FI68833C - REFRIGERATION FOR THERAPEUTIC USE OF THERAPEUTIC CYLINDER (4.5) PYRROLO (2,3-G) ISOKINOLINER - Google Patents

Description

roi m ANNOUNCEMENT, p Q "Z 7, UTLÄGGNINGSSKRIFT ° ^ ° ° w C (45) Pr.tcr.ni cycrnetty 11 11 1935 (51) Kv.ik.7int.Cl.4 C 07 D 487/04 // ( C 07 D 487/00, C 07 D 209: 00, 221: 00) FINLAND_FINLAND (21) Patent application - Patentansökning 801159 (22) Application date - Ansökningsdag 1 1.04.80 (23) Starting date —Giltighetsdag ^ 04. 8 0 (41) Became public - Blivit offentlig q8 81

Patent and Registration Office ...... ... . . . ,. „.

* (44) Date of issue and date of issue— p-

Patent and registration authorities Ansökan utlagd och utl.skriften publicerad * '.U / .öp (32) (33) (31) Privilege claimed - Begärd priority 28.02.80 USA (US) 125604 (71) F. Hoffmann-La Roche & C/o. Aktiengesel1schaft, Grenzacherstrasse 124-184, Basel, Switzerland-Switzerland (CH) (72) Leo Berger, Montclair, New Jersey, Gary Lee Olson, Westfield New Jersey, USA (74) Oy Kolster Ab (54) Method for Therapeutically Applicable for the preparation of cycloalka / 4,5_ / pyrrolo [2,3-g] isoquinolines 67548

The invention relates to a process according to patent application 793 183 for the preparation of therapeutically useful cycloalkaA, t) 7pyrrolo [2,3-g] isoquinolines of the general formula:

X

li R! -N ....... · - '

>, 1 (CH 2 N A

i

B

having C 1-4 alkyl, C 1-7 hydroxyalkyl, aryl-C 1-4 hydroxyalkyl, C 1-7 alkoxy-C 1-4 alkyl, arylcarbonyl-C 1-6 alkyl; ___ 2,68833 alkyl, aryl-C 1-4 alkyl or C 1-7 alkenyl, X is O or S; and n is 3, 4, 5, or 6, wherein the aryl is phenyl optionally substituted with halogen or C 1-6 alkoxy, for the preparation of optical and geometric isomers of these compounds and pharmaceutically acceptable acid addition salts thereof.

Compounds having the same tetracyclic ring system as compounds of formula A where n is 4 are described, for example, in DE-A-2 UM 3CU and U.S. Pat. No. 3,933,827. These aromatic compounds, which are differently substituted from the present compounds of the present invention have been shown to have antitumor and anti-leukemic or cisostatic activity.

Tricyclic pyrido / 2,3-g7 :! sok inolines and which lack a fused cycloalkane ring and are substituted differently from the compounds of the present application are described in Japanese Kokai Publication No. 76 118 799. The publication states that these compounds have central nervous system stimulating properties.

As used herein, the term "alkyl" means a straight or side chain saturated hydrocarbon, e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. The term "alkoxy" means an alkyl ether group in which the alkyl group is as previously described, e.g., nitro, ethoxy, propoxy, and the like. The term "alkenyl" denotes straight or side chain unsaturated hydrocarbons, e.g. vinyl, allyl and the like. The term "halogen" means halogens, i. bromine, chlorine, fluorine and iodine. The term "aryl" means phenyl or phenyl having one or more substituents which may be halogens or C 1-7 alkoxy groups.

The term "aralkyl" essentially means Bent warts and the like. Examples of arylcarbonyl-C 1-7 alkyl groups include 4- (U-fluorophenyl) -4-oxobutyl and the like. Examples of "C 1-7 hydroxyalkyl" groups include hydroxyethyl, 2-hydroxy-3,3-dimethylbutyl and the like. Examples of "aryl-C 1-7 hydroxyalkyl" groups include β-hydroxy-2-phenylethyl, 2-hydroxy-2- (U-chlorophenyl) ethyl and the like. Examples of "C 1-7 alkoxy-C 1-7 alkyl" groups include 2-ethoxyethyl, 3-methoxypropyl and the like.

3,68833

Preferred compounds of formula A are those wherein n is 3, 4, 5 or 6, is C 1-7 alkyl, C 1-7 hydroxyalkyl, aryl-C 1-7 hydroxyalkyl, C 1-7 alkoxy-C 1-7 alkyl, arylcarbonyl -C 1-7 alkyl or aryl-C 1-7 alkyl; and X is 0 or S.

More preferred compounds of formula A are those wherein n is 3 or 4, R 1 is C 1-7 alkyl, C 1-7 hydroxyalkyl, aryl-C 1-7 hydroxyalkyl, C 1-4 alkoxy-C 1-7 alkyl, arylcarbonyl-C 1-7 alkyl; -alkyl or aryl-C 1-4 alkyl; and X is 0.

