DE2514084A1 - NEW INDOL CONNECTIONS - Google Patents

Description

New indole compounds

After the introduction of reserpine and chlorpromazine into the Psychiatry in the early 1950s became more intense looked for other tranquilizers with an improved profile of action.

It has now been found that certain indoles, namely a series of 2-substituted 5-aryl-1,2,3,4-tetrahydro-y-earbolines and 2-substituted 4-aryl-1,2,3,4-tetrahydropyrrolo _i / 5t4- _> b7 "are indoles, extremely effective tranquilizers.

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γ-carbolines are not in the chemical and patent literature New. Antihi3taziin action is described in GB-Po 721 171, antidepressant Action in US-PSS 3,419,568, 3,687,960, 3,705,902 and 3,718,657, .. action against trypanosomes in the DT-PSS 2 117 286 and 2 115 738, antihypertensive and analgesic effect in Uo-PS 3 466 293 and tranquilizer effect attributed in U3-P3S 3,687,961 and 3,755,584.

The fused pyrrolo / 3 \ 4- _- b7i ^{n (} 3ol iting system. I ^s "& i * ^{1 is} relatively new to the chemical literature, and the first successful synthesis was by Southwich, et al., J. Org. 25, - 1133 (1960) The antitumor effect on account of which the compounds were prepared and tested could not be achieved with these simple 2-substituted 1,2,3,4-tetrahydropyrrolo / 3,4-b7 ~ indoles be detected.

The invention relates to tranquilizers of the formula

CCH ₂ ) -

and their pharmaceutically acceptable acid addition salts, wherein X is fluorine, chlorine, bromine, the methyl group or hydrogen, Z Fluorine, chlorine, the methoxy group or hydrogen, η the number 1 or 2 and R an alkyl radical with 1 to 6 carbon atoms, the benzyl radical or a substituted alkylene radical of the formula

509847/1120

-AT THE

represent, in which A is an alkylene rent with 1 to 5 carbon atoms, M one of the groups

11

OR ₁

t '

-CH = GH-, -OH ₂ -, -C-, -CH- or -C (CH ₃ ) -,

wherein R ₁ "is hydrogen or alkanoyl with 2 to 5 carbon atoms, and I is fluorine, chlorine, methyl or hydrogen, with the proviso that? dai3, when Z is hydrogen and. η is the number 2, X is fluorine, chlorine, - Means bromine or methyl

The compounds of the formula according to the invention

NH

where X, Z and η have the meaning given above, are intermediate products for the preparation of the invention Tranquilizers.

A preferred group of chemotherapeutic compounds according to of the present invention are the compounds of the formula I in which Z is fluorine, X is fluorine, chlorine, bromine, hydrogen or methyl, η the number? and K is a substituted alkylene radical of the formula:

509847/1 120

AT THE

represent, wherein A is a ^ alkylene radical with 1 to 5 carbon atoms, M one of the groups

O OR ₁ OR ₁

-GH = OH-, -OH ₂ -, -G-, -CH- or -0 (CH ₃ ) -,

where H _{1 is} hydrogen or alkanoyl having 2 to 5 carbon atoms, and Y is fluorine, chlorine, methyl or hydrogen.

A second group of preferred compounds corresponds to
Formula I, where Z is the methoxy group, X is fluorine, η is the number 2 and R is a substituted alkylene radical of the formula

A-M _ / \ _ϊ

X-I

represent, in which A. is an alkylene radical having 1 to 5 carbon atoms, M one of the groupings

0 OR ₁ OR ₁

-GH = GH-, -CH ₂ -, -G-, -CH- or -G (CH ₃ ) -,

wherein R is hydrogen or alkanoyl ait 2 to 5 carbon atoms

1
men and Y are fluorine, chlorine, methyl or hydrogen.

A third class of preferred compounds consists of compounds of the formula I in which Z is fluorine, X is fluorine, chlorine, bromine,
Hydrogen or methyl, η the number 2 and R represent the senzyl radical or an alkyl radical with 1 to 6 carbon atoms «

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A fourth preferred connection class consists of compounds of the formula I, in which Z is hydrogen, X is fluorine, chlorine, 3ron or methyl, η the number 2 and R is an alkyl radical with 1 to 6 carbon atoms or substituted alkylene radical of the formula

-AT THE

represent, v / orin A is an alkylene radical having 1 to 5 carbon

atoms, M one of the groupings

0 OJ

Il f

-CH = OH-J ^- -OH ₂ -, -C-, -CH- or -G (OH,) -,

0 OR ₁ OR.

wherein R _{1 is} hydrogen or alkanoyl having 2 to 5 carbon atoms, and Ϊ is fluorine, chlorine, methyl or hydrogen.

A fifth preferred class of compounds consists of compounds of the formula I, v / orin Z chlorine, X fluorine, chlorine, bromine or Methyl, η the number 2 and R a substituted alkylenreat the formula

-AH

represent, v / orin A is an alkylene radical having 1 to 5 carbon atoms, M the rest

OH

-CH-

and Y is fluorine, chlorine, methyl or hydrogen.

A sixth preferred class of compounds consists of compounds of the formula I, v / orin λ fluorine, Z fluorine, chlorine, hydrogen

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or Lletaoxy, η is the number 1 and d is a substituted alkylene radical of the formula

represent, in which A is an alkylene radical with 1 to 5 'carbon atoms, M one of the leftovers

-CH- or -G (GH ₃ ) -,

wherein R _{1 is} hydrogen or alkanoyl having 2 to 5 carbon atoms, and Y is fluorine, chlorine, methyl or hydrogen.

A preferred class of intermediates leading to those of the invention Leading therapeutic agents consists of connections the formula

NH

where X is fluorine, η is the number 1 or 2 and Z is fluorine, chlorine, meth =
mean oxy or hydrogen.

Related compounds of the formula also fall within the scope of the invention

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• N ^^ CCH

wherein X, Y, Z, η, M and A are as defined above, and ρ is the number 1 or 2.

The compounds according to the invention show against the most similar known compounds, namely the 5-phenyl- 2-methyl-1,2,3,4-tetrahydro-γ-carboline of GB-PS. 721 171 and the 5-phenyl-2-benzyl-1,2,3,4-tetrahydro- γ-carboline according to Spickett, J. Med. Chem., ^, 436 (1966) an unexpected, superior tranquilizer effect.

The following reaction scheme illustrates the process for the synthesis of the compounds according to the invention:

NHNH

Na ₂ CO ₃

II

CO ₂ C ₃ H ₅

III

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III KOH

C ₂ H ₅ OH / H ₂ O

I (R = H) R-Hal

I (R = H)

In this scheme, X, Z and n have the meaning given above, Hal denotes a halogen or a sulfonate ester and H denotes hydrogen, the benzyl radical, an alkyl radical with 1 to 6 carbon atoms or a substituted alkylene radical of the iOrmel

-AT THE

wherein A is an alkylene radical having 1 to 5 carbon atoms and M is the 2nd

-CHp- or -G- group

and Y has the meaning given above. The compounds of Pomol II are expediently starting from

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commercially available i-carbethoxy-4-piperidone and 1-carbethoxy-3-pyrrolidone and des; corresponding phenylhydrin produced by the classic Fischer ¹ see indole synthesis. Approximately equimolar amounts of the corresponding phenylhydrazine hydrochloride and piperidone are heated together in an inert solvent such as absolute ethanol.

The arylation of the compound II is carried out by reaction with an appropriately substituted p-bromobenzene derivative, working with a 2-3 fold molar excess of the bromobenzene derivative in order to achieve optimum yields of product III. In addition, equimolar amounts plus up to a 100 $ excess of cuprobromide and sodium carbonate are used in this reaction, in a reaction-inert solvent such as nitrobenzene, hexamethylphosphoramide or N-methyl-2-pyrrolidiinone at a temperature of 125 to 225 ^° C., preferably 175 up to 200 ⁰ C, works.

The hydrolysis of the compounds III is carried out by heating a methanolic solution of 2-carbethoxy-5-aryl-1,2,3,4-tetra = hydrocarbolins with at least two molar equivalents of potassium hydroxide.

This sequence of reactions becomes more according to the invention in the preparation Intermediate products of the formula I in which R ϊ / hydrogen is applied.

Compounds of the formula I in which X and Z are as indicated above Have meaning and R is an alkyl radical, the benzyl radical or a substituted alkylene radical of the formula

-AT THE

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AO

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represents, in which A is an alkene radical and M is -GHp- or -C- Group and Y has the meaning given above, are .sythetized by alkylating a compound of the formula I in which R is hydrogen.

The reaction is carried out with an equimolar amount plus up to 10 to 20fa excess of alkylating agent in an inert, aprotic, polar solvent such as tetramethylene sulfone, dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide or a dialkyl ketone, at elevated temperatures.

dis
guided. In order to facilitate complete conversion, a catalytically tight potassium iodide is added so that quantities of the encoded alkylating agent are produced in situ for the reaction. Furthermore, 5 to 6 mol of excess sodium carbonate are added to trap the hydrogen halide formed as a by-product in the alkylation.

For the preparation of the compounds of the formula I in which R is a Means alkyl radical, various other synthetic routes can be followed. The first alternative procedure is initially a phenylhydrazine derivative with a 1-alkyl-4-piperidone implemented, followed by arylation in the 5-3 position:

IV

IV

Na ₂ CO ₃

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The conditions of the Fischer indole synthesis leading to the compound IV and the subsequent arylation of IV to form I are similar to the reaction conditions described above.

The second alternative process, which leads to 2 ~ alkyl-5-aryl-1,2,3,4-tetrahydro-f-carbolines and 2-alkyl-4-aryl-1,2,3j4-tetrahydro = pyrrolo / 3 »4- ^ 7indoles leads via an acylation a compound of .Formel I, in which R is hydrogen, with the corresponding acid halide, anhydride or mixed Anhydride, followed by a reduction of the amide thus formed with a metal hydride:

NH R'COCl _Ύ
or
(R ¹ CO) _O 0

hydridi ■

In the above formulas, X, Z and η have the meaning given above, while R ^{1 represents} an alkyl radical having 1 to 5 carbon atoms.

The acylation of the compounds of the formula I (R = hydrogen) is done with an acid halide, acid anhydride, or mixed anhydride using equimolar amounts of the acylating agent plus up to $ 20 excess, in an inert Solvents such as a chlorinated hydrocarbon. Kin tertiary anine, for example triethylarcin,

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is added in an equimolar amount plus up to a two-fold excess to bring about complete reaction, "wherein
you can work at room temperature.

The reduction of the aylated compounds is best done with a metal hydride such as lithium aluminum hydride or aluminum hydride in a reaction-inert solvent, for example a dialkyl or cycloalkyl ether.

The acylation can also be carried out with the acid halide or acid anhydride an arylalkanecarboxylic acid of the formula

R "-CO ₂ H

be carried out, in which Y has the meaning given above and R ¹ · represents an alkylene radical having 1 to 5 carbon atoms.

The reduction of the amides formed. takes place with lithium aluminum hydride or aluminum hydride and leads to compounds whose 2-substituent is an aralkyl radical of the formula

M-A-

is wherein Y, M and A are as defined above.

A third synthesis for the preparation of the compounds of the formula I, in which R is keth.yl, consists in the reduction of Compounds of formula III

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3 i

III

with lithium aluminum hydride or aluminum hydride. The expert recognizes that you can use any carbalkoxy radical for the production the 2-l * ethyl compound can use.

Another process for the preparation of compounds of the formula I in which R is a radical of the formula

represents, wherein A and X have the meaning given above and M the q

—C group is as follows:

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Cl-A-CN

N-A-CN

2'n

XMg

The alkylation of compounds of the formula I in which R is hydrogen means, with a Li-haloalkylnitrile takes place under the alkylation conditions described above.

The reaction of the nitrile VI with the corresponding Grignard reagent leads to the desired ketone. Preferably be
4 moles of Grignard reagent are used per mole of nitrile, although
the desired product can also be obtained with a smaller excess, as is customary in Grignard reactions, the reaction is preferably carried out in a reaction-inert solvent such as diethyl ether.

/ The manufacture of
Compounds of the formula I, in which R is a radical of the formula:

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-OH

represents, in which A and Y have the meaning given above, is carried out by reducing the corresponding ketone with sodium borohydride according to the following equation:

AFTER

Here, one mole of ketone is reacted with about 4 moles of the hydride in a reaction-inert solvent such as ethanol at room temperature to an elevated temperature. The addition of tetrahydrofuran facilitates the reaction due to the increased solubility of the reactants.

Tertiary alcohols of the present invention are obtained by reacting the corresponding ketone with methyl magnesium iodide according to the following equation:

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^(C Vn

CH ₃ MgI

N-A-C

In the above formulas, X ₅ 2, η, A and Y have the meanings given above.

Although the starting materials react with one another in equimolar amounts, in the case of the above-described (s-rign a rd reaction, an excess of one S in Eietfaylmagnesium iodid of up to 1005 % Eexner 7 / ir-d the reaction preferably in a resion-inert Solvent such as diethyl ether carried out at room temperature, »

The erfindungsgenäßen alcohol 'smz-AESN easily ymgswandelt by acylation with a i5äurehalogenid ₉ S-äisrsaah.ydrid gessischten or anhydride in the ester. These acylation reactions can be v / grounded in solvents such as Seispial chlorisrtezi hydrocarbons u & ü "ant'är use of an Isertiärea Amiias like pyride in or SriätfeylaEis to ensure a complete conversion"

The erfiadungsgesäßen sekimclär-an alcohol-dsa who by treatment with 6 N hydrochloric acid at erhSfeten Sesperatyren under Behy- dratisierueg in? Erbinäungen übsrfü <irt ₉ in which M-CH = GH bedeuteto Eayfig it is preferred to Terwenducg a co-solvent such as Itaanol, to increase the solubility of Carboline. and Pvrrolo / ij 4-b7i: idol. "

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The required starting materials are either commercially available or their preparation is described in the chemical literature, or they can be prepared by methods known per se. For example, beef phenylhydrapines are commercially available or can be prepared by reducing the phenyldiazonium salts (see, for example, Wagner and Zook, "Synthetic Organic Chemistry", John Wiley & Sons, New York, NY, 1956, Chapter 26). The 1-substituted 4-piperidones are commercial preparations or can be prepared by the method of McElvain and Rorig, J. Am. Chaa. Soc, 70, 1826 (1943) can be prepared "The ω Halogenalkylarylketone the process of US Patent 2,997,472 are in accordance with (CA. 56, II6O3 /? 9627) is shown, and the 1-alkyl-3-pyrrolidinone can be prepared by the method von Gasy et al., J. Pharm. Pharmacol. JJ7 (3), 157 (1965) can be synthesized.

As already mentioned, the compounds according to the invention can Form acid addition salts. The basic compounds are made by reaction with an acid in aqueous or non-aqueous Medium converted into their acid addition salts. By treating the acid addition salts with an equivalent kenge an aqueous base, for example alkali metal hydroxide solution, alkali metal carbonate or alkali metal bicarbonate solution or with an equivalent amount of a metal cation which forms an insoluble precipitate with the acid anion, the regenerate free base. The bases regenerated in this way can be converted back into the same or a different acid addition salt will.

When utilizing the chemotherapeutic effect of the invention Compounds, of course, preference is given to the use of pharmaceutically acceptable salts. Y / water insolubility, high toxicity or lack of crystallinity may make some special salts unsuitable or unsuitable for pharmaceutical use make it less suitable; however, one can use the water-insoluble ones

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or, toxic tialze as described above in the corresponding pharmaceutically acceptable bases .overrun, oaer into any pharmaceutically acceptable acid addition salt.

Examples of acids that contribute pharmaceutically acceptable anions, are hydrochloric acid, hydrochloric acid, iodine chemical acid, nitric acid, sulfuric and sulphurous acid, Phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and gluconic acid.

