, m.p. 194-202°C. The analytical sample is recrystallized from acetone-diethyl ether, m.p. 224-226°C.

Analysis:

Calculated for C23HlgN2F2•HCl•1/8.H2O: C 69.2, H 4.9, N 7.0. Found: C 69.2, H 5.0, N 6.9.

Example 39

The procedure in example 38 is repeated starting from the appropriate alkylating agent and the necessary 4-aryl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, and the following analogues are obtained as hydrogen chloride salts:

Example 40

7- chloro- 4- phenyl- 2- i- propy1- 1, 2, 3, 4- tetrahydropyrrolo[ 3, 4- b] indole hydrogen chloride ( I; X = Cl, Z = H, n=logR= i- C-^H...,-) .

A) 7-chloro-2-i-propy1-1,2,3,4-tetrahydropyrrolo[3,4-b]indole

A mixture of 3.56 g (0.02 mol) p-chlorophenylhydrazine hydrogen chloride, 1.64 g (0.02 mol) sodium acetate and 2.54 g,

(0.02 mol) of 1-isopropyl-3-pyrrolidinone in 35 ml of water is stirred in

2 hours. The precipitated hydrazone is filtered, washed with water and dried.

To 2.82 g (0.01 mol) of the above hydrazone is added 20 ml of 85% phosphoric acid and the resulting mixture is stirred for a few hours, during which time the product precipitates from the solution. The reaction is stopped in water, the pH is adjusted to 7 with a dilute sodium hydroxide solution and the product is filtered and dried.

B) 7-chloro-4-phenyl-2-i-propy1-1,2,3,4-tetrahydropyrrolo[3,4-b]-indole hydrogen chloride

One mixture of 7.8 g (33.2 mmol) 7-chloro-2-i-propyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 18.23 g (0.116 mol) bromobenzene , 10.4 g (0.0364 mol) of cuprous bromide and 4.51 g (0.0364 mol) of sodium carbonate in 125 ml of N-methyl-2-pyrrolidinone are heated in a nitrogen atmosphere at an internal temperature of 184°C for 9 hours. The mixture is cooled, decanted into 300 ml of water containing

30 ml of ethylenediamine and sodium chloride and extracted with benzene.

The combined extracts are backwashed with a saturated salt solution, dried over magnesium sulfate and concentrated in vacuo.

The crude product is chromatographed on a silica gel column using methanol as eluent and fractions of 5 ml. Elution of the product is followed by thin-layer chromatography and fractions sdm containing the desired material are combined and concentrated under reduced pressure to dryness. The remaining material is dissolved in ether and sufficient ether saturated with hydrogen chloride gas is added to precipitate the corresponding hydrogen chloride salt, which is further purified by recrystallization from ethyl acetate-ether.

Example 41

Starting from the suitably substituted phenylhydrazine and the necessary 1-alkyl-3-pyrrolidinone and halobenzene and applying the procedure in example 40, one obtains the following 4-aryl-2-alkyl-1,2,3,4-tetrahydropyrrolo[ 3,4-b]indoles:

Example 42

7- fluoro- 4-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 3- butenyl]- 1, 2, 3, 4-tetrahydropyrrolo [ 3 , 4- b ] indole hydrogen chloride

( I: X and Z = F, A ^'-(CHj^, M = - CH=CH- and Y = F) .

A solution of 1.9 g (4.1 mmol) of 7-fluoro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo -[3,4-b]indole in 20 ml of ethanol and 50 ml of 6N hydrochloric acid is heated under reflux for 4 hours and then stirred at room temperature for a few days. The precipitated product is filtered and dried. Further purification is carried out by precipitation from methanol using diethyl ether.

Example 4 3

Starting from the carbinols in examples 30 and 31 and applying the procedure in example 42, the following is obtained:

Example 44 8-chloro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline acetate 5 g 8-chloro-5 -(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride in 75 ml of water is treated with 3 ml of water containing 1 .0 g of sodium hydroxide and the liberated base are extracted into 150 ml of diethyl ether. The ether layer is separated, dried over magnesium sulfate and

treated with 1 ml of glacial acetic acid. The organic solvent and excess acetic acid are removed under reduced pressure and the residue is triturated with hexane and filtered.

Example 4 5

8- chloro- 4-( p- fluorophenyl)- 2-[ 4-( p- fluorophenyl)- 4- hydroxybutyl 1-1, 2, 3, 4- tetrahydropyrrolo[ 3, 4-b] indole acetate

5 g of 8-chloro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole hydrogen chloride in 75 ml of water are treated with 3 ml of water containing 1.0 g of sodium hydroxide and the liberated base is extracted into 150 ml of diethyl ether. The ether layer is separated, dried over magnesium sulphate and treated with 1 ml of glacial acetic acid. The organic solvent and excess acetic acid are removed under reduced pressure and the residue is triturated with hexane and filtered.

Other acid addition salts can be prepared in a similar manner, especially those which are pharmaceutically acceptable.