The most preferred compounds of formula A of the invention are: 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta A, 5-7pyrrolo / 2,3-g7isoquinolin-10 (10H) one; 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-GH-cyclopenta A, 57pyrroloZ'2,3-g7isoquinoline-10 (10H ) -one hydrochloride, 0,5-molar hydrate *, 2- (2-phenylethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a- trans-6-cyclopentane, 57pyrrolo / 2,3-g7isokinolin-10 (10H) -one; 2- [4- (4-fluorophenyl) -4-oxobutyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta A, 5'-pyrrolo {2,3-g] isoquinolin-10- (10H) -one; (-) - 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [A, 57] pyrrolo [2,3-g] isoquinoline 10 (1 OH) -one; 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa A, 57pyrrolo [2,3-g] isoquinoline 11 (11H) -one; 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa A, 5,7-pyrrolo [2,3-g] isoquinolin-11 (11H) -one, 0.7 5-molar hydrate; 2- (2-phenylethyl) -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa [4,5] pyrrolo] -3 g7isoquinolin-11 (11H) -one; 2-N- (fluorophenyl) -4-oxobutyl_7-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexA, 5_ (pyrrolo) 2,3-g-isoquinolin-11 (11H) -one; and 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [5,5] pyrrolo [2,3-g] isoquinoline- 10 (10H) -thione.

As examples of compounds of formula A wherein n is 3, i.e. of a compound of formula "68833

X

I ------ __

R „—N 2 h I

j.6J /

B

wherein R 1 and X are as previously described are: 2-ethyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [5,7] pyrrolo 2,3-g-isoquinolin-10 (1OH) -one; 2- (2-hydroxyethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [3,5] pyrrolo [1,3-g] isoquinoline-10 ( 10H) -one; 2- (2-hydroxy-2-phenylethyl) -1,2,3,4,4a, S, 7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [5,5] pyrrolo [2,3-g] isoquinoline -10 (logon; 2- (2-ethoxyethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaA, 5.7pyrrolo [2 1,3-g / isoquinolin-10 (10H) -one, 2- (2-acetoxyethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a trans-6H-cyclopenta [alpha], sypyrrolo [1,3-g] isoquinolin-10 (1OH) -one, 2- [3- (4-fluorophenyl) -3-oxopropyl] -1,2,3,4,4a, 5,7,8, 9,10a-decahydro-4a, 10a-trans-6H-cyclopentaA, 57pyrrolo [1,3-g] isoquinolin-10 (10H) -one; 2-C1- (4-methoxyphenyl) ethyl] -1,2,3,4,4a 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ-4,57pyrrolo A, 3-g7 isoquinolin-10 (10H) -one; 2-allyl-1,2,3, 4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [3,5] pyrrolo [3,3-g] isoquinolin-10 (10H) -one; 2-benzyl-1,2 , 3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclo-Penta A> 57pyrrolo [2,3-g] isoquinolin-10 (10H) -one; - (2-hydroxy-3,3-dimethylbutyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaA > 57pyrroloA, 3-g7isokinoliini-10 (10H) -thione; 2- (2-phenylethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [A, 57] pyrrolo [1,3-g] isoquinoline-10 (10H ) -thione; and 2-A- (4-fluorophenyl) -4-oxobutyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaA, 57pyrroloA , 3-g7 isoquinoline-10 (10H) -thione.

Examples of compounds of formula A wherein n is 4, i. of the compounds of formula 6 o 8 3 3 / ϊ'νΐϊ'Ν._, '1 ί1 Η Λ · wherein R and X are as previously described are: 2- (2-hydroxy-3,3-dimethylbutyl) - 2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa-4,5-pyrrolo [2,3-g] isoquinolin-11 (11H) -one; 2- (2-ethoxyethyl) -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 10a-trans-1H, 6H-cyclohexaz * 4, sjpyrrolo [2,3-b] g7isokinolin-11 (IIh) -one; 2-Z3- (4-fluorophenyl) -3-oxopropyl] -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexyl " 4,57pyrrolo [2,3-g] isoquinolin-11 (11H) -one; 2- (2-propenyl) -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a » 11α-trans-1H, 6H-cyclohexa [4,5,5] pyrrolo [2,3-g] isoquinolin-11 (1H) -one; 2-benzyl-2,3,4,4a, 5,7,8,9,10,1la-decahydro-4a, 11a-trans-1H, 6H-cyclohexaZ "H, 5-7pyrrolo [2,3-g] isoquinolin-11 ( 11H) -one; 2- (2-phenylethyl) -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexyl "4, 57pyrrolo [2,3-g] isoquinoline-11 (11H) -thione; 2- [4- (4-fluorophenyl) -4-oxobutyl] -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexyl 4, 57pyrrolo / 2,3-g7 iso-quinoline-11 (11H) -thione.