As already said, the γ-carbonylines and pyrrolo ^ 3 »4 - ^ / indoles according to the invention are suitable for therapeutic use as tranquilizers for mammals , with the exception of the compounds of the formula I which are suitable as intermediates, in which R is hydrogen. The compounds 8 ~ fluoro-5- (p-fluorophenyl) -2- / 3- (p-fluorobenzoyl) propyl / -1,2,3 »4-tetrahydro-γ-carboline, for example, have an excellent effect in this area -Fluoro-5- (p-fluorophenyl) -2 - /? - (p-fluorophenyl) -4-hydroxybutyOj ⁷ -1,2,3,4-tetrahydro ~ y-carboline, 8-fluoro ~ 5- (p- fluorophenyl) -> 2- (4-phenyl-4-hydroxybutyl) -1, 2 _S 3, 4-tetrahydro- ^{γ-carboline, 8-Ji 1} IuOr-5- (p-fluorophenyl) -2- / 4 - (p-chlorophenyl) -4-hydroxybutyl7-i, 2,3 »4-tetrahydro-7-carboline, 8 ~ fluoro-5- (p-fluorophenyl) -2- / 4- (p-tolyl) -4- hydroxylbutyl / -1,2,3,4-tetrahydro-7-carboline, 8-Ji ¹ IuOr-S- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -4-acetoxybutyl7-1,2, 3,4-tetrahydro-y-earbolin, 8-fluoro-5 ~ (p-fluorophenyl-2- / 3- (p-fluoro = phenyl) -3-hydroxypropyl7-1,2,3,4-tetrahydro-y- carboline, 8-luoro-5- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -5-hydroxypentyl7-1,2,3,4-tetrahydro-γ-carboline, 8-fluoro-5 - (p-fluorophenyl) -2- / i- (p-fluorophenyl) -4-hydroxypentyl7-1,2,3, 4-tetrah.ydro-Y-carbo = lin, 8-fluoro-5- (p-fluorophenyl ) -2- / 4- (p-fluorophenyl) -3-butenyl7-1.2 | 3 »4-tetra hydro-γ-carboline, 8-chloro-5- (p-fluorophenyl) -2-Z3 * - (p-fluorobenzoyl) propyl7-1, 2, 3, ^ -tetrahydro-T-carboline, S-chloro-5- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl / -1 »2,3,4-tetrahydro-y-carboline, 3-chloro-5- (p-fluorophenyl; -2-

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/ 4- (p-fluorophenyl) -4-hyriroxypentyl7-1, 2, 3,4-tetrahydro-y-carbo = lin, 8-Brcm ~ 5- (p-fluorophenyl) -2- / 3- (p-fluorobenzoyl ) pronyl / -1 »2,3,4-tetrahydro-T-cfirbclin, 8-bromo-5- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl / -1,2, 3,4-tetrahydro-y-carbo = lin, 8-ethyl-5- (p-fluorophenyl) -2- / 5- (p-fluorobenzoyl) propyl7 ~ 1,2,3,4-tetrahydrc-T-carboline, 8 - ?. "ethyl-5- (p-fluorophenyl) -2-. ^ / 4- (p-fluorophenyl) -4-hydroxybutyl7-1,2,3,4-tetrahydro-r-earbo = lin, 8- i? luor-5- (p-methoxyphenyl) -2- _i / 4- (p-fluorophenyl) -4-hydro = xybutyl7-1,2,3,4-tetrahydro-7-carboline, 8-fluoro-5- (p-methoxy = phenyl) -2- / 4- (p-tolyl) -4-hydroxybutyl7-1., 2 _> 3,4-tetrahydro-ycarboline, 8-fluoro-5- (p-methoxy phenyl) - 2 - ^ / 4- (pc chlorophenyl) -4-hydroxybutyl7-1,2,3 »4-tetrahydro-T-carboline, 8-fluoro-5- (fluorophenyl) -1,2,3» 4-tetrahydro-Y -carboline, 8-i! ⁿ luoro-5- (p-fluoro = phenyl) -2-benzyl-1,2,3,4-tetrahydro-r-carboline, 3-i? luoro-5- (fluorophenyl) - 2fflethyl-1,2,3i4-tetrahydro-T-carboline, 8-fluoro-5- (p-fluorophenyl) -2-ethyl-1,2,3 »4-tetrahydro- |" - carboline, 8-f ¹ luoro-5- (p-fluorophenyl) -2-n-propyl-1,2,3 »4-tetrahydro-y-carbo = lin, 8-l ^il luor-5- (p- fluorophenyl) -2- (3,3-dimethyl-n-butyl) -1,2,3,4-tetrahydro-T-carboline, 8-fluorine-5- (p-ynethoxyphenyl) -1,2,3,4 -tetrahydro-T-carboline, 8-fluoro-5- (p-chlorophenyl)-1,2,3, 4-tetrahydro-r-carboline, 8-fluoro-5-phenyl-1,2,3,4 -tetrahydrocarboline, 8-fluorine-5-phenyl-2- / 4- (p-tolyl) -4-hydroxybutyl / -1, 2,3, 4-tetrahydro-r-carboline, 8-chlorine-5 -phenyl-2- / 4- (p-tolyl) -4-hydroxybutyl7-1,2,3,4-tetrahydro-y-carboline, 8-j? luoro-5-phenyl-2- / 3- (p- fluorobennoyl) propyl7-1,2,3,4-tetrahydro-Y-carb® = lin, 8-fluorine-5-phenyl-2- / 4- (p-fluorophenyl) -4-hydroxybutyl / -1 ^^, ' i-tetrahydro-T-carbclin, 8- ^ luoro-5-phenyl-2- / 4- (p-fluoro = phenyl) -4-hydroxypentyl7 ~ 1 »2,3,4-tetrahydro-T-carboline, 8- chloro-5-pheny1-2- / 4- (p-fluorophenyl) -4-hydroxybutyl7-1,2,3,4-tetrahydro-T-carboline, 3-i ^l luor-5-phenyl-2-methyl-1 , 2,3,4-te = trahydro-r-carboline, S-chloro-5-phenyl-2-methyl-1,2,3,4-tetra = hydro-γ-carboline, 8-chloro-5-phenyl -2-ethyl-1,2,3,4-tetrahyd ror-carbolin, 8-FIuOr, 5- (p-chlorophen ^ l) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl / -1,2,3,4-tetrahydro-T-carboline, 8-

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chlorophenyl) ~ 2 ^ / 4- (p-chlorophen; / l) - 'ih ^ dro>: ybuty3 _i 7-1,2,3 »4-tetrahydro-Y-carboline, 8-.z'luor-5- (p-cLlorpher.yl) -2- (4-phenyl-4-hydroxybutyl) -1,2,3,4-tetrahydro-y-carboline, 7-- ^rt1 luor-4 ~ (p-fluorophenyl) ~ 2- _{i (} / 4- (pf Iuophenyl) -4-hydroxybutyl / -1,2,3,4-tetrahydropyrrolo / 3, 4-_b / indole, 7-fluoro-4- (p-fluoropheriyl) -2- / 4- (p-fluorophenyl) -4-acetoxybutyl7 ~ 1,2,3,4-tetrahydropyrrolo- / 3j4- ^ 7indole, 7-fluoro-4- (p-fluorophenyl) -2- / 4 ~ (p-fluorophenyl) -4-hydroxypentyl7-1,2,3,4-tetrahydropyrrolo / 3, 4- ^ 7 ^iK idol and 7-fluoro-4- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) ~ 4-acetoxypentyl7 "-1» 2,3 »4-tetrahydropyrrolo / 3» 4 - ^ 7indcl. A preferred intermediate according to the invention is the compound 7-i? Luoro-4- (fluorophenyl) -1,2,3 »4-t et rahyd ropyrrolo / 5 »4-b / indole.

The tranquilizers according to the invention are characterized by the Relief of schizophrenic manifestations in people such as hallucinations, hostility, suspicion, emotional or social rejection, fear, restlessness and tension. Standard Methods for Determining and Comparing Tranquilizer Effect are based on the antagonism against through. amphetamine induced symptoms in rats according to A. Weissman et al., J. Pharmacol. Exp.Ther., 151 »339 (1966) and Quinton et al., Nature, _200, 173 (1963).

The f-carbolines and pyrrolo / 3,4-b7indoles and their pharmaceuticals Permissible salts that are suitable as tranquilizers can be therapeutic as individual therapeutic agents or in mixtures Funds are used. They can be administered alone, but are generally used in conjunction with a pharmaceutical one Carrier given, the choice of which depends on the route of administration and pharmaceutical practice. So you can make the connections to the For example, administer orally in the form of tablets or capsules, the excipients such as starch, lactose, certain types of clay and the like included. Furthermore, the compounds can be given in the form of elixirs or oral suspensions which

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the active ingredients in combination kit emulsifying and / or bus-pending agents contain. The compounds can also be administered parenterally, in which case they themselves or in the form suitable derivatives can be formulated into sterile aqueous solutions. The aqueous solutions can be buffered if necessary and should contain other solutes such as table salt or glucose, making them isotonic.

Mammals in general can use the compounds according to the invention but the preferred target of treatment is humans. To determine the effective dose for the Human therapy, the results of animal studies are often extrapolated, taking a relationship between animal behavior and the human dose suggested. If a commercial standard is available, the Dose in humans is often determined by comparing the behavior of the clinical test compound with the standard in animal studies compares. For example, a standard tranquilizer is used in a range of 100 to 400 mg daily with success on people administered, it is assumed with comparable activity of the compound according to the invention in animal experiments that similar Quantities will give similar reactions in humans.

Of course, the ArT; determine the dose im The individual case is best suited to the age, weight and response of the patient, the nature and extent of the symptoms and the pharmacodynamic properties of the particular agent. In general, small doses are given first, with gradual increase up to the optimal amount. In the case of oral administration, larger quantities of active ingredient are often required than with parenteral administration.

Taking the above factors into account, a daily dose of the compounds according to the invention in humans is

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■ hb. 1 mg to 100 and "preferably 1 to 50 rag considered effective, in patients in which the invention compounds buttocks FORTIFICATION a longer ut -ausüben., The dose may be 5 to 150 per reg uoche betragen-, wherein administration takes place one or sweimal These values are only exemplary and of course there may be individual cases in which higher or lower doses are advantageous.

example 1

8-ffluor-5- (p ~ fluorophenyl ) -1 , 2,3,4-tetrahydro ~ 7-oarboline (I; X = ff, Z = ff, n = 2 and R = H)

A. 8-fflu.or-2 ~ carbathox.y ~ 1, 2 , 3 _t ^ -tetrahydro-y-carboline (II: X = ff)

A mixture of 15.9 g (0.093 mol) of N-carbethoxy-4-piperidone and 15.1 g (0.093 mol) of p-fluorophenylhydrazine hydrochloride in 150 ml of ethanol is refluxed for 2 hours. The reddish reaction mixture is then cooled and filtered, the collected solids are washed with a little cold 95/6 strength ethanol. Here, 21.3 g (38 $ yield) of product from ff "1 69 170 ⁰ C. The analytical sample is recrystallized from ethanol / water, 169 ff -. 170 ⁰ C

Analysis:

Ber. for G ₁₄ H ₁₅ O ₂ N ₂ ?: G: 64.1; H: 5.8; N: 10.7-

Found: C: 63.8; H: 5.8; N: 10.6.

B. 8-ffluoro-5- (p-fluorophenyl) -2-carbethoxy-1,2,3,4-tetrahydro-y-carboline (Uli X and Z = ff)

To 30 ml of N-Metayl-2-pyrroli <$ m 3.45 g (0.013 mol) of 8-fluoro-2-carbethoxy-1,2,3,4-tetrahydro-T-carboline, 7.8 g (0.045 mole) p-fluorobromobenzene, 4.14 g (0.014 mole) cuprobromide and 1.5g (0.014 mol) of sodium carbonate were added and the resulting The mixture is heated to 200 ° G in an oil bath for 6 hours. Then it is allowed to cool to room temperature overnight, then

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send v / ird in 300 ml v / aaser containing 60 ml ethylenediainine, decanted. Thereafter, 200 ml of benzene are added and the two-phase system is filtered through a pillow of Suner-cel. The i'iltrat is several times with a total of 700 ml of benzene. extracted, the extracts are combined, washed successively with water and saturated sodium rid solution and washed over dried anhydrous sodium sulfate. After removal of the solvent, the crude product is obtained as a dark product that remains Oil.

The crude product is chromatographed in benzene on a silica gel column using 10 ^ ethyl acetate / benzene as the eluent. Fractions 1 to 16 of 10 to 25 ml each containing p-fluorobromobenzene are collected and discarded. Fractions 16 to 38 are combined and concentrated in vacuo to an oil which solidifies at 5 ° C. overnight. The product (3.5 g, 76% yield) is triturated with pentane and filtered. The analysis sample is recrystallized from pentane, ¥. 113 - 120 ⁰ G.

Analysis:

Ber. for ^C 2O ^H 18 ° 2 ^N 2 ^1? 2 ^: C: 67.4; H: 5 _t 1; N: 7.9.

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

C. 8-gluor ~ 5- (p ~ fluorophen.yl) -1,2,3 _> 4-tetrahydro-V-carboline (I; X and Z = ff, R = H)

A suspension of 3.56 g (0.01 mol) of 8 i? Luor-5 ~ (p-fluorophenyl) -2-carbethoxy-1,2,3,4-tetrahydro ~ 7 ~ earboline and 8.2 g (0.146 moles) of potassium hydroxide in 53 ml of ethanol containing 5 nil of water refluxed overnight. Then another 3.0 g of potassium hydroxide added and it is cooked for another 23 hours. The brownish solution is cooled and concentrated to dryness in vacuo and distributed between water and diethyl ether. The aqueous phase is extracted again with ether, the ether extracts

509847/1120

"* ~ Jt

ciilo are combined, with saturated sodium:. ricilösung gev.r ^ .- c ^ en and dried over i'-agnesiuinsu.lfat. Once the solvent has been cleaned up, the desired product is obtained: orange-colored solid matter in an oil, enre vcn 2.6 £ _s for 125 - 127 C. The test sample is through. Recrystallize fcus pentane obtained, F. 127 - 128 ⁰ C.

Analysis;

Ber. for C ₁₇ H ₁₄ N ₂ P ₃ : C? 71.3; H: 5.0; II: 9 »9.

Found: C: 71.65 H: 5.1; N: 10.2.

The hydrochloride is made by going into a solution the free base in diethyl ether initiates hydrogen chloride. It melts at 270 to 272 ° C.

Example 2

According to the procedure of Example 1, using the corresponding phenylhydrazine, the following 5-aryl-1,2,3,4-tetra = hydro-Y ^ -carbolines are prepared (free bases or hydrochlorides): 8-chloro-5- (p- fluorophenyl) -1,2,3,4-tetrahydro-Y-earbolin-hydrochloride, mp 269-271 ° C; 8-Broia-5-phenyl-1,2,3,4-tetrahydro = dro-f-carboline hydrochloride, m.p. 280-282 ⁰ C; 8-methyl-5-phe = nylr.1,2,3,4-tetrahydro) Pcarbolin, F. 288-289 ⁰ C; 8-fluoro-5-bd-chlorophenyl) -1,2,3,4-tetrahydro-y-carbclin-hydroehlorid, F. 283-285 ⁰ C; 8-chloro-5-phenyl-1,2,3,4-tetrahydro-γ-carboline hydrochloride, mp 276-278 ° C and the free bases 8-fluoro-5- (p-methoxyphenyl) -1,2,3 , 4-tetrahydro-γ-carboline, m.p. 119 122 ⁰ C; 8-chloro-5- (p-chlorophenyl) -1,2,3,4-tetrahydro-r-carbcline, 8-bromo-5- (p-fluorophenyl) -1,2,3,4-tetrahydro-y- carboline, 8-methyl-5- (p-chlorophenyl) -1 ^^^ - tetrahydro-y-carboline, 5- (p-? luophenyl) -1,2,3,4-tetrahydro-y-carboline and 5- (p-Chlorophenyl) 1,2,3,4-tetrahydro-γ-carboline.

509847/1120

Example 3

-5- (p - fl uorphheR.yl ) -2- (j; t-phe näthyl) -1,2,3,4-tetra = hydro-y-carbolir.-h / chloride (I. X and Z = P; η = 2: A = -CK ₂ -; M = -CII ₂ - and ϊ = H)

To a suspension of 1.4 g (4.9 killimoles) 8-ί1υοΓ-5- (ρ-fluorophenyl) -1 _t 2,3t4-tetrahydro-γ-carboline and 1.02 g (7.4 millimoles) potassium carbonate in 10 ml of dimethylformamide, which was heated to 60 ⁰ C, with stirring 1.09 g (5.9 millimoles) of ß-Phenäthylbromid in 10 ml of the same solvent was added dropwise. After 3.5 hours of heating, the reaction mixture is decanted into 200 ml of aqueous 2 ^c strength potassium carbonate solution and the resulting solution is then extracted three times with 200 ml of benzene each time. The combined extracts are washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo and the residual oil, which crystallizes on standing, is triturated with hexane and then filtered to give 1.6 g of J ?. 115 - 121 ° C.

The crude product is chromatographed on a silica gel column using 25% ethyl acetate / 7550 benzene as the eluent. Fractions 12 to 32, each of 5 to 7 ml consisting are collected and concentrated to ^x 'rockene. The remaining crystalline product is dissolved in diethyl ether / methylene = chloride and converted into the hydrochloride with gaseous hydrogen chloride. Yield 1.13 g (545 ^, P. 275 - 276 ⁰ C.

Analysis:

Ber. for -C ₂₅ H ₂₂ N ₂ F ₂ -HCl: C: 70.7; H: 5.5; N: 6.6.

Found: C: 70.4; H: 5.5; N: 6.5.

The procedure of Example 3 is followed with the corresponding t-p. Alkylating agents and the required 5-aryl-1,2,3,4-tetrahy =

509847/1120

25H084

δ ro-carfaolin repeats, ν, -obei ιώ f'orvr. the Hydrochloride receives:

following connections in

X Z A. y F- F- -CH ₂ " Cl- F- —CHo ~ H- Τ? - · F- - (CH ₂ ) 3- F- F- ~ (CH ₂ ) ₅ - F- F- Cl- -CH ₂ - Cl- P- Cl- - (CH ₂ ) ₃ - F- F- Cl- - (CH ₂ ) 3- F- F- Cl- - CCH ₂ ) ₄ - Cl- F- H- - (CH ₂ ) 3- F- Cl- H- -CH ₂ - H- Cl- H- - (CH ₂ ) 3 H- Cl- F- - (CH ₂ ) 3- F- Cl- Ρ— · - (CH ₂ ) 5- F— Cl- Cl- -CH ₂ - Cl- Cl- Cl- -CH ₂ - H- Br- Cl- - (CH ₂ ) ₄ - Cl- Br- Tl ¹ M- - (CH ₂ ) 3- F- Br- F- -CH ₂ - H- Br- H- -CH ₂ - Cl- CH ₃ - H- -CH ₂ - H- CH ₃ - H- - (CH ₂ ) '2 " H- CH ₃ - -i ^CH 2> 3- F- CH ₃ - F- - (CH ₂ ) 3- F- CH ₃ - P- -CH ₂ - H- H- F- - (CH ₂ ) 3- F- 5098 47/1 120

-'Jf-

Z A. 25U084 X F- -CH ₂ - γ I H- F- - (CH ₂ J ₄ - H- Cl- -CH ₂ - Cl- ι H- Cl- - (CH ₂ ) 3- H- j H- P- j

Example 5

3-fluoro-5- (p-fluorophenyl ~ 2- / 3 - * (p-fluorobenzoyl) propyl / - 1,2,3,4-tetrahydro-T-Garbolin hydrochloride

Il

(I: X and Z = j ¹ ; η = 2; A - - (CH ₀ ), -; M = -C- and Y = g)

Following the procedure of Example 3, 2.84 g (0.01 mol) 8-fluorine-5- (p-fluorophenyl) -1, 2,3, 4-tetrahydro-7-carboline, 2.8 g (0.01 mole) ω-chloro-p-fluorobutyrophenone, 3.15 g (0.03 mole) sodium carbonate and a trace (50 mg) of potassium iodide in 50 ml of 4- methyl-2-pentap-one after refluxing for 15 hours and Working up 2.6 g of the desired product in JPorm of the free Base, m.p. 150-155 ° above sea level.