Test methods and results

The effect of the compounds of the present invention on prominent amphetamine-induced symptoms was examined in rats according to a scoring scale designed according to

one indicated by Quinton, Halliwell and Weissman. Groups

of 5 rats were placed in cages that are covered with plastic and have the approximate dimensions: 26 cm x 42 cm x 16 cm. After a short acclimatization period in the cages, the rats in each group were treated intraperitoneally (i.p.) with the test compound. They were then treated 1, 5 and 24 hours later with d-amphetamine sulfate, 5 mg/kg, i.p. 1 hour after amphetamine was given, each rat was observed for the characteristic amphetamine behavior which includes movement in the cage. "On the basis of the dose-response after amphetamine it was possible to determine the effective dose of the compound necessary to counteract or block the characteristic amphetamine behavior of cage movement for 50% of the rats examined (EDo,.'O). The time for scoring was chosen so that it coincided with the peak effect of amphetamine, which is 60-80 minutes after treatment with the agent.

By applying the method described above,

the following compounds were tested for their ability to block the action of amphetamine, and the results are given as ED,-Q in mg/kg at the indicated time points

Pills

A tablet base was prepared by mixing the following ingredients in the indicated amounts by weight:

Sufficient 8-fluoro-5-(p-fluorophenyl)-2-14-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride was mixed into this tablet base to give tablets containing 1.0, 2.5, 5.0 and 10 mg of active ingredient per tablet. The preparations are compressed into tablets each weighing 360 mg using conventional means.

A tablet base was prepared by mixing the following ingredients in the specified amounts by weight:

Sufficient 8-fluoro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b] was mixed into this tablet base indole hydrogen chloride to give tablets containing 2.0, 5.0, 10.0 and 20.0 mg of active ingredient per tablet. The preparations are compressed into tablets each weighing 360 mg using conventional means.

Capsules

A mixture containing the following components is prepared:

To this mixture was added sufficient 8-chloro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b] indole hydrogen chloride to give capsules containing 2.0, 5.0, 10.0 and 20.0 mg of active ingredient per capsule. The preparations were filled into hard gelatin capsules in a quantity of 350 mg per capsule.

To the above mixture was added sufficient 8-chloro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride to to provide capsules containing 1.0, 2.5, 5.0 and 10 mg of active ingredient per capsule. The preparations are filled into conventional hard gelatin capsules in amounts of 350 mg per capsule.

Suspension

A suspension of 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-tolyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline sulfate was prepared which has the following composition:

Distilled water to 1 liter.

Various sweeteners were added to this suspension

and flavorings to improve the flavor of the suspension.

The suspension contains approx. 2 5 mg active agent per ml.

A suspension of 8-fluoro-4-(p-fluorophenyl)-2-[4-(p-tolyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b] was prepared -indole sulfate with the above-mentioned composition. Various sweeteners and flavorings were added to this suspension to improve the taste of the suspension. The suspension contains approx. 25 mg active agent per ml.

Injectable preparation.

Sesame oil was sterilized by heating to 120°C i

2 hours. To this oil was added a sufficient amount of powdered 8-fluoro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4 -b]indole hydrogen chloride of a 0.025% by weight suspension. The solid is well dispersed in the oil using a colloid mill. It is then filtered through a 100-250 mesh sieve, poured into sterile, small medicine bottles and sealed.

Sesame oil is sterilized as indicated above. To this oil is added a sufficient amount of powdered 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carboline hydrogen chloride for the preparation of a 0.025% by weight suspension. The solid material is well dispersed in the oil using a colloid mill. It is filtered through a sieve cloth of 100-250 mesh and poured into sterile small medicine bottles and sealed.

Claims (2)

1. Procedure for the preparation of indoline compounds of the formula: and pharmaceutically acceptable acid addition salts thereof, where X is fluorine, chlorine, bromine, methyl or hydrogen, Z is fluorine, chlorine, methoxy or hydrogen, n is 1 or 2 and R is alkyl containing 1-6 carbon atoms, benzyl or substituted alkylene of the formula where A is the alkylene containing from 1-5 carbon atoms, M is -CH=CH-, -CH2-, where is hydrogen or alkanoyl containing ^ 2-5 carbon atoms and Y is fluorine, chlorine, methyl or hydrogen, provided that when Z is hydrogen and n is 2, X is fluorine, chlorine, bromine or methyl, characterized in that reacts a compound of formula I, where X and Z are as defined above and R is hydrogen with a compound of the formula R-Hal, where R is as defined above and is not equal to hydrogen and Hal is halogen, or with an acid halide or anhydride of a compound of the formula R'C02 H or where Y is as defined above, R' is alkyl containing 1-5 carbon atoms and R" is alkylene containing 1-5 carbon atoms and subsequent reduction of the amide formed, or with a compound of the formula Cl-A-CN where A is as indicated above and subsequent reaction with a compound of the formula where Hal and Y are as indicated above and, if desired, reduction of the formed ketone or reaction thereof with methylmagnesium iodide and, if desired, conversion of the formed alcohols to esters by acylation with an acid halide or anhydride of a compound of the formula R^C 02H , where R^ is as indicated above or dehydration of secondary alcohols formed, and, if desired, preparation of acid addition salts by reaction of the formed base with an acid. 2. Process for the production of indoline compounds of formula I as stated in claim 1, where X, Z and n are as stated in claim 1 and R is hydrogen, characterized by arylating a compound of the formula: where X is as indicated above with a bromobenzene compound of the formula where Z is as indicated above and hydrolysis of the compounds formed.