For compounds of formula A-2 where X is 0, an alternative nomenclature may be used. Thus, e.g. ι Z ”4, fs / pyrroloZ 2,3,3-isoquinolin-11 (11H) -one and 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a 11a-trans-pyrido-Zα, 3-b / carbazol-11 (1H, 6H) -one are one and the same compound.

Examples of compounds of formula A wherein n is 5, i. of compounds of formula x 6 63833 \ I c 'a-3

B

wherein and X are as previously described are: 2-methyl-1,2,3,4,4a, 5,7,8,9,10,11,12a-dodecahydro-4a, 12-trans-6H-cyclohepta / ' 4,5,7-pyrrolo [2,3-g] isoquinolin-12 (12H) -one; 2-N- (fluorophenyl) -4-oxobutyl-1,2,3,4,4a, 5,7,8,9,10,11,12a-dodecahydro-4a, 12a-trans-6H-cyclohepta-4 ?, pyrroloZ 5_ ~ 2,3-g_7isokinolin-12 (12H) -one; 2- (2-phenylethyl) -1,2,3,4,4a, 5,7,8,9,10,11,12a-dodecahydro-4a, 12a-trans-6H-cyclohepta [4,5] pyrrolo [2,3-g] isoquinolin-12 (12H) -one; 2- [4- (4-fluoritenyl) -4-oxobutyl] -1,2,3,4,4a, 5,7,8,9,10,11,12a-dodecahydro-4a, 12a-trans-6H-cyclohepta [4,5] pyrrolo [2,3-g] isoquinoline-12 (12H) -thione; 2- (2-phenylethyl) -1,2,3,4,4a, 5,7,8,9,10,11,12a-dodecahydro-4a, 12a-trans-6H-cyclohepta [4,5-pyrrolo] -2, 3-g_isoquinoline-12 (12H) -thione.

Examples of compounds of formula A wherein n is 6, i. compounds of formula

X

A _. / \ R -N 21 Y 13 | 1 '! 6, j, A-4

^ N

B

wherein and X are as previously described are: 2- [4- (4-fluorophenyl) -4-oxobutyl] -2,3,4,4a, 5,7,8,9,10,11,12,13a- dodecahydro-4α, 13α-trans-1H, 6H-cycloocta [4,5] pyrrolo [2,3-g] iso-quinolin-13 (13H) -one; 2- (2-phenylethyl) -2,3,4,4a, 5,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-1H, 6H-cycloocta / 4, 5_ (pyrrole o) 2,3-g. 7 isoquinolin-13 (13H) -one; 2- (2-hydroxy-3,3-dimethylpropyl) -2,3,4,4a, 1,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-H, 6 H cycloocta / 4,57-pyrrolo / 2,3-g7-isoquinolin-13 (13H) -one; 7,68833 2-methyl-2,3,4,4a, 5,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-1H, 6H-cyclooctaZ, 4,5-pyrrolo 1,3-gioisoquinolin-13 (13H) -one; 2-7,4- (fluorophenyl) -4-oxobutyl-2,2,3,4,4a, 5,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-1H, 6H-cyclo octaZ4, 57pyrrolo72,3-g / isoquinoline-13 (13H) -thione; 2- (2-phenylethyl) -2,3,4,4a, 5,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-1H, 6H-cyclooctaZ4,57pyrrolo / "2,3-g-isoquinoline-13- (13H) -thione; and 2- (2-ethoxyethyl) -2,3,4,4a, 5,7,8,9,10,11,12,13a-dodecahydro- 4α, 13α-trans-1H, 6H-cycloocta [4.57] pyrrolo [2,3-g] isoquinoline-13 (13H) -thione.

The compounds of the invention wherein n is 3 may exist as 4a, 10a-trans or 4a, 10a-cis isomers or mixtures thereof; The 4a, 10a trans isomers are preferred.

The compounds of the invention wherein n is 4 may exist as 4a, 11a-trans or 4a, 11a-cis isomers or mixtures thereof; 4a, 11a trans trans isomers are preferred.

The compounds of the invention wherein n is 5 may exist as 4a, 12a-trans or 4a, 12a-cis isomers or mixtures thereof; The 4a, 12a trans isomers are preferred.

The compounds of the invention wherein n is 6 may exist as 4a, 13a-trans or 4a, 13a-cis isomers or mixtures thereof; The 4a, 13a trans isomers are preferred.

More specifically, compounds of formula A wherein X is 0 are represented by formula 0

II

1 [T Jj i] (CVn I

OF

B

in the form where n and are as previously described and may be prepared as shown and subsequently described in connection with Schemes I, II, m and IV.