The crude base is converted into the hydrochloride in diethyl ether with hydrogen chloride gas. 2.72 g are obtained, mp 235 ° C. (decomposition). By recrystallization from a little diethyl ether containing. Ethanol gives 2.2 g of the pure product, F. 237-23B ⁰ C.

Analysis:

Ber. for C ₂₇ H ₀₅ ON ₂ F ₅ -HCl ^ iA H _o 0: C: 66.3; H: 4.9; N: 5.7

Found: C: 66.3; H: 5.2; N: 5.6.

Example 6

Using the alkylation procedure of Examples 3, 4 and 5 are obtained from :? the corresponding alkylating agent

rnno / 1 / Hin

Zi 25U084

and 1,2,3,4-tetrahydro-Y-carboline, the following analogous compounds:

8-U ¹ IuO r-5- (pf luo rphenyl) -2- / 2- (pf luo rbenzoyl) ät hyl7 ~ 1 ^^^ - tetrahydro-y-carboline hydrochloride, mp 195-198 ° C.

Analysis:

Ber. for C ₂₆ H ₂₁ ON ₂ F ₃ -HCl '"! ^ H ₃ O: G: 65.5; H: 4.7; N: 5.9

Found: O: 65.6; H: 4.7; N: 5.9;

8-fluoro-5- (p-fluorophenyl) -2- / 4- (p-fluorobenzoyl) butyl / -1,2,3,4-tetrahydro-y ~ carboline hydrochloride ^ F. 242 - 244- ⁰ C. Analysis :
Ber. for O ₂₈ H ₂₅ ON ₂ F ₅ -HOl-IA H ₂ O: C: 66.8; H: 5.3; N: 5.6

Found: C: 66.8; H: 5 ₉ 3; N: 5.5;

8 ~ fluoro-5- (p-fluorophenyl) -2- (3-benzoylpropyl) -1,2,3,4-tetrahydro-y-carboline hydrochloride, F. 208-211 ⁰ G. Analysis:
Ber. for C ₂₇ H ₂₄ ON ₂ P ₂ CHCl-H ₂ O: G: 66.9; H: 5 _S 6; N: 5.8

Found: 0: 67.2; H: 5.4; N: 5.8;

8-fluoro-5- r (p-fluorophenyl) _{-2-i (/} 5- (p-toluoyl) per pyl7 ~ 1,2,3,4-tetrahydro-y-carboline, m.p. 125-127 ⁰ C. Analysis:

Ber. for ^c ₂ 8 ^H 26 ^0Ii 2 ^? 5 ^{'1/4 ¥: G: 74 »9; H: 5>8; N: 6} ' ²

Found: C, 74.6; H: 6.0; N: 6.0;

8-fluoro-5- (p-fluorophenyl) -2 / 3- (p ~ chlorobenzoyl) -propyl7 ~ 1 »2,3,4-tetrahydro-y-carboline hydrochloride, m.p. 201-203 ⁰ C.

Analysis:

Berc for C ₂₇ H ₂₃ ON ₂ ClF (free base): C: 69.7; H: 5.0; N: 6.0

Found: 0: 69.4; H: 5.0; N: 5.9;

8-Fluo r-5- (p-trifluorine methyl phenyl) -2- / 5- (p-fluorobenzoyl) -propyl7-1,2,3,4-tetrahydro-y-earboline hydrochloride, m.p. 245-247 ⁰ C.
Analysis:
Ber. for C ₂₈ H ₂₃ ON ₂ F ₅ -HCl: C: 62.9; H: 4.5; N: 5.5

Found: C: 62.5; H: 4.5; N: 5.2;

509847/1120

3-Fluo r-5- (m-1 rif luormet hylpheny 1) -2- / 3- (p-f luo rb enzoyl) propyl. 7-1 , 2,3,4-tetrahydro ~ y ~ carboline hydrochloride, F.

24 "7 - 243 ⁰ G.

Analysis:

Ber. for C ₂₈ H ₂₃ ON ₂ P ₅ -HGl'I / 3 H ₃ O: C: 62.2; H: 4.6; N: 5.2

Found: G: 62.2; H: 4.5; N: 5.2;

8-fluoro-5- (p-methoxyphenyl) -2- / 3- (p-fluoro rben zoyl) -propyl7-i ^^^ - tetrahydro-y-carboline hydrochloride, F. 209 - 211 ⁰ G. Analysis:
Ber. for G ₂₈ H ₂₆ O ₂ N ₂ F ₂ -HCl.1 / 4 H ₂ O: G: 67.1; H: 5.5; N: 5.6

Found: G: 67.3; H: 5.3; N: 5.5;

8-chloro-5- (p-fluorpheny3 ^ -2 / 3- (p-fluorobenzoyl) propyl7-1,2,3,4-tetrahydro-Y-carboline hydrochloride, m.p. 233-235 ⁰ C. Analysis:
Ber. for G ₂₇ H ₂₃ ON ₂ ClF ₂ -HCl: C: 64.7; H: 4.8; N: 5.6

Found: C: 64.3; H: 4.8; N: 5.7.

Example 7

Furthermore, repeating the alkylation process of Examples 3, 4, 5 and 6 from the required starting materials the following connections established:

χ Z A. Y F- F- - (CH ₂ ) YY- P. F- F- -CH ₂ - . Cl- F- Cl- - (CH ₂ ) ₃ - P- F- Cl- - (CH ₂ J ₃ - Cl- F- Cl- - (CH2) ₃ ~ CH ₃ - jp— OCH ₃ - - (CH ₂ J ₂ - F- Ρ · * OCH ₃ - - (CH ₂ J ₂ - H- F- OCH ₃ - - (CH ₂ ) 3- Cl- - (CH ₂ ) ₃ - F- Cl- F- -CH ₂ - Cl- Cl- F- - (CH ₂ J ₃ - Cl- Cl- F- - (CH ₂ J ₃ - CH ₃ - Cl- H- - (CH ₂ J ₃ - F- Cl- H- - (CH ₂ J ₅ - F- Cl- Cl- - (CH ₂ J ₃ - F- Cl- OCH ₃ ^ - (CH ₂ J ₃ - P- Cl- OCH ₃ - - (CH ₂ J ₃ - CH ₃ - Br- H- - (CH ₂ J ₃ - F- Br- Η— - (CH ₂ J ₃ - H- . Br- H- - (CH ₂ J ₄ - Τ? - Br- OCH ₃ -CCH ₂ J ₂ - F-

509847/1120

Z A. 25H084 X OCH ₃ - - (CH ₂ J ₃ - Y Br- F- - (CHp), - Br- Cl- - (CH ₂ ) ₂ - Γ Br- Cl- - (CH ₂ J ₃ - Ρ
Ι CHo " Cl- - (CH ₂ J ₅ - CH ₃ - F- - (CH ₂ J ₃ - F- - j
t CH ₃ - OCH ₃ - - (CH ₂ J ₃ - CH ₃ - CH-- OCH ₃ - - (CH ₂ J ₄ - H- CH ₃ -, H- - (CH ₂ J ₃ - F- CH ₃ - OCH ₃ - - (CH ₂ J ₃ - F- H- OCH ₃ - - (CH ₂ J ₃ - F- H- OCH ₃ - - (CH ₂ J ₂ - CH ₃ - TT - OCH ₃ - - (CH ₂ J ₅ - F- H- Cl- // 1TT \ · - Cl- H- Cl- - (CH ₂ J ₅ - CH ₃ - H- H- Example 8 F- H-

8-chloro-5- (p-fluorophenyl) -2- / 4- (p-fluorophen.yl) -4-hydroxy butyl / -1,2,3,4-tetrahydro-γ-carboline hydrochloride

OH

(I: X = Cl; Z = F; η = 2; A = - (CH ₂ J ₃ -; M = -CH- and Y = P)

To 575 mg (15.2 millimoles) of sodium borohydride in 25 ml of ethanol 1.8 g (3.8 millimoles) of 8-chloro-5- (p-fluorophenyl) -2- / 5- (p-fluorobenzoyl) propyl7-1,2,3,4-tetrahydro-Y-carboline in a warm solution of 40 ml of ethanol and 10 ml of tetrahydrofuran in added dropwise at such a rate that the mixture boils gently on the Kückfluii. After the addition has ended, another 1 3 hours

509847/1120

25U08.4

on: refluxed and then cooled to room temperature. The supernatant liquid is decanted off in 200 ml of water, and organic solvents are removed from the aqueous solution in vacuo. The remaining aqueous solution is extracted three times with 75 ml of methylene chloride each time, the organic phases are combined, backwashed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is dissolved in diethyl ether / methylene chloride. Hydrogen chloride gas is carefully passed into the solution until the formation of precipitates ceases. The desired product is filtered off and dried, yield 1.9 g, mp 245-246 ⁰ C.

Analysis:

Ber. for C ₂₇ H ₂₅ ON ₂ ClIyHCl ⁰ H ₂ O: C: 62.2; H: 5.4; N: 5.4

Found: C, 62.3; H: 5.1; N: 5.3.

Example 9

The reduction process according to Example 8 is followed by the corresponding Repeated ketone using the following γ-carbolines receives:

8-fluoro-5- (p-methoxyphenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl7-1,2,3,4-tetrahydro-y-carboline hydrochloride,

F. 235 - 236 ⁰ C.

Analysis:

Ber. for C ₂₈ H ₂₈ O ₂ N ₂ P ₂ -HCl: C: 67.4; H: 5.9; N: 5.6

Found: C; 67.7; H: 5.8} N: 5.6;

8-Pluor-5- (m-trifluoromethylphenyl) -2- ^ 4- (p-fluorophenyl) -4-thiydroxy butyl / -1 ^^^ - tetrahydro-f-carboline hydrochloride, F. 243 - 245 ⁰ C.
Analysis:

Ber. for C ₂₃ H ₂₅ ON ₂ P ₅ 'HCl "1/2 H ₃ O: C: 61.6; H: 5.0; N: 5.1

Found: C, 61.6; H: 4.8; N: 5 _S1 ;

509847/1120

. 25-084

8-fluoro-5- (p-fluorophenyl) -2 - /? - (p-tolyl) -4-hydroxybutyl7-1,2,3,4-tetrahydro-γ-carboline hydrochloride, E. 236-257 ° C .

Analysis:

Ber. for O ₂₈ H ₂₈ ON ₂ F ₂ «HC1 · 1 _; 2 H ₂ O: C, 68.3; H: 6.1; N: 5.7

Found: G: 63.7; H: 6.3; N: 5.6; -

8-fluoro-5- (p-fluorophenyl) -2 / 3- (p-chlarphenyl) -4-hydroxybutyl7-1,2,3,4-tetrahydro-y-carboline hydrochloride, m.p. 242 244 C ⁰
Analysis:

Ber. for C ₂₇ H ₂₅ ON ₂ F ₂ Cl-HClOA H ₃ O: C: 62.7; H: 5.1; N: 5.4

Found: C, 62.7; H: 5.1 .; N: 5.3;

8 ~ Fluor_5 - (pf luo rphenyl) -2- / 4 "-In-1 ril ^ uo rme thylphenyl) 4-hydroxybutyl / -1,2,3,4-tetrahydro-7-carboline hydrochloride, F. 225 - 227 ⁰ C
Analysis;
Ber. for C ₂₃ H ₂₅ ON ₂ F ₅ • HCl »1/4 H ₂ O: C: 62.2; H: 4.7; N: 5.2

Found: C, 62.2; H; 4.9; N: 5.2;

8-fluoro-5- (p-fluorophenyl) -2- / 5- (p-fluorophenyl) -4-hydroxypropyl / -1 ^^^ - tetrahydro-γ-carboline hydrochloride, m.p. 237-239 ° C. Analysis:

Ber. for C ₂₆ H ₂₃ ON ₂ F ₃ ^ 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-hydroxy = butylZ-i ^^^ - tetrahydro-y-carboline hydrochloride, F. 249 250 ⁰ C.
Analysis:
Calcd for C ₂₇ H ₂₅ ON ₂ F ₃ -HCl-I / 1 H ₂ O: C: 65.4; H: 5.5; N: 5.6

Found: C, 65.6; H: 5.4; N: 5.6;

8-fluoro-5- (p-fluorophenyl) -2- (4-phenyl-4-hydroxybutyl) -i ^^^ - tetrahydro-y-carboline hydrochloride, F. 236 - 238 ⁰ C. Analysis:
Ber. for U ₂₇ H ₂₆ ON ₂ F ₂ -HCl * 1/2 H ₃ O: C: 68.0; H: 5.7; N: 5.9

Found: C: 67.7; H: 5.8; N: 5.3;

509847/1120

3- ^ luoro-5- (p-fluorophenyl) -2 - /? - (4-chloro-3-trifluoromethyl = phenyl) ~ 4-hydroxybutyl7-1 »2,3,4-tetrahydro-1-carboline-hydro = Chloride, i ¹ . 216-217 ° C

Analysis:

Ber. for C ₂₅ H ₂ ON ₂ F ₅ ClrHCl: C: 53.9; H: 4.4; N: 5.0

Found: 0: 58.7; H: 4.5; N: 5.0;

8. Fluoro-5- (p-fluorophenyl) -2- / 5- (p-fluorophenyl) -5-hydroxy = pentyl7-1,2,3,4-tetrahydro-Y-carboline hydrochloride, J ?. 207 208 ⁰ C-.
Analysis:

Ber. for O ₂₃ H ₂₇ QN ₂ JyHCl-3/4 H ₃ O: C: 65.4; H: 5.8; N: 5.4

Found: C, 65.2; H: 5.6; N: 5.4.

Example 10

i ^x Z A. y ! .P- TP- - (CH ₂ ) 5- F- P- F- -CH ₂ - Cl P- Cl- - (CH ₂ ) 3- F- P- Cl- -CCH ₂ I ₃ - Cl

B098A7 / 1120

X ? 35 - (CH ₂ J ₃ - γ P- Cl- - (CH ₂ J ₂ - CH ₃ - F- CH ₃ O- - (CH ₂ J ₅ - F- F- . CH ₃ O- - (CH ₂ J ₃ H- F- CH ₃ O- - (CH ₂ J ₃ - Cl- Ρ— TT- -CH ₂ - F- Cl- F- - (CH ₂ J ₃ - Cl- Cl- F- - (CH ₂ J ₃ - Cl- Cl- F- - (CH ₂ J ₃ - CH ₃ - Cl- H- - (CH ₂ J ₅ - F- Cl- H- - (CH ₂ J ₃ - F- Cl- Cl- - (CH ₂ J ₃ - F- Cl- CH ₃ O- - (CH ₂ J ₃ - F- Cl- CH ₃ O- - (CH ₂ J ₃ - CH ₃ ^ Br- H- - (CH ₂ J ₃ - F- Br- H- - (CH ₂ J ₄ - H- · Br- H- - (CH ₂ J ₂ - F- Br- CH ₃ O- - (CH ₂ J ₃ - F- Br- CH ₃ O- - (CH ₂ J ₃ - F- Br- F- - (CH ₂ J ₂ - Ρ— Br- Cl- - (CH ₂ J ₃ - F- CH ₃ - CH ₃ O- - (CH ₂ J ₅ - CH ₃ ^ CH ₃ - CH ₃ O- - (CH ₂ J ₃ - H- CH ₃ - F- - (CH ₂ J ₃ - F- CH ₃ - CH ₃ O- - (CH ₂ J ₄ - F- CH ₃ - CH ₃ O- - (CH ₂ J ₃ - F- CH ₃ - H- - (CH ₂ J ₃ - CH ₃ - H- CH ₃ O- - (CH ₂ J ₃ - F- H- CH ₃ O- - (CH ₂ J ₂ - Cl- H- F- - (CH ₂ ) ₅ - CH ₃ - H- F- - (CH ₂ J ₃ - H- H- Cl- - (CH ₂ J ₅ - F- TT- Cl- 120 H- 509847/1

Example 11

3 ~ i luor-5 ~ (l pf uorphenyl) ~ 2V4 * - (p ~ fluorophenyl) ~ 4-hyctroxy-pentyl7-1,2,3, 4-tetrah.ydro-Y-carboline-hydr o chloride

"f

(I: X and Z = F; η = 2; A = - (CH ₂ ), -; M = -C (CH ₅ ) - and Y = F)

A solution of 3.3 g (7.3 millimoles) 8-I ¹ luoro-5- (p-fluorophenyl) -2- / 3- (p-fluorobenzoyl) propyl7 ~ 1 ^^^ - tetrahydro-y-carboline in 15 ml of tetrahydrofuran is added dropwise to a cooled solution of methylmagne3ium iodide in 30 ml of diethyl ether (prepared from 4.56 g (32.2 millimoles) of methyl iodide and 788 mg (32.2 millimoles) of magnesium metal) and the resulting reaction mixture is poured over Stirred overnight at room temperature. The mixture is then decanted into 150 ml of ice water and the organic solvent is removed in vacuo. The aqueous solution is extracted three times with 75 ml of methylene chloride each time and the organic extracts are combined, dried over magnesium sulfate and concentrated under reduced pressure to a yellow oil. This product is converted into the hydrochloride in diethyl ether with hydrogen chloride gas. The resulting precipitate is filtered and dried, yield 1.35 g »i \ 216-217 ° C.
Analysis:

Ber. for C ₂₈ H ₂₇ ON ₂ P ₅ ^ HCl "1/3 H ₂ O: C: 66.3; H: 5.6; N: 5.5

Found: G: 66.6; H: 5.7; N: 5.6.