8 68833

Reaction Scheme I

OCH., OCH ,,

H 'I Ri I J

_V, L ^ J ^ 'och3 och3 IV v

0 L

, I! n 0 kNnH A, Y "^ V — λ

I + (C, H2> n 'Δ "(CHJ

A / AA A - 7 Aa

O HON or H „N

I VI_ vii viH I

o // 0 r \ h A a. uan ^ jl I 'Π ^ IAn I I I, (OH,) -> ^ aVAh ^

I I

H H

IX la where n is as previously described and R 1 is C 1-4 alkyl or C 1-7 alkoxy-C 1-7 alkyl.

II

9,68833

According to Reaction Scheme I, compounds of formula Ia are prepared from known compounds of formula IV wherein R 1 is C 1-7 alkyl or C 1-7 alkoxy-C 1-7 alkyl. Reduction of Birch using an amine of formula IV with lithium in ammonia-containing t-butanol gives a dihydroamine of formula V. Other variants of Birch reduction may also be useful. Thus, an amine of formula IV may be reacted with an alkali metal such as sodium, lithium, potassium or cesium in ammonia or an amine such as methylamine or ethylamine in the presence of a lower alkanol such as ethanol, butanol or t-butanol. The reaction is generally carried out at or below the boiling point of the solvent, for example, between -78 ° and 15 ° C. If ammonia is used, the reaction is carried out at boiling temperature. Optionally, additional solvents such as diethyl ether or tetrahydrofuran may be added.

The hydrolysis of the dihydroamine of formula V is readily carried out by conventional methods used in the hydrolysis of enol ethers, e.g. with aqueous acid. Examples of useful acids are hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid and perchloric acid. These can be used as aqueous solutions or solvent mixtures. At least two equivalents of water are required per mole of dihydroamine and more than one equivalent of acid. Examples of useful solvents are tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile. For example, hydrolysis of a dihydroamine of formula V wherein R 1 is methyl in 2N hydrochloric acid at room temperature or higher in aqueous acetic acid at a temperature between 50 ° C and boiling point provides a diketone of formula VI wherein R 1 | is methyl.

The diketone of formula VI is condensed using Knorr condensation to give the methyl aminoketone of formula IX. Knorr condensation is a well-known method for preparing pyrroles and can be used in any of the well-known variations, see Model Conditions 10 688 3 3 in J.M., Patterson, Synthesis, 281 (1976) and references therein. For example, the reaction of an isonitroSoketone of formula VII in the presence of a reducing agent, for example with zinc in aqueous acetic acid or hydrochloric acid, is considered to be via an aminocarbonyl compound of formula VIII which then condenses with a diketone of formula VI to give methylaminoethyl ketone of formula IX. product. Alternatively, the condensation may be performed with an aminocarbonyl compound of formula VIII or a precursor thereof, such as an aminoketone hydrochloride salt, or a ketal derivative of an aminoketone. The use of an aminoketone precursor is recommended because such substances tend to self-condense. They are best used in situ if the aminocarbonyl component is released in the presence of a diketone of formula VI. The aminocarbonyl component reacts immediately to form a compound of formula IX. It is not necessary to isolate the diketone of formula VI before carrying out the Knorr condensation because the reaction conditions used are sufficient to hydrolyze the dihydroamine of formula V to the diketone of formula VI. Condensation of Knorr is best performed at a pH between about 2-6. At pH well above 6, the yield loss is considerable due to the formation of self-condensation products of the aminocarbonyl compound of formula VIII.

The isonitrosoketone of formula VII is condensed with zinc dust in aqueous acetic acid using essentially a diketone of formula VI wherein R 1 is methyl to give a methylaminoethyl ketone product of formula IX having methyl.

The condensation of Knorr is carried out mainly at a temperature in the range of about room temperature - Boiling point. The isonitrosoketones of the formula VII are known compounds or can be readily prepared by nitrosation of the corresponding / ketoester, for example with sodium nitrite, see, for example, T.A. Geissman and M.J. Schlatter, J.Org. Chem. 11, 7 71 (1946), /.

Examples of isonitrosoketones of formula VII that can be used in the condensation of KnorrVin include: U 68833 2-isonitrocyclopentanone; 2-isonitrososykloheksanoni; 2-isonitrososykloheptanoni; and 2-isonitrosocyclooctanone.

Examples of aminocarbonyl precursor compounds of formula VIII that can be used in the Knorr condensation include: 2-aminocyclohexanone, hydrochloride; 2-aminocyclopentanone hydrochloride; 2-aminocycloheptanone, hydrochloride; and 2-aminocyclooctanone, hydrochloride.

Said compounds are known or can be prepared by reduction of the corresponding isonitrocoketone, for example by catalytic hydrogenation in the presence of hydrogen chloride.

The amine of formula IX is converted to the compound of formula Ia by utilizing the intramolecular Mannich reaction. The Mannich reaction is usually carried out starting from a ketone and a dialkylamine salt, e.g. dimethylamine hydrochloride and formaldehyde (for example as an aqueous solution, paraformaldehyde or trioxane) in an alcoholic solvent such as ethanol at the boiling point of the reaction mixture. In this variation described, the acid addition salt of a methylaminoethyl ketone of formula IX is reacted with formaldehyde added as paraformaldehyde, trioxane or aqueous formaldehyde in a solvent. In this case, for example, a high-boiling hydroxyl solvent such as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyl ether can be used; a high boiling polar aprotic solvent such as dimethylformamide, N-methylpyrrolidone or diethylene glycol dimethyl ether; a polar solvent having a lower boiling point, such as ethanol, butanol or 2-propanol, under pressure; or a lower boiling point aprotic solvent may be used under pressure, such as dioxane or tetrahydrofuran at a temperature in the range of about 135 ° C to about 200 ° C, to give cycloalkane / 4,5 / pyrrolo / 2,3-g / isoquinolines of formula Ia. In the reaction, especially at temperatures below 150 ° C, a mixture of cis- 6 8 8 3 3 and trans isomers is formed, i.e. for example, when is methyl, compounds of the formulas. ~ ϊλ_ο “‘ TAA Jy! / ”2’1’

H I

trans H

la

O

CH3_1 1 Π ^

H H

cis I "a

Heating the reaction mixture over a long period of time or heating the mixture of isomers of the hydrochloride salts of formulas I'a and I "a separately, e.g. as the predominant isomer, which is readily isolated by crystallization or chromatographic separation.

For example, by reacting the hydrochloride salt of an amine of formula IX wherein R 1 is methyl with paraformaldehyde in butanol at 180 ° for 2 hours, the product is isolated as the trans isomer.

Il i3 6 8 8 3 3

Reaction Scheme II

"K

'J l: | '

/ I

J H

v o C, H.O-C-N k "N-ζ \ 2 3 k ^^ \, A_y: H2> n

XIII, H

N / O

H - -f \ | (CH2) ii XIVa

B

where n is as previously described.

14 68833

The N-demethylation of a compound of formula Ia * can be performed by standard N-dealkylation methods, such as the Braun method / M. A.Hageman, Org. Reactions, 7, 198 (1953) 7, or by hydrolysis with an acid or base of a urethane derivative, e.g. the urethane derivatives listed in K.C. Rice /J.Org.Chem., 40, 1850 (1975) 7. In one process for the dealkylation of a compound of formula Ia ', this is done via a urethane of formula XIII and hydrolysis with an acid to give a secondary amine of formula XIVa. For example, when a compound of formula Ia , a compound of formula XIII wherein n is 4 is obtained. Hydrolysis of the above compound with 30% aqueous sodium hydroxide in ethanol-dioxane at reflux for 24 hours gives a compound of formula XIIIa wherein n is 4.

Reaction Scheme III

0

^ X

H-N '' N

li (CH2) n XIVa i

B

b

V

R1 \ - .., 7. ,, N 'Y Y-ΓΓ I I I li (CH2> n 1

B

wherein n and R 1 are as previously described.

15 638 3 3

According to Reaction Scheme III, compounds of formula I are prepared from a secondary amine of formula XIVa, the starting material used in the preparation of the numerous derivatives of formula I, by placing substituents on the basic amine nitrogen (N-2). For example, treating a compound of formula XIVa with an alkyl halide such as ethyl bromide, an alkenyl halide such as allyl bromide, an aralkylalalide such as benzyl bromide, or an acylalkyl halide such as V-chloro-p-fluorobutyrophenamide in the presence of a base, e.g. potassium carbonate, in the presence of 2 a substituted compound of formula I, i.e. a compound having C 1-6 alkyl, C 1-6 alkenyl, aryl-C 1-6 alkyl or arylcarbonyl-C 1-6 alkyl. When highly reactive halides are used, the reaction can be carried out at room temperature; in the case of less reactive halides, boiling temperatures are used, and, in some cases, the rate of the reaction can be enhanced by adding an iodine salt, such as lithium iodide, to the reaction mixture.

Reaction of a compound of formula XIVa with epoxyalkanes gives a compound of formula I having a hydroxyalkyl substituent. Treatment with a substituted epoxyalkane gives 2-substituted-2-hydroxyalkyl analogs of the compound of formula I; for example, reaction of a compound of formula XIVa with styrene oxide gives a compound of formula I wherein R 1 is 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the presence of an alcoholic solvent such as methanol at a temperature between about room temperature and the boiling point of the mixture. Epoxy alkanes are either available as technical preparations or are prepared by epoxidation of the corresponding olefins, or by coupling methylene to a ketone using a sulfonium methylide or sulfoxonium methyldi reagent, e.g. dimethylsulfonium methylide. Thus, e.g., treatment of benzaldehyde with dimethylsulfonium methylide gives styrene oxide.