Example 12

From methylmagnesium;] odide and the 5-aryl-2-benzoylalkyl-1,2,3,4-tetrahydro-γ-carbolines of Examples 6 and 7, the following analogs are prepared using the method of Example 11:

509847/1120

25U084

SJ

X Z A. Y F- F- - (CH ₂ J ₅ - F- F- F- - (CH ₂ J ₄ - CH ₃ - F- F- - (CH ₂ J ₄ - Cl- F- Cl- - (CH ₂ J ₃ - F- F- Cl- - (CH ₂ J ₃ - Cl- F- Cl- - (CH ₂ J ₃ - CH ₃ - F- CH ₃ O- - (CH ₂ J ₂ - F- F- CH ₃ O- - (CH ₂ J ₅ - H- F- CH ₃ O- - (CH ₂ J ₃ - F- F- CH ₃ O- - (CH ₂ J ₃ - Cl- F- H- - (CH ₂ J ₃ - F- Cl- F- -CH ₂ - Cl- Cl- F- - (CH ₂ ) ₃ - Cl- Cl- F- - (CH ₂ J ₃ - CH ₃ - Cl- H- - (CH ₂ J ₃ - F- Cl- H- - (CH ₂ J ₅ - F- Cl- Cl- - (CH ₂ J ₃ - F- Cl- CH ₃ O- - (CH ₂ J ₃ - F- Cl- CH ₃ O- - (CH ₂ J ₃ - CH ₃ - Br- H- "(CH ₂ J ₃ - F-

509847/1120

H- si T-T-. 4-tetrahydro-y-oarboline = - (CH ₂ K-; M = OR ₁
ι ' Br- H- ' - (CH ₂ J ₃ - F- = -CH- where R ₁ = - Br- CH ₃ O- .. - (CH ₂ J ₄ - F- = F; η = 2; A. Br- CH ₃ O- - (CH ₂ J ₂ - F- Br- F- - (CH ₂ J ₃ - F-. ; Br- Cl- - (CH ₂ J ₃ - Br- Cl- - (CH ₂ J ₂ CH ₃ - CH ₃ - Cl- - (CH ₂ J ₃ - H- ^ CH ₃ - F- - (CH ₂ J ₅ - F- CH ₃ - CH ₃ O- - (CH ₂ J ₃ - F- CH ₃ - CH ₃ O- - (CH ₂ J ₃ - τ ** - CH ₃ - H- - (CH ₂ J ₄ - CH ₃ - CH. * - CH ₃ O- - (CH ₂ J ₃ - F- H- CH ₃ O- - (CH ₂ J ₃ - Cl- H- Τί ¹ - · - (CH ₂ J ₃ - CH ₃ - H- F- - (CH ₂ J ₂ - H- H- Cl- - (CH ₂ J ₅ - F- H- Cl- H- H- / ΛΤΤ \ Example 13 8-J ¹ IuO r-5- (p-fluorphe n ^ l) -2- / 4- (p-fluorophenyl) -4-ace toxy- buty17-1,2,3, (Ii X and Z COCH ₃ , and Y =

260 mg (3.3 millimoles) of acetyl chloride in 10 ml of methylene chloride become a cold solution of 1.0g (2.2 millimoles) 8-

509847/1120

-16-

25U084

:> - (pf luophenyl) -2- / 4- (pf luorphenyl) -4-hydroxybutyl7--1 »2,3,4-tetrahydro-y-carboline in 30 ml of methylene chloride, which contains 350 mg (4.4 millimoles) Contains pyridine, added dropwise. When the addition is complete, the reaction mixture is allowed to warm to room temperature and is stirred overnight. The mixture is decanted into cold saturated aqueous sodium bicarbonate solution and the crude product is extracted three times with 50 ml of methylene chloride each time. The combined organic extracts are dried over magnesium sulfate and concentrated to an oil. This is chromatographed on a silica gel column using 1: 1 benzene / ethyl acetate as the eluent, the purified product being obtained in fractions 4 to 7 as a yellow oil (yield 392 mg).
Analysis:

Ber. for G ₂₉ H ₂₇ O ₂ N ₂ F ₃ : G: 70.7; H: 5.5; N: 5.9

Found: G: 70.6; H: 5.4; N: 5.8.

Example 14

Following the procedure of Example 13, starting from the corresponding Garbinol according to Examples 8 to 12 and the the following esters for the respective acid chloride or acid anhydride:

CH ₃ O-

F-

F-

F-

F-

Z A

- (CH ₂ ) 3-

(CH ₂ J ₃ -

CH ₃ CO-CH ₃ CH ₂ CO- (CH ₃ ) 3CCO-CH ₃ CO-CH ₃ CO-

509847/1120

25U084 HO

X Z A. ^R l Y "Ε ¹ - Cl- - (CH ₂ J ₃ - CH ₃ (CH ₂ J ₂ CO- Cl- H- - (CH ₂ J ₃ - CH ₃ CO- F- Cl- F- - (CH ₂ J- ₃ - (CH ₃ J ₂ CHCO F- Cl- F- CH ₃ (CH ₂ J ₄ CO- Cl- Cl- XT- " - (CH ₂ J ₅ - CH ₃ CO- F- Cl- W— - (CH ₂ J ₅ - (CH ₃ J ₃ CC0- F- Cl- CH ₃ O- - (CH ₂ J ₃ - V ^ ti o ¹ ^ "O ^ ¹ ^ F- Cl- CH ₃ O- - (CH ₂ J ₃ - CH ₃ CO- CH ₃ Cl- Cl- - (CH ₂ J ₃ ~ CH ₃ CO- F- Cl- Cl- - (CH ₂ J ₃ - CH ₃ (CH ₂ J ₃ CO- F- Br- H- - (CH ₂ J ₄ - CH ₃ CO- _F - Br- CH ₃ O- - (CH ₂ J ₂ - (CH ₃ CH ₂ J ₂ CHCO- F- Br- CH ₃ O- - (CH ₂ J ₃ - CH ₃ CH ₂ CH (CH ₃ ) CO- F- Br- F- - (CH ₂ J ₃ - CH ₃ CO- F- Br- Cl- - (CH ₂ J ₂ - (CH ₃ ) ₂ CHCH ₂ CO- TU * - · CH ₃ - Cl- - (CH ₂ J ₅ - CH ₃ CO- H- CHn "" Cl- - (CH ₂ J ₃ - CH ₃ CO- CH ₃ CH ₃ - Cl- - (CH ₂ J ₃ - (CH ₃ ) ₃ CCO- CH ₃ CH ₃ - F- - (CH ₂ J ₃ - CH ₃ (CH ₂ ) ₂ C0- F- CH ₃ - CH ₃ O- - (CH ₂ J ₃ - CH ₃ CO- F- CH ₃ - CH ₃ O- - (CH ₂ J ₄ - CH ₃ CO- p- CH ₃ - CH ₃ O- - (CH ₂ J ₄ - CH ₃ CH ₂ CO P- CH ₃ - Η— - (CH ₂ J ₃ - CH ₃ CO- CHg CH ₃ - W— - (CH ₂ J ₃ - (CH ₃ J ₂ CHCO- CH ₃ H- CH ₃ O- - (CH ₂ J ₃ - CH ₃ CO- F- PT— CH ₃ O- - (CH ₂ J ₃ - CH ₃ CO- Cl-
V H- F- - (CH ₂ J ₂ - CH ₃ (CH ₂ J ₄ CO- CH ₃ H- F- - (CH ₂ J ₅ - CH ₃ (CH ₂ J ₂ CO- H- H- Cl- - (CH ₂ J ₅ - CH ₃ CO- TT ₁₁₁ 5098A7 / 1120

25U084

X Z H- Cl- H- Cl- H- Cl- and

- (CH ₂ J ₃ -

- (CH ₂ ) 3-

CH ₃ CO-CH ₃ CH ₂ CO- (CH ₃ ) ₃ CC0-

X Z Ά ^Λ 1 γ F- F- - (CH ₂ J ₃ - CH ₃ CH ₂ CO- F- F- F- - (CH ₂ ) ₃ - (CH ₃ J ₃ CCO- F- F- F- - (CH ₂ ) ₄ - CH ₃ CO- CH ₃ F- Cl- - (CH ₂ ) ₃ - CH ₃ CO- Cl- F- CH ₃ O- - (CH ₂ J ₂ - (CH ₃ ) ₂ CHCH ₂ CO- F "" F- CH3O- - (CH ₂ ) ₅ - CH ₃ CO- H- F- H- - (CH ₂ ) ₃ - CH3CO- F- F- H- - (CH ₂ J ₃ ) - (CH ₃ CH ₂ ) ₂ CHC0- F "* Cl- F- -CH ₂ - CH ₃ CO- Cl- Cl- F- - (CH ₂ ) ₃ - CH ₃ CO- Cl- Cl- - (CH ₂ J ₃ - CH ₃ (CH ₂ J ₂ CO- CH ₃ Cl- H- - (CH ₂ J ₃ - CH ₃ CO- F- Cl- H- - (CH ₂ J ₅ - CH ₃ (CH ₂ J ₃ C0- F- Br- Τ? - - (CH ₂ J 3 ~ (CH ₃ CH ₂ J ₂ CHCQ F- Br- H- - (CH ₂ J ₄ - CH ₃ CH ₂ CO- F- 5098Α7 / 1 120

Br- CH ₃ O- - (CHo) -J- CH ₀ CO- F-

Br- Cl- - (CH ₂ ) ₂ - CH ₃ (CH ₂ ) 4CO- F-

CH ₃ - Cl- ~ ( ^CH 2 ^ 3 ~ CH ₃ CO- CH ₃ -

CH ₃ - Cl- - (CH ₂ J ₅ - CH ₃ CO- «H-

CH ₃ - F- - (CHo) ₀ - (CH-,) ,, CCO- F- j

CH ₃ - CH ₃ O- - (CHoJo- (CH ₀ JnCCO- F-

CHo- CH ₀ O- - (CHo) λ ~~ CH ₀ CO- F-

CH ₃ - H- - (CH ₂ J ₃ - CH ₃ CO- CH ₃ - j

H- ^CH 3 ° ~ - (CHoJo- CH-JCHoCH (CHo) CO- F-

H- CH3O-

H- F-

H- F-

H- Cl- - (CHo), - CH0.CO- ΓΗ- Cl-H- Cl-

Example 15

8-fluoro-5- (P-fluorophenyl) -2-ethyl-1,2,3,4-tetrahydro-Y- carboline hydrochloride (I: X and Z = F; η - 2 and R = ^C ₂ ^H 5 ^

A. 8-fluoro-5- (p-fluorophenyl) -2-acetyl-1,2,3,4-tetra hydro-Y-carboline (V: X and Z = F and R ¹ = GH,)

To a solution of 1.4 g (4.9 millimoles) of 8-fluoro-5- (p-fluoro = phenyl) -1,2,3,4-tetrahydro- "y-carboline in 10 ml of methylene chloride, which is cooled in a bath, 1.49 g (5.4 Millimoles) of triethylamine are added and the solution is stirred for 5 minutes. With stirring, 423 mg (5.4 millimoles) of acetyl = Chloride dissolved in 5 ml of methylene chloride, and the remainder

(CH ₂ ) 2- CH ₃ CO- (CH ₂ ) ₂ - CH ₃ (CH ₂ J ₄ CO- (CH ₂ ) 3- CH ₃ CO- (CH ₂ ) ₅ - CH ₃ CO- (CH ₂ J ₃ - (CH ₃ J ₃ CCO- (CH ₂ J ₃ - (CH ₃ J ₃ CCO- (CHo / A ~~ CH ₃ CO- (CH ₂ J ₃ - CH ₃ CO- (CH ₂ J ₃ - CH ₃ CH ₂ CH (CH ₃₎ C (CH ₂ J ₃ - CH ₃ CO- (CH ₂ J ₂ - CH ₃ CO- (CH ₂ J ₄ - (CH ₃ CH ₂ J ₂ CHCO- (CH ₂ J ₃ - CH ₃ CO- (CH ₂ J ₃ - CH ₃ (CH ₂ J ₂ CO- (CH ₂ J ₃ - CH ₃ (CH ₂ J ₄ CO-

509847/1 120

_ ^ 25H084

action is stirred for 1 hour at room temperature. The mixture is then decanted into 75 ml of cold, saturated sodium bicarbonate solution and then extracted three times with 50 ml of methylene chloride each time. The combined extracts are backwashed with saturated sodium chloride solution and dried over magnesium sulfate. By removing the solvent under reduced pressure, the product is obtained as a glass-like solid, which crystallizes when triturated with hexane to form a white powder. Yield 1.55 g, mp 150-152 ⁰ C. Analysis;

Ber. for C _1g H ON ₂ F ₂ : C: 69.9; H: 4.9; N: 8.6 ¹⁶ found. C: 69.9; H: 5.3; N: 8.4.

B. 8-fluoro-5- (P-fluorophenyl) -2-ethy1-1,2,5,4-tetra = hydre-Y-carboline hydrochloride

A slurry of 243 mg (6.4 millimoles) of lithium aluminum hydride in 20 ml of diethyl ether and 10 ml of tetrahydrofuran is ^{cooled to 0 to 5 °} C. and treated with 283 mg (2.1 millimoles) of aluminum chloride, whereupon the mixture is stirred in the cold for 30 minutes will. With cooling, 871 mg (2.6 millimoles) of 8-fluoro-5- (p-fluorophenyl) -2-acetyl-1,2,3,4-tetrahydro-γ-car = bclin in 15 ml of tetrahydrofuran in the course of 20 Minutes added dropwise to the metal hydride mixture. When the addition is complete, the reaction mixture is stirred for a further 2 hours and then quenched in water. The ether is separated off and the aqueous phase is extracted again with the same solvent. The combined ether extracts are dried and concentrated to dryness, the crude base being obtained as a semi-crystalline oil in a narrow range of 868 mg. 818 mg of the crude base, dissolved in diethyl ether, are converted into the hydrochloride with hydrogen chloride gas. Yield 848 mg, mp 250-253 ⁰ C. Analysis;

Ber. O, ^ ₁₅ N ₃ F ₂ · HCl-1/2 H ₂ O: C: 63.8; H: 5.6; N: 7.8

Found: C, 63.7; H: 5.5; N: 8.1.

5098A7 / 1120

3 example 16

8-fluoro-5- (p-fluorophenyl) -2-methyl-1,2,3 »4-tetrahydro ~ ycarboline hydrochloride

To 316 mg (8.3 millimoles) of lithium aluminum hydride in 30 ml of tetrahydrofuran are 2.7 g (7.53 millimoles) of 8-fluoro-5- (p-fluoro = phenyl) -2-carbethoxy-1,2,3,4 Tetrahydro-Y-carboline in 65 ml of the same solvent is added dropwise, then the reaction mixture is stirred at room temperature for 2 hours. The reaction is then quenched with 5 ml of water and the mixture is filtered. The filtrate is concentrated in vacuo and the remaining oil is partitioned between benzene and water. The organic phase is separated off, dried over magnesium sulphate and concentrated under reduced pressure to give 2.6 g of a yellow oil. The crude product is chromatographed on a silica gel column with methanol as the eluent, 5 to 10 ml of each fraction being collected. fractions 24 to 39 combined earth v /, and concentrated in vacuo to a yellow solid, which yields the hydrochloride g of hydrogen chloride gas in diethyl ether in a narrow ^ "of 1.06, F. 295-297 ⁰ C. analysis:

Ber. for S ₁₃ H ₁ gNglg'HCl: C: 64.6; H: 5.1; N: 8.4

Found: C: 64.3; H: 5.2; N: 8.4.