In the reactions shown in Reaction Schemes I, II and III, the compounds of formula I as well as the trans isomers of formula 68833 16 R. il «Ytri (rtVn r

H I

B

wherein n and are previously described as cis isomers of the formula H 0

Rj. / LJA

> f | Γ || <CH2> n T "fr v— ^

B

B

wherein n and are as previously described, may be formed such that the trans isomer predominates. The pure trans isomer can be isolated by chromatography or crystallization. In addition, the mixture may be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formulas Iqa and Ia, or by equilibration with a base catalyzed, for example, with sodium hydroxide in ethanol.

17,688 3 3

Reaction Scheme IV

OCH.j 0CH3 R1 - ___ * ^ 0 (: H3 ^ OCH-

IV / X

OCII3 4 -ςΑ xi OCHo / l) - 1 f I 1 4 j, vfjn h / ji 1 fv ,,

X0 _ H2N

XII VII or VIII

ο Γ Λv ^ r | - n y 'N ----- ^ jJv y * 2} n Ia I ^ H 1 where n and R1 are as previously described.

18 6 88 33

An alternative synthesis of compounds of formula Ia is shown in Reaction Scheme IV, in which an isoquinoline ring is formed prior to pyrrole ring formation. According to Reaction Scheme IV, (3,5-dimethoxyphenyl) ethylamine of formula IV is boiled with aqueous formaldehyde to give tetrahydroisoquinoline of formula X. Performing a Birch reduction of a tetrahydroisoquinoline of formula X with lithium in liquid ammonia, including t-butanol, under conditions substantially the same as those described for Birch reduction of a compound of formula IV, a hexahydroisoquinoline of formula XI is obtained. Hydrolysis of the crude hexahydroisoquinoline of formula XI under conditions substantially the same as those described for the hydrolysis of the dihydroamine of formula V gives the diketone of formula XII. The compound of formula XII is reacted using Knorr condensation as described for the preparation of methylaminoethyl ketone of formula IX with an isonitrocoketone of formula VII or an aminocarbonyl compound of formula VIII to give a cycloalkane of formula Ia, 5'-pyrrolois. Preferred is the series of reactions of Reaction Scheme IV starting from an amine of Formula IV wherein R 1 is methyl to give the corresponding N-methyl-cycloalkane / 1, 57-pyrroloisoquinoline of Formula Ia as a mixture of the trans isomer I'a and Formula I " a cis isomer.

The same methods as described previously for the isomerization of a mixture of cycloalca 2, 57pyrrolo.isoquinolines of formulas I 'and I "can be used to give essentially the trans isomer of formula I'a.

Compounds of formula A wherein X is S are represented by formula II

II

19 68833 n JJ ^ y'Vn

B

where n and are as described above.

and can be prepared as shown in Reaction Schemes V and VI and further described later in the following description.

Reaction Scheme V

· '- rrVr ~ -

B

P9S_ L)

V

n, l -.- VS — r- '

'' E H

wherein n is as previously described; and R 1-6 is C 1-7 alkyl, C 1-7 alkoxy-C 1-7 alkyl, aryl-C 1-7 alkyl or C 1-5 alkenyl.

20 68833 T ------------

According to Reaction Scheme V, compounds of formula IIe are prepared by heating compounds of formula Ie with phosphorus pentasulfide in a neutral organic solvent.

Preferred solvents are tetrahydrofuran, benzene, toluene or dioxane, and the reaction is usually carried out at boiling temperature.

which compounds of formula II are prepared as described in connection with Reaction Scheme VI. According to Reaction Scheme VI, a compound of formula XIVb is reacted to give a compound of formula IId, followed by the methods detailed in Reaction Scheme III for the preparation of the corresponding oxo compounds of formula I.

A compound of formula XIVb can be prepared by reacting a compound of formula XIVa with phosphorus pentasulfide in an inert organic solvent.

21 68833

Reaction Scheme VI 0 “nn, / \ A_ ί I I ij (CH ,,) XlVa

B

v S

H ^ I

\ ^ V Ί ~ - JJ ^^ yV ,, XIVb

B

^ • Vw ^ ^ xX ^ x ^ MivJ / H ", n 11

B

wherein n and are as previously described 688 33 These reactions can form compounds of formula II as well as trans isomers of formula H

V

K.J, '' 11 'H Ί1

B

where n and are previously described as cis isomers of formula v -i Ϊ

'COrOH'A

Λ I

H i where n and are as previously described, with the tmns isomer predominating. The pure trans isomer can be isolated by chromatography or crystallization. In addition, the mixture can be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formulas I'a and I "a.

ii 23 68833

The compounds of formula A form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable acid addition salts with both pharmaceutically acceptable organic and inorganic acids, e.g., hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, toluenes of other inorganic acids such as sulfuric acid, acetic acid, alkanoic acid, phosphoric acid, or , benzenesulfonic acid or the like, salts of other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like. The non-pharmaceutically acceptable acid addition salts of the compounds of formula A may be converted into pharmaceutically acceptable acid addition salts by conventional skin reactions, wherein the non-pharmaceutically acceptable anion is replaced with a pharmaceutically acceptable anion; or alternatively, by neutralizing the non-pharmaceutically acceptable acid addition salt and then reacting the free base thus obtained with a reagent which forms a pharmaceutically acceptable acid addition salt. Acid addition salts can also form hydrates.

The compounds of formula A and their pharmaceutically acceptable acid addition salts have a stress-relieving effect. Accordingly, the compounds of formula A are useful as medicaments for the prevention of mental illness, e.g. in the treatment of appendicitis. The potency of the compounds of formula A, which make them useful as drugs for the prevention of mental illness, can be demonstrated in warm-blooded animals according to known methods.

For example, in one method, trained rats are placed in test compartments equipped with a backlash lever, a steel mesh floor for delivering an electric shock, and a speaker for delivering auditory stimuli. Each experiment includes a fifteen-second warning sound, (indirect stimulus), followed by another fifteen seconds, followed by an electric shock (immediate stimulus; 1.0 mA, 350 V.A.C.). Rats can interrupt the experiment at any time from 2-63833 by pressing the reaction lever. The reaction during the first fifteen-second warning sound terminates the experiment before the shock is administered and is considered a avoidance reaction, while the events of the reaction during the shock administration are considered an escape reaction. The experiments are performed every two minutes during the one-hour trial period (30 trials per cycle).

In trained rats, the baseline of avoidance behavior remains reliable (zero to three avoidance errors per cycle). The compounds are administered at appropriate pre-treatment intervals to at least three to four rats per dose level in the dose range. During control periods, rats receive vehicle only. One control and one test period are alternated during each week.

The episode is divided into three consecutive twenty-minute (ten experiments) sections. Reaction rates are summed for all experimental animals that received a given dose during each portion.

The number of experiments in which rats did not show a avoidance reaction (avoidance inhibition; AB) or did not show an escape reaction (escape inhibition; EB) is determined from the part where such an effect is greatest for each dose. This figure is expressed as a percentage of the total number of trials. The dose estimated to cause a 50% avoidance agglomeration (ADB 50) is obtained from a dose-response regression curve made using the least squares method. The lowest dose that causes a 20% escape response (EBD 20) is read from the graphical dose-response curve.

Once these values are obtained, the percentage effect is recorded relative to the logarithm of the dose.

Mental anti-mental drugs are distinguishable from other types of drugs that have an effect on the behavior of rats in this method due to the greater difference between the doses that cause the mapping inhibition reaction and the doses that cause the escape inhibition reaction. The clinical efficacy of anti-mental drugs with known therapeutic uses and properties is significantly and very well correlated with their efficacy in this method.

li 68833

Thus, the compounds of formula A may be used therapeutically in dosage ranges commensurate with their efficacy in the test method.

When 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-depahydro-Ua, 10a-trans-6H-cyclopenta [4,57] pyrrolo [2,3-g] isoquinoline 10 (iGH) onion, a tension-triggering effect is observed at an ABD of 0.98 mg / kg po

In the same manner as 2-Z4 (4-fluorophenyl) -4-oxobutyl-1,2,3,4,4a5,7,8,9,10a-decahydro-4a, 10a-transS '6 H is used as a test substance. - cyclopenta [4,5] pyrrolo [2,3-g] isoquinolin-10 (10H) -one, a tension-triggering effect is observed at 0.15 mg / kg po. o ·

In the same manner as 2- / 4- (4-fluorophenyl) -4-oxobutyl-7-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a -trans'1, 6H-cyclohexane / 4,57pyrrolo [2,3-g] isoquinolin-11 (11H) -one, a stress-triggering effect is observed at ABDj-0.73 mg / kg Ρ · ° ·

In the same manner as 2-methyl-2β, 3,4a, 5,7,8,9,10,11a-decahydro-4α, 11α-trans-1H, 6H-cyclohexa-Z-4,57pynrolo [2], 3-gisoquinolin-11 (11H) -one, hydrochloride, δ 7 5-mol · hydrate, which has given an LD 1 -Q value of, for example, 650 mg / kg po in mice, a tension-triggering effect is observed

ABDr n * n at 5> 5 mg / kg p.o. b U

In the same way as 2-methyl-2,3,4,4a, 5,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-1H, 6H-cycloocta / 4 , 57pyrroloZ2,3-g7isoquinolin-13 (13H) -one, a tension-triggering effect is observed at 8 mg / kg po, with an avoidance of 63%.