Example 17

Using the process indicated, the following 2-alkyl-1,2,3,4-tetrahydro-T-carboline hydrochlorides are obtained from the corresponding reactants;

X ^ R

509847/1120

Z 18th t ι R. F. ⁰ C 25H084 X H- CH- 281-283 procedure Cl- H- CH- 279-281 Example 16 Br- H- CH ₃ - 250-252 Example 16 F- H- CH ₃ - 247-250 Example 16 H- Η— CH, - 128-13O ⁺ Example 16 CH, - H-
F- CH, -
CH, - 265-266
262-265 Example 16 CH ₃ O- F-
H- Ti 286-283
272-274 Example 16
Example 16 Cl-
Cl- F- 11-C ₃ H ₇ - 276 (2ere.) Example 16
Example 15 F- F- (CH ₃ ) ₃ C (CH ₂ ) ₂ 274-276 Example 15 F- ⁺ free base Example 15 example

Following the procedure of Example 15 or 16, the following 2-alkyl-1,2,3 _f 4-tetra = hydro-7-carbolines are prepared from the corresponding amide or ester:

8-fluoro-5- (p-methoxyphenyl) -2-methyl-1,2,3 »4-tetrahydro-ycarboline (Example 16); 8-chloro-5- (p-methoxyphenyl) -2-methyl-1j2,3,4-tetrahydro-γ-carboline (Example 16); 8-Kethyl-5 ~ (p-r methoxyphenyl) -2-methyl-1,2,3,4-tetrahydro-Y-r.carboline (Example 16); 8-fluoro-5- (p -chlorophenyl) -2-methyl-1,2,3,4-tetra = hydro-f-carboline (Example 16); 8-chloro-5- (p -chlorophenyl) -2-methyl-1,2,3,4-tetrahydro-γ-carboline (Example 16); 8-methyl-5- (p -chlorophenyl) -2-methyl-1,2,3,4-tetrahydro-γ-carbo = lin (example 16); 8-fluoro-5- (p-fluorophenyl) -2-n-butyl-1,2,3,4-tetrahydro-γ-carboline (Example 15); 8-fluoro-5- (p-fluorophenyl) -2-isobutyl-1,2,3,4-tetrahydro-γ-carboline (Example 15); 8-fluoro-5- (p-methoxyphenyl) -2-n-hexyl-1,2,3,4-tetrahydro-γ-carboline

5098A7 / 1120

(Example 15); 8-fluoro-5- (p-chlorophenyl) -2-neopentyl-1,2,3,4-tetrahydro-7-carboline (Example 15); 8-chloro-5- (p-fluorophenyl) -2-ethyl-1,2,3,4-tetrahydro-rY-carboline (Example 15); 8-methyl-5-phenyl-2-n-pentyl-1 ^^ t ^ -tetrahydro-V-carboline (Example 15); and 5-p-methoxyphenyl-2-n-propyl-1,2,3,4-tetrahydro ~ ycarboline (Example 15).

Example 19

8-chloro-5-phenyl ~ 2 ~ methyl ~ 1,2,3 »4-tetrahydro-y-carboline hydrochloride (I. X = Cl; Z = H; η« 2 and R = CH ₅ )

A. 8-chloro-2-methyl-1,2,3,4-tetrahydro-1 ^/> ^ carboline

To 35.6 g (0.2 mol) of p-chlorophenylhydrazine hydrochloride, while cooling in an ice bath, 22.6 g (0.2 mol) of 1-methyl-4-piperidone in 400 ml of ethanol which is saturated with hydrogen chloride gas , admitted. When the addition is complete, the ice bath is removed and the mixture is refluxed for 2 hours and then left to stand cold overnight. 100 ml of ethanol are then added and the precipitate is left to stand at 5 ° C. for 3 hours. Br is then filtered and dried at 50 ⁰ G and 22 mm pressure for several days, yield 11.0 g. The free base is released by treating the hydrochloride with 40% sodium hydroxide solution and extracted with diethyl ether. After removal of the ether, the product is obtained as a brown solid in an amount of 7.3 g, mp 194 ° -196 ° C.

B. 8-Gh.lor-5-phenyl-2-meth.yl-1,2,3,4-tetrahydro-Y-carboline hydrochloride

A mixture of 7.3 g (33.2 millimoles) of 8-chloro-2-methyl-1,2,3,4-tetrahydro-Y-carboline, 18.23 g (0.116 mol) of bromobenzene, 10.4 g ( 0.0364 mol) of cuprous bromide and 4.51 g (0.0364 mole) of sodium carbonate in 125 ml N-methyl-2 "ßyrrolidinon is heated in a nitrogen atmosphere to 9 hours on an internal temperature of 184 ⁰ g. Then the mixture is cooled in 300 ml of water, which contains 30 ml of ethylenediamine and sodium chloride, decant

509847/1120

25U084

and extracted with benzene. The combined extracts are backwashed over with saturated sodium chloride solution
Magnesium sulfate dried and concentrated in vacuo.

The crude product is on a silica gel column with methanol as
Eluent chromatographed while collecting 5 ml fractions. «The elution of the product is followed by thin layer chromatography and the fractions containing the desired material are combined and concentrated to dryness under reduced pressure» The residue is crystallized by trituration with cold ethyl acetate, the yield
is 945 mg, P.-124 - 126 ⁰ G.

The hydrochloride is prepared by treating a methanolic solution of the free base with hydrogen chloride gas to saturation and adding an equal volume of diethyl ether;
F. 281-283 ⁰ C
Analysis:

Ber. for C ₁₈ H ₁₈ N 1 Cl ₂ -HCl: C: 64.9; H: 5.4; N: 8.4

Found: C: 64.6; H: 5.5; N: 8.4.

Example 20

Following the procedure of Example 19, the following 5-aryl-2-alk _v l-1,2,3,4-tetrahydro-Y-carbolines are synthesized from the correspondingly substituted phenylhydrazine and the required 1-alkyl-4-piperidone and halobenzene:

509847/1120

25Η08Α

X Z R. F- F- F- "Κ ¹ - (CH ₃ ) ₂ CH- F- F- (CH ₃ ), C- TP- CH ₃ O- (CHqCHo) «CH—! F- Cl- (CH ₃ J ₂ CH- I F- ~ Cl- CH ₃ (CH ₃ CH ₂ JCH- Cl- Cl- (CH ₃ J ₃ C-: Cl- Cl- (CH ₃ J ₃ C- Cl- F- (CH ₃ J ₂ CH- Cl- F- (CH ₃ J ₂ CH- Cl- H- (CH ₃ CH ₂ J ₂ CH- Cl- H- CH ₃ (CH ₃ CH ₂ ) CH- Br- CH ₃ O- (CH ₃ ) ₃ C- Br- CH ₃ O- (CH ₃ ) ₃ C- Br- CH ₃ O- (CH ₃ CH ₂ J ₂ CH- Br- F- (CH ₃ ) CH- CH ₃ - F- (CH ₃ ) CH- CH ₃ - F- (CH ₃ J ₂ CH- CH ₃ - CH ₃ O- (CH ₃ ) ₃ C- CH ₃ - CH ₃ O- (CH ₃ CH ₂ ) ₂ CH- CH ₃ - Cl- CH ₃ (CH ₃ CH ₂ ) CH- H- Cl- (CH ₃ CH ₂ ) ₂ CH- H- (CH ₃ J ₃ C- H- H- (CH ₃ J ₃ C- FT— · F- H- F- (CH ₃ J ₂ CH- (CH ₃ J ₂ CH- (CH ₃ (CH ₃ CH ₂ ) CH-

509847/1120

Example 21

25U084

5- (fluorophenyl) -2- (3-benzo y lprop.yl) -1,2,3 _? 4- tetrahydro-Y-carboline (I: X and Z = J ?; η = 2; A = - (C

M = -G-; and Y = H)

A » 8-ffluoro-5- (p-fluorophenyl) -2- (3-cyanopropyl) -1,2,3» 4-tetrahydro-Y-carboline

A mixture of 25.0 g (0.038 mol) of 8-fluoro-5- (p-fluorophenyl) -1,2,3,4-tetrahydro-Y-carboline, 13.3 g (0.1232 mol) of bromobutyro = »nitrile , 27.7 g (0.264 mol) of sodium carbonate and 100 mg of potassium iodide in 250 ml of 4-methyl-2-pentanone is refluxed for 2 hours. The reaction mixture is then cooled and poured into an equal volume of water. The solvent phase is separated off and concentrated in vacuo and the oil that remains is taken up in methylene chloride. The solution is washed successively with water and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated under reduced pressure to give 30 g of a reddish oil. A sample of the product in diethyl ether gives the hydrochloride of S ¹ on treatment with hydrogen chloride gas. 234 236 ⁰ C.

B. 8-Fluoro-5- (p-fluorophenyl) -2- (3-benzoylpropyl) -1 «2,3 _> 4-tetrahydro-Y-carboline hydrochloride

Phenylmagnesium bromide prepared under the usual conditions of the Grignard reaction from 4τ8 bromobenzene and 1.1 g magnesium powder is converted into 4.0 g (0.114 mol) 8-I ¹ IuOr-S- (pf luorophenyl) -2- (3- cyanopropyl) -1,2,3,4-th t rahyd roy-carboline was added dropwise in the course of 30 minutes. The reaction mixture is refluxed for 1 hour and then cooled, whereupon the ether is decanted off from the precipitate formed. The residue is washed several times with ether and then

509847/1120

25H084

SO

30 ml of 12fi-oalic acid in sis added. The acidic mixture is refluxed for 1.5 hours, cooled to room temperature and treated with enough 1On aqueous sodium hydroxide solution that the solution becomes basic. The product, which separates out as an oil, is extracted into ether. After removing the solvent, 3.3 g of product are obtained from the extract in the form of the free base. A small sample is transferred to the hydrochloride, F. 203-211 ⁰ C.

If the above procedure is repeated with the corresponding 5-aryl-2-cyanoalkyl ~ 1,2,3,4-tetrahydro-7-earbolin and G-rignard reagent, the ketones of Examples 5-6 and 7 can be prepared in this way.

Example 22

8-.B ¹ IuO r-5- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -3-buteny 17-1,2,3,4-tetrahydro-Y-carbonyl (I; X and Z = g; n = 2; A =) ₂ -; M = -CH = GH-; and Y = F)

A solution of 2.0 g (4.1 millimoles) of 8-j? Luor-5 ~ (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl7-1, 2,3,4-tetrahydro-7'-car = Bolin in 20 ml of ethanol and 50 ml of 6n-3al% acid are 4 hours refluxed, then stirred for several days at room temperature. The precipitate is filtered off and dried, Yield 1.8g. Further purification is carried out by recrystallization from ethanol; F. product 258-259 ° C.

Example 23

Following the procedure of Example 22, starting from the carbolines of Examples S, 9 and 10 following Y-carbolines;

A-CH = CH

S0SP8U / 1120

25U084

Z 51 Y I. X CH ₃ O- A. F- i
F-. F- F- - (CH ₂ J ₂ - F- F- Cl- F- - (CH ₂ ) 2- CH ₃ -! Cl- τ? - F- - (CH ₂ ) ₉ - Cl- F- F- Τ * - - (CH ₂ ) ₂ - T? - F- 3? - F- F- F- Ti ¹ - F- - (CH ₂ J ₂ - H- ί F- F- F- - (CH ₂ J ₂ - P- CH ₃ - F- F- - (CH ₂ J ₃ - H- F- Cl- - (CHo) - F- Cl- CH ₃ O- -CH ₂ - F- Cl- CH ₃ O- -CH ₂ - CH ₃ - Cl- H- -CH ₂ - F- Br- H- -CH ₂ - Cl- Br- CH ₃ O- - (CH ₂ J ₂ - H Br- CH ₃ - - (CH ₂ J ₅ - H- Br- Cl- -CH ₂ - CH ₃ - Cl- -CH ₂ - CH ₃ - F- - (CH ₂ J ₃ - CH ₃ - CH ₃ O- - (CH ₂ J ₄ - CH ₃ - W— -CH ₂ - CH ₃ - CH ₃ O- -CH ₂ - H- CH ₃ O- -CH ₂ - H- F- -CH ₂ - TT- Cl- - (CH ₂ ) ₃ - H- - (CH ₂ J ₃ -

509847/1120

•. 25U084

Example 24

7-? Luoro-4- (p-fluorophenyl) -1,2,3,4-tetrahydropyrrolo / 5, 4-b7-iadoSr-hyd ro chlorine (I: X and Z = ff; η = 1 and R = H )

i: 7-ffluoro-2-carbethoxy-1,2,3,4- tetrahydropyrrolo- / 3,4-b / indcl (I I : X = P)

To a suspension of 5.67 g (0.035 mol) of p-fluorophenylhydrazine hydrochloride and 2.37 g (0.035 mol) of sodium acetate in 200 ml of water, 5.5 g (0.035 mol) of 1-carbethoxy-3- pyrrolidinone was added dropwise in 50 ml of the same solvent. After stirring for 20 minutes, the precipitated hydrazone is filtered off, washed with water and dried, yield 9.0 g. The analysis sample is recrystallized from methylene chloride / hexane, h \ 157 - 160 ⁰ C.

25 ml of 85% phosphoric acid are added to 3.9 g (14.7 millimoles) of this hydrazone; Within 30 minutes, the mixture turns into a semi-solid mass which is treated with a further 10 ml of phosphoric acid, whereupon the mixture is stirred until a uniform brown suspension is obtained. Then the reaction mixture with 2OU ml of cold Wasserjversetzt is, the resulting precipitate is filtered and dried, yield 2.19 g · Recrystallization from ethanol / water gives 1.4 g of the desired product, melting at 248-249 ° 0 · Analysis:

Ber. for G ^ H ^ OgN ^: 0: 62.9; H: 5.2; N: 11.3

Found: C, 62.9; H: 5.3; N: 11.5-

B. 7-.Pluoro-4- (p-fluorophenyl) -2-carbethoxy-1,2,3,4-tetrahydropyrrolo / 5,4-b7indole (III; X and Z = F)

A mixture of 6.6 g (0.028 mol) of 1-fluoro-2-carbethoxy-1,2,3,4-tetrahydropyrrolo / 3,4- ^ b7indole, 8.86 g (0.031 mol) cuprobromide, 3.28 g (0.031 mol) sodium carbonate and 17.2 g (0.098 mol) p-

. 509847/1120

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Bromofluorobenzene in 75 ml of N-methyl-2-pyrrolidinone is boiled on a river for 4 hours. Then the reaction mixture is cooled and poured into a mixture of ice and V / aaser, which contains 40 tablespoons of ethyl amine. The tfeiaisch is extracted with benzene, the benzene extracts are then backwashed with water and saturated sodium chloride solution and dried over magnesium sulfate. Yields 145 ⁰ C - Upon removal of the solvent in vacuo, a gum which when Verreichen with hexane 5.8 g of product as a brown solid, mp 143 is obtained.

jC. 7 - Pluor ~ 4- (p ~ fluorophenyl) ~ 1,2,3,4-tetrahydropyrrolo- / 5,4-b7indole hydrochloride (I; X and Z = F and R «H)

342 mg (0.001 mol) of 7-fluoro-4- (p-fluorophenyl-2-carbethoxy-1,2,3,4-tetrahydropyrrolo / 3 \ 4-b7indole and 1.12 g (0.02 idol) of potassium hydroxide in 20 ml of ethanol and 2 ml of water are refluxed for 24 hours, then the solution is concentrated to a brown gum, the residue is partitioned between ethylene chloride and water, the organic phase is separated off, washed with water and dried over magnesium sulfate solvent gives the product as a brown solid · by dissolving in diethyl ether and treated with an ethereal hydrogen chloride solution to obtain 193 mg of the hydrochloride, mp. 145 - -150 ⁰ C.

Example 25

Following the procedure of Example 24, starting from the corresponding phenylhydrazine, the following 4-aryl-1,2,3,4-tetra »hydropyrrolo / 3» 4-7indoles are obtained in the form of the free bases and hydrochlorides: 7-chloro-4- ( p-fluorophenyl) -1,2,3,4-tetrahydropyrrolo- / 3t 4-j37 ^Z indole; 7-bromo-4-phenyl-1,2,3,4-tetrahydropyrrolo / 5,4-Jt>7-indole; 7-methoxy-4- (p-fluorophenyl) -i, 2,3,4-tetrahydropyrrolo-Z3 ~> 4-] j / indole; 7-fluoro-4- (p-methoxyphenyl) -1,2,3,4-tetrahydro = »pyrrolo / 5,4-jb7indole; 7-methyl ~ 4 ~ phenyl-1,2,3,4-tetrahydropyrro = *

7-fluoro-4- (p -chlorophenyl) -1,2,3,4-tetrahydro =

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pyrrolo / 3 »4-b7indole; 7-fluoro-4-phenyl-1,2,3,4-tetrahydro = pyrrolo / 3 »4-b7indole; 7 _r ühlor-4-phenyl-1, 2,3, .4-tetrahydro pyrrolo = / 3,4-Jo7indol; 7-0hlo.r-4- (p-chlorophenyl) -1,2,3 »4-tetra = hydro pyrrole o / 51 4- ^ 7indole; - · 7- £ rom-4- (p-fluorophenyl) -1 2,3,4-tetrahydropyrrolo / 3 \ 4-b7indole; 7-methyl-4- (p -chlorophenyl) -1,2,3,4-tetrahydropyrrolo / 5f4-_b7indole; 4-phenyl-1,2,3.4-

4- (p-fluorophenyl) -1,2,3,4-4- (p-chlorophenyl) -1,2,3,4-tetrahydropyrrolo / 3 »4-b7indole and 7-chloro-4- (p-methoxyphenyl) -

Example 26

7-fluoro-4- (p-fluorophenyl) -2-methyl-1,2,3 »4-tetrahydropyrrolo- / 3,4-b7indole (I: X and Z = F; η = 1" and R = CH, )

To a mixture AU3 244 mg (6.4 mmol) in 20 ml dry tetrahydrofuran Lithiumaltaminiumhydrid be in nitrogen atmosphere and ¹ Juft5 ¹ ung 234 mg (2.1 millimoles) of aluminum chloride was added at -10 ⁰ C and the resulting reaction mixture is stirred for 30 minutes. Then 2.9 millimoles of 7-fluoro-4- (p- (fluorophenyl) -2-carbethoxy-1,2,3,4-tetrahydropyrrolo- / 5,4-b7indole in 10 ml of the same solvent of the cold solution with stirring After one hour, 5 ml of v / water are added dropwise to quench, the mixture is allowed to warm to room temperature, it is then filtered and the solids are washed with hot tetrahydrofuran dissolving in diethyl ether and addition of saturated hydrogen chloride ether 448 mg of the desired product, mp 160 - 165 ⁰ C yields.

Example 27

If the procedure of Example 26 is repeated starting from corresponding 4-aryl-2-carbethoxy-1,2,3 »4-tetrahydropyrrolo-

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4-_b7indole, the following analogues are obtained:

N-CH.

Cl-Br-

CH ₃ OF-

CH ₃ -

• ^CH 3 ~
P-

P-

Cl-

Cl-

Br-

CH ₃ -

Cl-

CH ₃ O-

P-

H-

Cl-

H-

H-

Cl-

F-

Cl-

H-

F-

Cl-

CH ₃ O-

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Example 28

7-fluoro-4- (pf luo rphenyl) -2- / 5- (p-fluoro rb enzoyl) propyl7-1 , 2,3,4-tetra hydro pyrrolo /; ^ Ab / in dol hydrochloride

0 η

(Ij X and Z = ί ¹ ; η = 1; A = - (CHg) ₅ -; M = -C- and Y = F)

6.02 g (22.2 millimoles) 7-fluoro-4- (p-fluorophenyl) -1,2,3,4-tetrahydropyrrolo / 3 »4-b7indole, 6.7 g (33» 3 millimoles) ^ - Chloropluorobutyrophenone, 4.28 g (23.4 millimoles) of potassium iodide and 7.05 g (66.6 millimoles) of sodium carbonate in 175 ml of dimethylformamide are heated to 90 ° C. for 8 hours and then stirred at room temperature over Racht. The mixture is again heated to 9O ⁰ C, treated with one gram of decolorizing carbon and filtered. The filtrate is poured into ice and water. The suspension is extracted with chloroform and the combined extracts are dried and concentrated, 10.5 g of crude product being obtained. The residue is chromatographed on 200 g of silica gel using 3: 1 diethyl ether / ethanol as the eluent and collecting 30 to 40 ml fractions. The desired product, which is isolated from the fractions 6 to 14 is inserted into the hydrochloride to yield (Yield 1.76 g.) And then recrystallized from acetonitrile-methanol to give 850 mg, melting at 175 - 179 ⁰ C is obtained.
Analysis:

Ber. for Cg ₆ H ₂₁ ON ₂ F ₅ -HCl: C: 66.3; H: 4.7; N: 6.0

Found: C: 65.3; H: 4.7; N: 5.8. Mass spec. Ber. M (free base): 434

Found: 434.

Example 29

The procedure of Example 28 is repeated using the appropriate (γ-haloalkylaryl ketone and 4-aryl-1,2,3,4-tetrahydropyrrolo / 3,4-b7indole according to Example 24 or 25, see above

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the following connections are obtained:

N-A-C

V /

X Z A. y_ F- F- - (CH ₂ J ₂ - F- F- F- - (CH ₂ J ₄ - F- - (CH ₂ J ₃ - H- F- - (CH ₂ J ₃ - CH

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X Z se
A. ■ 25U084
y F- F- - (CH ₂ ) 3- Cl- F- CH ₃ O- - (CH ₂ J ₃ - F- P- F- - (CH ₉ ) - F- P- F- -CH ₂ - Cl- F- Cl- - (CH ₂ J ₃ - F- F- Cl- - (CH ₂ J ₃ - Cl- F- Cl- - (CH ₂ J ₃ - CH ₃ - F- OCH ₃ - - (CH ₂ J ₂ - p- F- OCH ₃ - - (CH ₂ J ₂ - H- F- OCH ₃ - - (CH ₂ ) ₃ - Cl- F- H- - (CH ₂ ) ₃ - F- Cl- F- _ // 1TJ \ _ . F- Cl- F- -CH ₂ - Cl- Cl- F- - (CH ₂ ) ₃ - Cl- Cl- F- - (CH ₂ ) ₃ - CH ₃ - Cl- H- - (CH ₂ J ₃ - F- Cl- H- - (CH ₂ J ₅ - F- Cl- Cl- - (CH ₂ J ₃ - F- Cl- OCH ₃ - - (CH ₂ J ₃ - P-. Cl- OCH ₃ - - (CH ₂ J ₃ - CH ₃ - Br- H- ¹ - (CH ₂ J ₃ -, F- Br- H- -CCH ₂ J ₃ - H- Br- H- - (CH ₂ J ₄ - TP- Br- OCH ₃ - - (CH ₂ J ₂ - F- Br- OCH ₃ - - (CH ₂ J ₃ - F- Br- F- -CCH ₂ J ₃ - Br- Cl- -CCH ₂ J ₂ - F- CH ₃ - Cl- -CCH ₂ J ₃ - CH ₃ - CH ₃ - Cl-
5098 Λ7 / 11 20 H-

251A084

CH ₃ - TP- - (CH ₂ ) 3 "* ^F ~ 4-tetrahydropyrrolo / '5,4-b7indole hydrochloride 1 ; A = - (GH ₂ ), OH
I. CH ₃ - OCH ₃ - (CH ₂ ) ₃ - F- I.
-; M = -GH- and Y = F) CH ₃ - OCH ₃ - - (CH ₂ ) = F; η = CH ₃ - H- - (CH ₂ ) H- OCH ₃ - -CCH ₂ ) H- OCH ₃ - - (CH ₂ ) H- OCH ₃ - - (CH ₂ ) 3 "* ^CH 3 ~ H- OCH ₃ - (CH ₂ ) 3 * ". *" * T-f— Cl- - (CH ₂ ) ₃ - Cl- H- Cl- - (CH ₂ ) 2 " ^CH ₃ - Example 30 ₅ - H- 3 ". ^P - 5- ^H - 7-fluoro-4- (p-fluoro phenyl) -2- / 4- (p-fluorophenyl) -4-hyd roxy- butyl7-1,2,3, (I: X and Z

To a solution of 2.4 g (5.5 milliinol) 7-i ¹ luoro-4- (p-fluoro = phenyl) -2- / 5- (p-fluorobenzoyl) propyl7-1,2,3,4- tetrahydropyrrolo-Z3 »4-, b7indole in 35 ml of dry tetrahydrofuran, which contains 12 ml of ethanol, 1.2 g of sodium borohydride are added in portions over the course of 2 hours. The brownish solution is then concentrated to dryness and the residue is partitioned between water and diethyl ether. The organic phase is separated off, dried over magnesium sulfate and concentrated to dryness in vacuo. The residue is crystallized after conversion to the Hydroehlorid from acetonitrile to give 430 mg of pure product is obtained, melting at 210 to 211.5 ^O ü. A second fraction of 290 mg is isolated from the filtrate, at 203-205 ° G.

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Example 31

The reduction procedure according to Example 30 is repeated with others suitable ketones according to Example 23 or 29 repeated, wherein the following garbinols are obtained:

Cl-Cl-

CH ₃ O

F-

F—

F- "

P- '

F-

Cl-

Cl-

Cl-

CH3O-

CH ₃ O-

CH ₃ O-

H-

F-

AFTER

- (CH ₂ ) ■ 3 " - (CH ₂ ) 3 " - (CH ₂ ) 3 " -CCH ₂ ) 2 " - (CH ₂ ) 4 " -CCH ₂ ) 5 " -CH ₂ - -CCH ₂ ) 3- - CCH ₂ ) 3 " -CCH ₂ ) 3 ~ - (CH ₂ ) 2 ~ - (CH ₂ ) S " - (CH ₂ ) 3 ~ - (CH ₂ ) 3 " -CH ₂ -

- CCH ₂ ) ₃ -

Y

F-

CH ₃ -

Cl-

F-

F-

Cl-

Cl-

CH ₃ -

F-

H-

Cl-

Cl-

F-

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ι Z A. ■ 25H084 X F- -CCH ₂ J ₃ Y Cl- F- - (CH ₂ J ₃ - Cl- Cl- H- -CCH ₂ J ₃ - CH ₃ - Cl- H*- -CCH ₂ J ₅ - F- Cl- Cl- -CCH ₂ J ₃ - F- Cl- CH ₃ O- -CCH ₂ J ₃ - P- Cl- CH ₃ O- -CCH ₂ J ₃ - F- Cl- H- -CCH ₂ J ₃ - CH ₃ - Br- H- -CCH ₂ J ₃ - F- Br- H- -CCH ₂ J ₄ - H- Br- CH ₃ O- -CCH ₂ J ₂ - F- Br- CH ₃ O- -CCH ₂ J ₃ - p- Br- F- -CCH ₂ J ₃ - Br- CH ₃ O- -CCH ₂ J ₃ - F- CH ₃ - CH ₃ O- -CCH ₂ J ₅ - CH ₃ - CH ₃ - F- -CCH ₂ J ₃ - H- CH ₃ O- - (CH ₂ J ₃ - F- CH ₃ - CH ₃ O- -CCH ₂ J ₄ - F- CH ₃ - -CCH ₂ J ₃ - F- CH ₃ - CH ₃ O- - (CH ₂ J ₃ - CH ₃ - H- CH ₃ O- - (CH ₂ J ₃ - F- H- F ~ " - (CH ₂ J ₂ - Cl- H- F- - (CH ₂ J ₅ - CH3- H- Cl- - (CH ₂ J ₃ - H- H- Cl- - (CH ₂ J ₅ - F- W— H-

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Example 3 2

7 ~ fluoro-4- (p- fluorophenyl) - 2 ~ / 4- (p-fluorophenyl) -4-hydroxy = pentyl7-1,2,3,4 ~ tetrahydrop.yrrolo / 3 *, 4 ~ b7indole- hydrochloride

OH t

(I: X and Z = F; η = 1; A = - (CH ₂ J ₅ -JM = -C (GH ₃ ) - and Y = ί ¹ )

One aug 852 mg (6 millimoles) methyl iodide and 144 mg (6 millimoles) Magnesium methyl Grignard reagent prepared in 40 ml of diethyl ether is divided into two equal portions. Half a portion of 500 mg (1.1 millimoles) 7-fluoro-4- (fluorophenyl) -2- / 5- (p-fluorobenzoyl) propyl7 ~ 1,2,3,4-tetrahydro = ground pyrrolo / 5,4- ^ 7'indole hydrochloride in 20 ml of tetrahydrofuran was added and the mixture is stirred for 1 hour. Then the other half of the Grignard solution is added to the mixture and thereafter is stirred for another 30 minutes. Then the business > Poured mixed in ice and water and extracted with ether. the combined ether extracts are dried over magnesium sulfate, concentrated to dryness and the residue is added to 20 g Silica gel using 3: 1 diethyl ether / ethanol as the eluent to collect 3 ml fractions of chromato- graphed. Fractions 10 to 27 are combined and the product thus obtained is converted into the hydrochloride, yield 180 mg

Mass spectrum M ⁺ : 450
Found; 450

Example 33

From methylmagnesium;) odid and corresponding 4-aryl-2-benzoyl = alkyl-1,2,3,4-tetrahydropyrrolo / ^, 4- ^ 7indoles according to the examples 28 and 29, following the procedure of Example 32, the following compounds are obtained:

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X Z A. Y F- Ti ¹ - - (CH ₂ J ₅ - F- F- - (CH ₂ J ₄ - CH ₃ P- P- - (CH ₂ J ₄ - Cl- F- Cl- - CCH ₂ ) 3- F- TP- Cl- - (CH ₂ J ₃ - Cl- F- Cl- - (CHj) ₃ - CH ₃ F- CH ₃ O- - (CHj) ₂ - F- F- CH ₃ O- F- CH ₃ O- - (CHj) ₃ - F- F- CH ₃ O- - (CHj) ₃ - Cl- F- H- - (CHj) ₃ - F- Cl- 'P- -CH ₂ - Cl- Cl- F- - (CHj) ₃ - Cl- Cl- F- - (CH ₂ ) 3- CH ₃ Cl- H- - (CHj) ₃ - F- Cl- H- - (CHj) ₅ - F- Cl- Cl- - (CHj) ₃ - F- Cl- CH ₃ O- - (CHj) ₃ - F- Cl- CH ₃ O- - (CHj) ₃ - CH ₃ Br- ΤΤ · ~ - (CHj) ₃ - F- Br- H-
509847/1 - (CHj) ₃ -
120 ² H-

Z A. 2514084 4-tetrahydropyrrolo / 3 »4-b7indole (I: X and Z = OR ₁
! V = COCH _5Λ and Y = F] _ X H- - (CH ₂ ) ₄ - Y = -GH- where S ₁ Br- CH ₃ O- - (CH ₂ ) ₂ ~ P- . - (CH ₂ ) ₃ -; M = Br- CH ₃ O- - (CH ₂ J ₃ - F- Br- F- - (CH ₂ J ₃ - F- Br- Cl- -CCH ₂ J ₂ - F- Br- Cl- -CCH ₂ J ₃ - . F-. CH ₃ - Cl- - (CH ₂ J ₅ - CH ₃ - CH ₃ - F- - (CH ₂ J ₃ - H- CH ₃ - CH ₃ O- -CCH ₂ J ₃ - F- CH ₃ - CH ₃ O- -CCH ₂ J ₄ - F- CH ₃ - H- - (CH ₂ J ₃ - F- CH ₃ - CH ₃ O- -CCH ₂ J ₃ - CH ₃ - H- CH3O- -CCH ₂ J ₃ - F- H- τ? - - /.OTT% _ Cl- H- P- - CCH ₂ ) ₅ - CH ₃ - H- Cl- - CCH ₂ ) ₃ - H- H- Cl- - CCH ₂ ) ₅ - F- H- H- Example 34 7-ii ^l luor-4- (pf luorpheny3) -2- / 4- (pf luorphenyl) -4-acetoxy = but _f yl7-1t2.3, F ; η = 1; A =

260 mg (3.3 millimoles) acetyl chloride in 10 ml methylene chloride become a cold solution τοη 959 mg (2.2 millimoles) 7-J'luoro-4- (p-fluorophenyl 5-2- / 4- (p-fluorpheQjl) -4-hyd ro xybutyl7-

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1,2,3,4-tetrahydropyrrolo ^ 3 »4-_b7i ^ dol in 30 ml of methylene chloride, that contains 350 mg (4.4 milliisol) of pyridine, added dropwise. After finished The reaction mixture is allowed to be added. clean up Warm up temperature, then stir overnight. The genic is decanted into a cold, saturated aqueous sodium bicarbonate solution and the crude product is washed three times with 50 ml of methylene chloride each time extracted. The combined organic extracts are dried over magnesium sulfate and concentrated to an oil, that when chromatographing on a silica gel column using 1: 1 benzene / ethyl acetate as the eluent gives the purified product.

Example 35

If the procedure of Example 34 is repeated, but with the corresponding Garbinol according to Examples 30 to 33 and. the respective acid chloride or acid anhydride, the following esters are obtained:

X Z A. "1 Y F_ CH ₃ O- - (CH ₂ ) 3- CH3CO- F- F- P- - (CH ₂ ) 3- CH ₃ CH ₂ CO- F-
I. P- - (CH ₂ ) 3- (CH ₃ ) ₃ CCO CH ₃ - TP— » F- - (CH ₂ ) ₃ - CH3CO- Cl- F- τ? - - (CH ₂ ) 4- CH3CO- F- F- Cl- - CCH ₂ ) 3- CH ₃ (CH ₂ ) ₂ C0- Cl- F- XJ-. - (CH ₂ ) 3- CH ₃ CO- P- Cl- F- - (CH ₂ ) 3- (CH ₃ ) ₂ CHCO- F- Cl- F- -CH ₂ - CH ₃ (CH ₂ ) ₄ C0- Cl-!

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X Z A. "1 Y F- F- - (CHj) ₃ - CH ₃ CH ₂ CO- F- F- F- - (CHj) ₃ - (CH ₃ ) ₃ CCO- F- F- F- - (CHj) ₄ CH ₃ CO- CH ₃ F- Cl- - (CHj) ₃ - CH ₃ CO- Cl- F- CH ₃ O- - (CHj) ₂ - (CH ₃ ) ₂ CHCH ₂ CO-. F- F- CH ₃ O- - (CHj) ₅ - CH ₃ CO- H- F- H- - (CHj) ₃ - CH ₃ CO- F— H- - (CHj) ₃ - (CH ₃ CH ₂ ) ₂ CHC0- p- Cl- F- -CHj- CH ₃ CO- Cl- Cl- F- - (CHj) ₃ - CH ₃ CO- Cl- Cl- F- - (CHj) ₃ - CH ₃ (CH ₂ ) jCO- CH ₃ Cl- H- - (CHj) ₃ - CH ₃ CO- F- Cl- H- - (CHj) ₅ - CH ₃ (CH ₂ ) ₃ C0- F- Br- H- - (CHj) ₃ - (CH ₃ CH ₂ J ₂ CHCO- F- Br- H- - (CHj) ₄ - CH0CH0CO— F- Br- CH ₃ O- - (CHj) ₂ - CH ₃ CO- F- Br- Cl- - (CHj) ₂ - CH ₃ (CH ₂ ) ₄ C0- F- CH ₃ - Cl- - (CH ₂ ) 3- CH ₃ CO- CH ₃ CH ₃ - Cl- - (CHj) ₅ - CH ₃ CO- H- CH ₃ - F- - (CHj) 3- (CH ₃ ) ₃ CCO- F- CH ₃ - CH ₃ O- - (CH ₂ ) 3- (CH ₃ ) ₃ CCO- F-

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χ Z A. ^R l Y Cl- H- - (CH ₂ ) ₅ - CH ₃ CO-. F- Cl- H- - (CH ₂ ) ₅ - (CH ₃ J ₃ CCO- F- Cl- CH ₃ O- - (CH ₂ ) 3- CH ₃ CH ₂ CO- Cl- CH ₃ O- - (CH ₂ ) 3- CH ₃ CO- CH ₃ Cl- Cl- - (CH ₂ ) 3- CH ₃ CO- F- Cl- Cl- - (CH ₂ ) 3- CH ₃ (CH ₂ ) ₃ CO- F- Br- H- - (CH ₂ J ₄ - CH ₃ CO- F- Br- CH ₃ O- - (CH ₂ J ₂ - (CH ₃ CH ₂ ) ₂ CHC0- F- Br- CH ₃ O- - (CH ₂ J ₃ - CH ₃ CH ₂ CH CCH ₃ ) CO- F- Br- F- - (CH ₂ J ₃ - CH ₃ CO- F- Br- Cl- - (CH ₂ J ₂ - (CH ₃ J ₂ CHCH ₂ CO- F- CH ₃ - Cl- - (CH ₂ J ₅ - CH ₃ CO- H- CH ₃ - Cl- - (CH ₂ J ₃ - CH ₃ CO- CH3 CH ₃ - Cl- - (CH ₂ J ₃ - (CH ₃ ) ₃ CCO- CH ₃ CH ₃ - F- - (CH ₂ J ₃ - CH ₃ (CH ₂ ) ₂ C0- F- CH ₃ - CH ₃ O- - (CH ₂ J ₃ - CH ₃ CO- F- CH ₃ - CH ₃ O- - (CH ₂ ) ₄ - CH ₃ CO- F- CH ₃ - CH ₃ O- - (CH ₂ J ₄ - CH ₃ CH ₂ CO- F- CHrj— H- - (CH ₂ J ₃ - CH ₃ CO- CH ₃ CH ₃ - H- - (CH ₂ J ₃ - CCH ₃ ) ₂ CHC0- CH ₃ H- CH ₃ O- 2 CH ₃ CO- F- H- CH ₃ O- - (CH ₂ J ₃ - CH3CO- Cl- H- F- - (CH ₂ J ₂ - CH ₃ (CH ₂ ) ₄ C0- CH ₃ H- F- \ vfl +) J C CH ₃ (CH ₂ ) ₂ CO- H- H- Cl- - (CH ₂ J ₅ - CH ₃ CO- H- H- Cl- - (CH ₂ J ₃ - CH ₃ CO- F- H- Cl- - (CH ₂ J ₃ - CH ₃ CH ₂ CO- F- H- Cl- - (CH ₂ ) 3- (CH ₃ ) ₃ CCO- F-

509847/1120

C * Z A Example 36 25H084 ^R l X and Z = F; η = 1; and R = - (GH ₂ } ₂ G (CH ₃ ) ₃ ). : J. and Z = F and Y CH ₃ O- - (CH ₂ J ₄ - CH ₃ Co- 7-fluoro ~ 4- (p-fluorophenyl) -2-t-butylacetyl-1,2,3,4- F- X H- - (CH ₂ J ₃ - · CH ₃ CO- tetrahydropyrrolo / 3,4-b7indole (¥ CH--
■ 3 i CH ₃ - CH-jO— - (CH ^) - J- CH ₃ CH ₂ CH (CH ₃ ) CO- -GH ₂ G (GH ₃ ) ₃ ). Τ
ι CH ₃ - CH ₃ O- - (CH ₂ J ₃ - CH ₃ CO- Cl- j F- - (CH ₂ J ₂ - CH ₃ CO- CH ₃ - H- F- - (CH ₂ J ₄ - (CH ₃ CH ₂ ) ₂ CHCO- H- H- Cl- - (CH ₂ J ₃ - CH ₃ CO- F- H- Cl- - (CH ₂ J ₃ - CH ₃ (CH ₂ J ₂ CO- F- H- Cl- - (CH ₂ ) 3- CH ₃ (CH ₂ ) ₄ C0- ^p - ι H- H- 7-fluoro-4- (p-fluorophenyl) ~ 2- (3,3-dimethyl-1-propyl) -1,2, 3.4- tetrahydropyrrolo / 3,4-b7indole hydrochloride (I: A. R «=

To a suspension of 1.0 g (3.7 milliiaoles) of 7- ^ ¹ IuOr-4- (fluorophenyl) -1,2,3,4-tetrahydropyrrolo / 5.4- ^ 7indole in 10 ml of methylene chloride 860 mg of t-butyl acetic acid produced t-butyl acetyl chloride and 10 ml of thionyl chloride (CA 45 »1050 g) in 10 ml of the same solvent are added, then the mixture is heated to steam temperature for 30 minutes. The reaction mixture is then treated with colored charcoal and filtered, and the H ¹ Utrate is concentrated to 5 ml under reduced pressure. The precipitated upon cooling and trituration precipitation, mainly of AusgangsEateril is trated abfil- and dried (231 mg, T ^1. 159 - 174 ⁰ G). When diluting

509847/1120

- ** - 25U084

* 9

of the filtrate with ether, the crude product precipitates in a narrow range of 277 mg, mp 163-174 ° C. Further product in a narrow range of 403 mg, P. 170-174 ° C, becomes dry when the ether filtrate is concentrated obtain.

The crude products are combined and used in the following reaction without further purification.

B. 7-ffluoro-4- (P-fluorophenyl) -2- (3,3-dimethyl-1-propyl) -1,2,3,4-tetrahydropyrrolo / 5,4-b7indole hydrochloride (I: X and Z = F and R = - (CH ₀ )

To a suspension of 133 mg (3 _} 7 millimoles) of lithium aluminum hydride in 5 ml of dry tetrahydrofuran, 630 mg (1.85 millimoles) of 7-fluorine-4- (fluorophenyl) -2-t-butylacetyl-1,2 are slowly added in a nitrogen atmosphere , 3,4-tetrahydropyrrolo / 3,4- ^ 7 ~ indole in 5 ml of the same solvent was added. After stirring for 2 hours at room temperature, the mixture is cooled in an ice bath and the reaction is stopped by adding dropwise water. The tetrahydrofuran is removed in vacuo and the residue is partitioned between 25 ml of water and methylene chloride. The organic phase is separated off, backwashed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue remaining after the solvent has been removed under reduced pressure is dissolved in ether, some insoluble material is filtered off, and diethyl ether saturated with hydrogen chloride is carefully added. The precipitated hydrochloride is filtered and dried, yield 441 mg, m.p. 200-208 ⁰ C. receives Recrystallization from benzene / methylene chloride, 166 mg of the desired product of melting point 222-223 ° C.

Mass spectrum M (free base) calc .: 355

Found: 355.

509847/1120

25H084

Example 37

Repeating the procedure of Example "56 using the appropriate 4-aryl-1,2,3,4-tetrahydropyrrolo / 3,4-b7-indole and acid chloride" gives the following compounds:

NO

F-

F-

F-

F-

F-

F-

Cl

Cl-

CH ₃

Br-

Br-

Cl-

F-

H-

CH ₃ O

H-

F-

nC ₄ H ₉

neo-C5 C ₂ H ₅ HC ₅ H ₁₁ nC ₃ Hy

^C 2 ^H 5 ~

509847/1120

25U084

Example 38

7-ffluoro-4- (p-fluorophen.yl) -2-benzyl ~ 1, 2, 5 »4-te1ira hydro pyrrolo / 5,4-b7indol-hydr oc falorid (I; X and Z = F; η = 1 and R =

A solution of 500 mg (1.63 milliinoles) of 7-fluoro-4- (p-fluoro = phenyl) -1,2,3,4 ~ tetrahydropyrrolo / 3 \ 4-b7indole, 418 mg (2.44 millimoles) Q Bromotoluene and 526 mg (4.08 millinoles) of N, N-diisopropylethylamine in 5 ml of toluene are refluxed 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 then such an amount of ether saturated with hydrogen chloride is added that the product precipitates completely as the hydrochloride (pH 2 to 3). The crude product is _a bf iltriert and dried, yield 658 mg, M, 194-202 ⁰ C. The analytical sample is / diethyl ether recrystallized from acetone, F "224-226 ⁰ C.

Analysis: Ber. for

Example 39

1/8 H ₃ O: C, 69.2; H: 4.9; N: 7, p. Found: C: 69.2; H; 5.0; N: 6.9o

The procedure of Example 38 is followed with the appropriate alkylating agent and corresponding 4-aryl-1,2,3,4-tetrahydropyrrolo- / 3 * »4-b7indole repeated, the following compounds being obtained as hydrochlorides:

AFTER

509847/1120

_Z_ U Ά 25H084 Y I. X P- -CH ₂ - Cl- - !
I. F- F- -CH ₂ " H F- F- . - (CHj) ₃ - F- F— F- - (CH ₂ ) ₅ - Ti ¹ - I.
! F- Cl- -CH ₂ - - F-; F- Cl- - (CHj) 2 ~ Cl- F- Cl- - (CHj) ₄ - H- F- H- - (CHj) ₃ - Tf _mmm F- H- -CHj- Cl- H- - (CHj) ₃ - Cl- j Cl- F- - (CH ₂ ) 3- F-: Cl- F- - (CH ₂ ) ₅ - Cl- I
ί Cl- Cl- -CH ₂ - I.
F- · I Cl- Cl- -CH ₂ - H- ".j Cl- Cl- - (CH ₂ J ₄ - HI Br- F- - (CH ₂ ) ₃ - F- Br- F- -CH ₂ - F- Br- H- -CH ₂ - Br- H- -CH ₂ - CH ₃ - H- - (CH ₂ ) ₂ - CH ₃ - H- - (CH ₂ ) ₃ - Cl- j CH ₃ - F- - (CH ₂ ) 3- H- CH ₃ F- -CH ₂ Cl- CH ₃ F- - (CHj) ₃ - F- H- F- -CHj- H- H- F- - (CH ₂ ) 4- Cl- H Cl -CH ₂ - H- H Cl- - (CHj) ₃ - H- H F- F- H F-

609847/1120

: 25U084

Example 40

7-0'hlor- 4- phenyl-2-i3opropyl-1,2,3,4-tetrahydropyrrolo- / 3,4-b / indole-hydrochloride (I; X = Eq; Z = H; η = 1 and R = i — GH - ")

A) 7-chloro-2-isopropyl-1,2,3 »4-tetrahydropyrroleq- / 3,4 ~ b7indole.

A mixture of 3.56 g (0.02 mol) of p-chlorophenyl hydrazine hydrochloride, 1.64 g (0.02 mol) of sodium acetate and 2.54 g (0.02 ul) of 1-isopropyl-3-pyrrolidinone in 35 ml of water are used for 2 hours touched. The hydrazone which separates out is filtered off, washed with water and dried.

20 ml of 85% phosphoric acid are added to 2.82 g (0.01 mol) of the hydrazone added and the resulting mixture is stirred for several hours, during which time the product precipitates out of solution. The reaction mixture is poured into water, the pH value is raised with dilute sodium hydroxide solution 7 set and the product is filtered off and getrock-f net.

B) 7-chloro-4-phen.yl-2-i3opropyl-1 ₁ 2,3 »4-tetrahydropyrrol0 / 3,4-b7indole hydrochloride

A mixture of 7.8 g (33.2 millimoles) 7-chloro-2-isopropyl-1> 2,3,4-tetrahydropyrrolo / 5,4-b7indole, 18.23 g (0.116 mol) bromobenzene, 10.4 g (0.0364 mol) of cuprous bromide and 4.51 g (0.0364 mole) of sodium carbonate in 125 ml N-methyl-2-pyrrolidinone is heated in a nitrogen atmosphere to 9 hours on an internal temperature of 184 ⁰ g. The mixture is cooled, decanted into 300 ml of water which contains 30 ml of ethylenediamine and sodium chloride and extracted with benzene. The combined extracts are backwashed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.

509847/1120

25U084

The crude product is in a dilicagel-liäiale with methanol as Eluting agent chromatographed to collect 5 ml fractional ions. The. Elution of the product is by thin layer chromatography tracked, 'and the -f'ralrüioneii containing the desired material are combined and reduced Pressure concentrated to dryness. The residue is dissolved in ether and mixed with ether saturated with hydrogen chloride that the hydrochloride precipitates, which then send is purified by recrystallization from ethyl acetate / ether.

Example 4 1

The procedure of Example 40 is repeated starting from the correspondingly substituted phenylhydrazine and the respective i-Alkyl-3-pyrrolidinone and halobenzene, the following are obtained 4-Aryl-2-alkyl ~ 1,2,3 »4-tetrahydropyrrolo / 5» 4-b7indole:

Z Z R. X F- (CH ₃ ) ₂ CH- F- F- (CH ₃ ) ₃ C- F- F- (CH ₃ CH ₂ ) ₂ CH- F- CH ₃ O- (CH ₃ ) ₂ CH- F- Cl- CH ₃ (CH ₃ CH ₂ ) CH F— Cl- (CH ₃ ) ₃ C ~ F- Cl- (CH ₃ ) ₃ C- Cl

5098Λ7 / 1120

25H084

Cl- K f; A = - (CH ₂ ) ₂ - ; M = -GH = GH-; and Y = P). Cl- Cl- F- (CH ₃ ) ₂ CH- Cl- H- (CH ₃ ) ₂ CH Cl- H- (CH ₃ CH ₂ J ₂ CH- Cl- CH ₃ O- CH ₃ (CH ₃ CH ₂ ) CH- Br- CH ₃ O- Br- CH ₃ O- Br- F- Br- F- (CH ₃ ) ₃ C- CH ₃ F- (CH ₃ ) ₃ C- . CH ₃ CH ₃ O- (CH ₃ CH ₂ ) ₂ CH- CH ₃ CH ₃ O- (CH ₃ ) CH- CH ₃ Cl- (CH ₃ ) CH- CH ₃ Cl- (CH ₃ ) ₂ CH- H- H- (CH ₃ ) ₃ C- H- H- (CH ₃ CH ₂ ) ₂ CH- H- F- CH ₃ (CH ₃ CH ₂ ) CH- H- F- (CH ₃ CH ₂ ) jCH'- H- (CH ₃ ) ₃ C- Example 42 (CH ₃ ) ₃ C- (CH ₃ ) ₂ CH- (CH ₃ J ₂ CH- CH ₃ (CH ₃ CH ₂ ) CH- 7-i'luoro-4- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -3-butenyl7- 1,2,3 »4-tetrahydropyrrolo / 5j4-b7indole hydrochloride (I: X and Z =

A solution of 1.9 g (4.1 millimoles) of 7-fluoro-4- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl7-1 »2,3,4-tetrahydropyrrolo

509847/1120

25U084

A-- Ja / indole in 20 ml ethanol and 50 ml 6 ~ n-3alic acid is boiled for 4 hours at the flow and then stirred for several periods at room temperature. The precipitated product is filtered off and dried. Further purification is carried out by precipitation from methanol with diethyl ether. -

Example 43

Follow the procedure of Example 42 using the Garbinols according to Examples 30 and 31, the following pyrrolo-Z?, 4-b7indoles manufactured:

A-CH = CH

509847/1120

Z ν? A. 25 ' 4084 γ I X CH ₃ O- - (CH ₂ J ₂ - F- i F- F- F-! Cl- F- - (CH ₂ J ₂ - CHo-. ί F- F- - (CH ₂ J ₂ - Cl- F- F- F- F- - (CH ₂ ) ₂ - F- F- F- - (CH ₂ ) ₂ - F- F- - (CH ₂ J ₃ - F- F- F- - (CH ₂ ) ₄ - F- F- Cl- -CH ₂ - F- Cl- CH ₃ O- -CH ₂ - F- Cl- CH ₃ O- -CH ₂ - Cl- Cl- H- -CH ₂ - F- Br- H- - (CH ₂ ) ₂ - F- Br- CH ₃ O- - (CH ₂ ) ₅ - F- Br- CH ₃ - -CH ₂ - F- " Br- Cl- -CH ₂ - CH ₃ - 3 * " Cl- - (CH ₂ ) ₃ - H- CH ₃ - F- F- CH ₃ - CH ₃ O- -CH ₂ - F- CH ₃ - H- -CH ₂ - CH ₃ - CH ₃ - CH ₃ O- -CH ₂ - F- H-. CH ₃ O- -CH ₂ - Cl-. H- - (CH ₂ ) 3- H- H- Cl- - (CH ₂ J ₃ - H- H-

S098A7 / 1120

Example 44

S-ChI o r-5- (pf Ιυο rph en.yl ) ~ 2 ~ / 4 * - (pf luo rphenyl) -i -hydroxy = butyl / -1,2,3t 4-tet rahjdro-T ~ carb oline acetate

5 g of S-chloro-5- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) ~ 4-hydroxy = butyl / -1,2,3,4-tetrahydro-T-carboline-hydrocalcrid in 75 ml Water with 3 nl water, ci & s contains 1.0 g sodium hydroxide, treated, then the base released is extracted into 150 ml of diethyl ether. The ether phase is separated over Magnesium sulfate dried and treated with 1 ml of glacial acetic acid. Organic solvent and excess acetic acid will be removed at reduced pressure and the residue is with Triturated hexane and filtered off.

Example 45

8-chloro-4- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) ~ 4-n-hydroxybutyl / ~ 1,2,3,4-tetrahydropyrrolo / 3, 4-b / irtdol acetate

5 g of 8-chloro-4- (p-flu (? Rphenyl) -2- / 4- (p-fluorophenyl) -4-hydroxy = butyl / -1 ^^^ - tetrahydropyrrolo / Ü », 4-.b7indole hydrochloride in 75 ml of water are treated with 3 ml of water, which 1.0 g Contains sodium hydroxide, and the released base is in 150 ml of diethyl ether extracted. The ether layer is separated off, dried over magnesium sulfate and mixed with 1 ml of acetic acid treated. Organic solvent and excess acetic acid are removed under reduced pressure and the residue is triturated with hexane and filtered off.

In the same way, other acid addition salts, in particular pharmaceutically acceptable oil salts.

Test procedure and results

The effect of the compounds according to the invention on clear, Amphetauin-induced symptoms were studied in rats using a rating scale similar to that of

509847/1120

25H084

Quinton and Halliwell and -Veissman had been modeled. Groups of 5 each were placed in covered plastic cages of about 26 by 42 by 16 cm. After a short acclimatization period in the cage, the hats of each group were treated intraperitoneally with the test compounds. Then they received. after 1.5 and 24 hours, d-amphetamine sulfate in an amount of 5 mg / kg by the intraperitoneal route. An hour after. Administration of the amphetamine, the hats were observed with regard to the characteristic amphetamine behavior, which is expressed by walking around the cage. Based on the dose-dependent effect after amphetamine administration could be the effective dose of the test compound to totagonisieren / or blocking of the characteristic Amphe- tamin behavior is required for 50fo the tested rats determined (ED ™). The evaluation time coincides with the peak effect of the amphetamine, which occurs after 60 to 80 minutes after treatment with this agent.

Using the above procedure, the following compounds were tested for their ability to block amphetamine behavior, the results being expressed as ED ^ ₀ in mg / kg at the indicated time:

509847/1120

Z R. l _; 0-3.2 5 Stft mg./kg. F- CH ₃ - 3 _; 2-10 - 24 ^ Ji. F- H- CH ₃ - 1.0-3.2 - - F- F- CH ₃ - 3.2-10 - - Cl- CH ₃ - 3.2-10 - - Br- H- CH ₃ - 3 _T 2-10 - - Cl- F- c ₂ % - 3.2-10 > 10 - F- F- ! 1-C ₃ H ₇ - 1.0-3.2 > 10 > 10 F- F- (CH ₃ ) ₃ C (CH ₂ ) ₂ - 3 _f 2-10 > 10 > 3.2 F- F- C ₆ H ₅ CH ₂ - 3.2-10 > 10 > 10 F- F- P-FC ₆ H ₄ CH = CH- (CH ₂ ) ₂ - 3, 2-10 1.0-3.2 > 10 F- F- O
Il
P-FC ₆ H ₄ C (CH ₂ ) ₃ - > 10 > 3.2 F- OH 0, l-0 _? 32 —__ F- P-FC ₆ H ₄ CH (CH ₂ ) ₃ - - Cl- OH 1.0-3.2 ... F- P-FC ₆ H ₄ CH (CH ₂ ) ₄ - 10-32 1.0-3.2 F- H- CH ₃ - > 32 > 3 _; 2 H- H- CH ₂ C ₆ H ₅ - 3.2-10 H- H- C ₂ H ₅ - Cl-

509847/1120

X Z

Cl- F-

OH

P-CH ₃ C ₆ H ₄ CH (CH ₂ ) 3-

F- OCH ₃ - P _- -FC ₆ H ₄ C (CH ₂ ) ₃ ~

OH

P- OCH ₃ - P-FC ₆ H ₄ CH (CH ₂ ) ₃ -

0 ι

ρ_ ρ_ P-CH ₃ C ₆ H ₄ C (CH ₂ ) ₃ -

CH ^, t ^J

P- P- P-FC ₆ H ₄ -C- (CH ₂ ) ₃ -

OH

OH ι

F-P-P-FC ₆ H ₄ CH- (CH ₂ ) ₂ -chlorpromazine

F- P-

C ₆ H ₅ C- (CH ₂ ) ₃ -

ED

50

_; mg./kg

4084

οία. 5 ίϊ

24

1-3.2

1-3,

3 _; 2-10 1-3.2 1-3.2> 3.2

3.2-10

1 ■ ^ED 50; mg. Ag. 24 3. 7th XZ R 3 a.td .. 5 hrs. - F- F- CH ₃ , 2-5.6 10 • OH - F-F-P-FC ₆ H ₄ CH (CH ₂ ) ₃ ~ 1-3.2 1-3.2 Chlorpromazine > 10

609847/1120

- «£ - 25H084

Tablets

A tablet base is made by mixing the following ingredients manufactured:

Cane sugar U.3.P ..-............. 80 _s 3 wt. ^

Tapioca starch 13.2 wt.> $

Magnesium stearate. 6.5 Gewo ^ o

With this tablet base, such an amount of 8-]? Luo r-5- (p ~ fluorophenyl) -2- / 4- (pf luo rphenyl) -4-hydroxybutyl7-1,2,3,4 ~ tetrahydro- "y-carboline hydrochloride is mixed so that tablets containing 1.0, 2.5, 5 _s 0 or 10 mg of active ingredient per tablet are obtained. The resulting mixtures are compressed in a conventional manner to tablets of 360 mg each

A tablet base is made by mixing the following ingredients manufactured:

Cane Sugar, U.S.P .....-.- $ 80.3 wt

Tapioca starch 13.2 wt

Magnesium stearate 6.5 wt

Such an amount of S-Pluor-4- (p-fluo phenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl7 ~ 1,2,3,4-tetrahydropyrrolo / 5,4- ^ 7indole hydrochloride incorporated, that tablets with 2.0, 5.0, 10.0 and 20.0 mg of active ingredient per tablet are obtained. The respective mixtures are in conventional compressed into tablets weighing 360 mg each.

Capsules

A mixture is made from the following components:

Calcium Carbonate U.S.P 17.6 mg

Dicalcium phosphate 18.8 mg

Magnesium Trisilicate, U.S.P .... 5.2 mg.

509847/1120

For this jerr.i ^ cn weii a sufficient i.en ^ G 8 — Ghlor-4— (p-f luu rphenyl) -2- / 4- (p-f υο rphenyl) -4-hydroxy butyl / -1,2,3,4-tetrahydropyrrolo / 3 »4-_b7inJol hydrochloride added, so that capsules with .2.0, 5.0, 10.0 and 20.0 mg IYi rk st off per capsule receives. The resulting mixtures are in an amount of 350 mg per capsule filled into hard gelatin capsules.

To the. The above basic gem also becomes a sufficient amount 8-chloro-5- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl7-1,2,3,4-tetrahydro-γ-carboline hydrochloride Issued so that ran Kapnein with 1.0, 2.5, 5.0 and 10 cig of active ingredient per capsule receives. The resulting mixtures are in a close range of mg per capsule filled into standard hard gelatin capsules.

ouspension

An S-fluoro-5- (p-fluorophenyl) -2- / 4- (p-tolyl) -4-hydroxybutyl 7 Suspension containing 1f2,3,4-tetrahydro-Y-carboline-3ulfate is made from the following components:

Active ingredient 25.0 g

70 ?; watery Sorbitol 741.29 g Glycerin, U.3.P. 185.35 g

Gum acacia (i05o ige

Solution) 100.00 ml

Polyvinylpyrrolidone 0.50 g of distilled water per 1 liter.

Sweeteners and flavorings are added to this suspension in order to improve the taste. The suspension contains approx. 25 mg active ingredient per milliliter.

According to the above formulation, a suspension of 3-fluorine-4- (p-fluorophenyl) -2 - /? - (p-tolyl) -4-hydroxybutyl7-1,2,3,4-tetrahydropyrrolo / 3,4-b7indole- sulfate manufactured. Sweeteners and flavorings are added to this suspension.

509847/1120

The suspension contains approx. 25%. active ingredient per milliliter.

Injectable preparation

Sesame oil is ^{sterilized at 12O 0} G for 2 hours, too. Powdered 8-fluoro-4 - (pf luo rphenyl) -2- / pf luo r = phenyl) -4-hydroxybutyl / -1, 2,3j 4-tetrahydropyrrolo / 3, 4-b7-indole hydrochloride is added to this oil added in such i ^ tight that a suspension with 0.025 wt. ^ active ingredient is obtained. The solid is carefully dispersed in the oil with a colloid mill. It is then sieved through a sieve with a mesh size of 0.15 to 0.063 mm, the suspension is filled into ampoules and these are sealed.

Sesame oil is sterilized as described above, then powdered 3-fluoro-5- (p-fluorophenyl) -2- / 4- (p-fluorophenyl) -4-hydroxybutyl7-1,2,314-tetrahydro-γ-carboline hydrochloride is made added in such an amount that a suspension containing 0.025% by weight of active ingredient is obtained. The solid is made with a colloid mill thoroughly dispersed in oil, then the dispersion is sieved through a sieve with a mesh size of 0.15 to 0.063 mm, filled into sterile ampoules and these are sealed.

509847/1120

Claims (1)

Claims Indole compound of the formula
X 25H084 and their pharmaceutically acceptable acid addition salts, where X is fluorine, chlorine, bromine, the methyl group or hydrogen, Z is fluorine, chlorine, the methoxy group or hydrogen, η is the number 1 or 2 and R is an alkyl radical having 1 to 6 carbon atoms, the benzyl radical or a substituted one Alkylene radical of the formula -AT THE represent, in which A is an alkylene radical having 1 to 5 carbon atoms, M one of the groupings OR OR -CH = CH- Il I 'L _x -CH ₉ -, -C-, -CH- or -C (CH,) -, where R _{1 is} hydrogen or an alkanoyl radical having 2 to 5 carbon atoms, and Y is fluorine, chlorine, methyl or hydrogen, with the proviso that when Z is hydrogen, hydrogen and η is the number 2, X is fluorine, chlorine, bromine or methyl means. 5098A7 / 1120 Compound according to claim 1, characterized in that Ζ Fluorine, X fluorine, chlorine, bromine, hydrogen or the methyl group, η the ^ ahl 2 and K a substituted alkylene- rest of the formula -AT THE represent. Compound according to Claim 1, characterized in that X is fluorine, η the 2 _a hl 1 and R is a substituted alkylene radical of the formula -AT THE represent, in which A is an alkylene radical having 1 to 5 carbon atoms, M is a remainder of the formula -CH- or -C (CH ₃ ) -, wherein R * is hydrogen or alkanoyl having 2 to 5 carbon atoms and Y is fluorine, chlorine, the methyl group or hydrogen. 4 «compound according to claim 2, characterized in that X is fluorine, A _n - (CH ₂ ) ₃ -, M -C- and Y is fluorine. 5. A compound according to claim 1, characterized in that 509847/1120 25U084 * i X and Z fluorine. /: represents the substituted alkylene radical, wherein A- _OR . ■ ■ - (CH ₂ ) -, - and ti -GH-, v / obei R _{1 is} hydrogen and Y is fluorine. 6. A compound according to claim 2, characterized in that X is fluorine, _OR A - (CH ₂ J ₅ -, M -CH-,
wherein H _{1 is} hydrogen and Y is hydrogen. 7. A compound according to claim 2, characterized in that X is fluorine, OH ₁ A - (CH ₂ ) ₅ -, M -CH-,
wherein R- is hydrogen and Y is chlorine. 3. A compound according to claim 2, characterized in that X is fluorine, OR ₁ A - (CH ₂ ) ₅ -, M -CH-,
wherein R- is hydrogen and Y is methyl. 9. Connection according to - "- claim 1> characterized in that X and Z represent fluorine and R represents the substituted alkylene radical ^ where A OE ₁ - (CH ₂ ) "" and M -CH-,
where R _{1 is} acetyl and Y is fluorine. Connection according to claim 2, characterized in that 509847/1 120 25U084 ie X fluorine, _0R A - (0H ₂ ) ₂ -, M -OH-, wherein R _{1 is} hydrogen, - and X is fluorine 11. A compound according to claim 2, characterized in that X fluorine, A OK - (GH ₂ ) ₄ -, M -CH-,
wherein R _{1 is} hydrogen and Y is fluorine. 12. A compound according to claim 1, characterized in that X and Z represent fluorine, and R represents the substituted alkylene radical, where A - (GH ₂ ) ₅ - and M -C (GH ₃ ) -, where R _{1 is} hydrogen and Y is fluorine. 13 · Connection according to claim 2, characterized in that X fluorine, A - (GH ₂ J ₂ -, M -CH = CH-
and Y meant fluorine 14. A compound according to claim 3, characterized in that Z is fluorine, A - (CHg) ₃ -, M -C (CH ₃ ) -, where R _{1 is} acetyl and Y is fluoro. 509847/1120 25UQ84 15 »compound according to ü-naprucli 2, characterized in that X chlorine, ₀ Il A - (GH ₂ ), -, M -Crt- and Y is fluorine. 16. A compound according to claim 2, characterized in that Chlorine, OR ₁ A - (CH ₂ ) ₃ -, M -CH-,
wherein R ^ is hydrogen and Y is fluorine. 17 · Compound according to claim 2, characterized in that X is chlorine, A ~ (CH ₂ ) ₃ -, M -C (CH ₃ ) -, where R _{1 is} hydrogen and Y is fluorine. 13. A compound according to claim 2, characterized in that X bromine, q Il A - (CH ₂ ), -, M -C-
and Y is fluorine. 19 · Compound according to claim 2, characterized in that X is bromine, _QR A ~ (CH ₂ ) ₃ -, M -CH-,
wherein R _{1 is} hydrogen and Y is fluorine. 20. A compound according to claim 2, characterized in that X the L 'ethyl group « 509847/1120 25H084 A - (CH ₂ J ₃ -, K -C-rind Y Zluor means * 21. A compound according to claim 2, characterized in that ■ Σ the methyl group, 1
A - (GH ₂ ), -, M -GH-, where R .. Y / ass is only off, and Y is fluorine. 22. A compound according to claim 1, characterized in that Z is the methoxy group, X is fluorine and R is a substituted one Alkylene radical of the formula -AT THE represents. 23 · Connection according to claim 22, characterized in that A OR ₁ I ¹ - (CH ₂ ) ₃ -, M -CH-,
wherein R _{1 is} hydrogen and Y is fluorine. 24 · Connection according to claim 22, characterized in that dai3 A .- (CH ₂ ) ₃ -, M -CH-,
wherein R _{1 is} hydrogen and Y is methyl, 509847/1120 ' 25U084
Bi 25. A compound according to claim 22, characterized in that ^A OR ₁ - (CH ₂ ) ₅ -, M -GH-, where H _{1 is} hydrogen and Y is chlorine « 26 * connection according to claim 1, characterized in that
Z is fluorine, η is the number 2 and R is the benzyl radical or an alkyl radical with 1 to 6 carbon atoms. 27 · Connection according to opposition 26, characterized in that X is fluorine and R is the benzyl radical. 28 «Compound according to claim 26, characterized in that X denotes fluorine and R denotes the methyl radical. 29 · Connection according to claim 26, characterized in that X is fluorine and R is the ethyl radical. 30. A compound according to claim 26, characterized in that X denotes fluorine and R denotes the n-propyl radical. 31. A compound according to claim 26, characterized in that X denotes fluorine and R denotes 3,3-dimethyl-n-butylre3t. 32. A compound according to claim 1, characterized in that Z is hydrogen, η is the number and R is the substituted alkylene radical the formula represents η <i α L 7/11 ο η '25U084 33 * connection according to claim. 32, characterized in that X A - (GHg) ₃ -, M.-C- and Y means fluorine. 34. A compound according to claim 32, characterized in that _o X is fluorine, A - (CH ₂ ) -, M -GH-, where R _{1 is} hydrogen and Y is fluorine. 35. A compound according to claim 32, characterized in that X is fluorine, OR ₁ A - (GH ₂ J ₃ -, M -G (CH ₃ ) -, where R _{1 is} hydrogen and Y is fluorine. 36. A compound according to claim 32, characterized in that X is chlorine, A - (CHg) ₃ -, M -CH-, where R _{1 is} hydrogen and Y is fluorine. 37. A compound according to claim 32, characterized in that X is fluorine, _OR A - (CHg) ₃ -, M -CH-, where R _{1 is} hydrogen and Y is methyl. 509847/1120 251A08A 3 ^ * compound n ^ ch - «nspruch 52, characterized in that X is chlorine, _0R where R ^ 'is hydrogen and ϊ is Kethyl. 39 · Connection according to claim 1, characterized in that Z is hydrogen, X is fluorine, chlorine, bromine or the methyl group, η is the number 2 and R is an alkyl radical with 1 to 6 carbon atoms represents. 40. A compound according to claim 39 »characterized in that X denotes fluorine and R 'denotes the ethyl group. 41 «Compound according to claim 39», characterized in that X denotes chlorine and R denotes the methyl group. 42. A compound according to claim 39 »characterized in that X is chlorine and R is the ethyl group. 43 · Connection according to claim 1, characterized in that Z is chlorine, X is fluorine, chlorine, bromine or the methyl group, η is the number 2 and R is a substituted alkylene radical of the formula -AT THE represents, in which A is an alkyl radical having 1 to 5 carbon atoms, M the j 1 -CH- group, in which R _{1 is} hydrogen and Y is fluorine, chlorine, methyl or hydrogen. 44. A compound according to claim 43, characterized in that X is fluorine, A - (0H ₂ ), - and Y is x ^ luor. 609847/1120 25H084 45. Compound according to ^ Hprucii 43, characterized in that X is fluorine, A - (GH ₂ ) -, - and Ϊ is chlorine. 46 «Compound according to claim 43, characterized in that X is i? Luor, A - (GH ₀ ) - and Y means hydrogen« ¹ 3 47o connection according to claim 1, characterized in that
R is hydrogen and X, Z and η are those in claim 1
have given meaning. 48 »Connection according to claim 47» characterized in that X means fluorine. 49o connection according to claim 47> characterized in that Z meant fluorine 50 «Connection according to claim 47», characterized in that Z is the methoxy group. 51. A compound according to claim 47, characterized in that Z means chlorine. 52. Compound according to claim 47 »characterized in that . Z hydrogen means « 53. Pharmaceutical preparation, characterized by a
A compound according to any one of claims 1 to 46 and a
Carrier. For: Pfizer Inc. New York, ^ .Y., V.St.A. ι . Dr.H.J.Wolff Attorney at Law