In the same way as 2-methyl-1,2,3,4,4a, 5,7,8,9,10,11,12a-dodecahydro-4a, 12a-trans-6H-cycloheptaA, 5'-pyrrolo is used as test substance (2,3-g) isoquinolin-12 (12H) -one, a tension-triggering effect is observed at 16 mg / kg po, with an avoidance of 50%.

The compounds of formula A and their pharmaceutically acceptable acid addition salts have anti-mental effects which are qualitatively similar to haloperidol and trifluoriperazine11a, which are known for their therapeutic use and properties. Thus, the compounds of formula A are consistent in their combination of activity with anti-mental drugs of known potency and safety.

The compounds of formula A and their pharmaceutically acceptable acid addition salts may be used in the form of conventional pharmaceutical preparations. By way of example, suitable oral dosage units comprise or range from 0.05 to 50 mg, and suitable oral dosage regimens for warm-blooded animals comprise or range from about 0.001 mg / kg / day to about 10 mg / kg / day. However, the specific dosage regimen for any particular warm-blooded animal may be varied and must be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the compound of formula A or a pharmaceutically acceptable acid addition salt thereof. In addition, the frequency of administration of such a dosage form to be administered will vary depending on the amount of active drug present and the needs and requirements of the pharmacological situation.

For the disclosed use, the compounds of formula A and their pharmaceutically acceptable acid addition salts are mixed, using conventional neutral pharmaceutical excipients, into dosage forms suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions, and the like. In addition, the compounds of formula A may be formulated into suitable hard or soft capsules and administered in that form, those skilled in the art will be immediately aware of the properties of the neutral excipients used in mixing the compounds of formula A and their pharmaceutically acceptable acid addition salts into oral or parenteral dosage forms. These excipients, of the inorganic or organic type, are, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, resins, 68833 polyalkylene glycols, etc. In addition, such mixtures may be mixed, if desired, with preservatives, preservatives, stabilizers, salts for varying the osmotic pressure, buffers, or the like.

Because the compounds of formula A and their pharmaceutically acceptable acid addition salts have asymmetric carbon atoms, they are usually obtained as racemic mixtures. The resolution of such racemates into optically active isomers can be performed by known methods. Some racemic mixtures can be precipitated as eutectic mixtures and these can then be separated. However, chemical decomposition is more desirable. In this process, diastereomers are formed from a racemic mixture of an optically active resolving agent, e.g. an optically active acid such as (+) - tartaric acid, (+) - di-benzoyl-D-tartaric acid, (+) - d-camphorsulfonic acid, (-) - 3 -pinane carboxylic acid and the like to form a diastereomeric salt. The diastereomers formed are separated by fractional crystallization and can be converted into the corresponding optical base isomer. Thus, the invention encompasses the optically active isomers of the compounds of formula A as well as their racemates.

Furthermore, due to the possible different spatial organization of the atoms, it is clear that the compounds of this invention can be obtained in more than one possible geometric isomeric form. All such isomeric forms are intended to be included in the compounds of formula A which have been described and claimed.

Accordingly, the examples appended herein are to be construed as illustrative of mixtures of certain geometric isomers or individual geometric isomers and not as limiting the scope of the invention.

The following examples further illustrate the invention. All temperatures are in degrees Celsius unless otherwise noted.

28 688 33

Example 1 a) Preparation of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine 185.2 g of N-methyl- (3,5-dimethoxyphenyl) -ethylamine hydrochloride were dissolved in 1600 ml. water and the solution was made alkaline with 160 ml of ammonium hydroxide. The mixture was extracted with 3 x 1000 mL of dichloromethane and the combined extracts were washed with 1000 mL of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 35-40 ° gave 156.0 g of the free base.

4.0 L of dry ammonia was condensed in a 12-liter 3-neck flask equipped with a mechanical stirrer and two dry coolers, one with a gas inlet tube and the other with a soda-lime drying tube. A solution of 156.0 g of the free base in 400 ml of t-butanol and 400 ml of dry ether was added to the ammonia over 15 minutes. A total of 33.6 g of lithium wire cut into 2.5 inch pieces was added to the stirred solution over 50 minutes. The insertion rate was adjusted so that yarn was added at 5 inches per minute. After the entire batch of lithium was added, the deep blue mixture was stirred at reflux for 2 hours. Thereafter, 2.8 L of dry ether was added to dilute the mixture, the drying tube was removed to release hydrogen, and a total of 280 g of ammonium chloride powder was slowly added over 30 minutes until the blue color disappeared. The dry ice-cooler was removed and the mixture was stirred and the ammonia was allowed to evaporate overnight. 2.8 L of ice water was added to the residue.

The mixture was transferred to a separatory funnel, shaking with 800 mL of ether, and the layers were separated. The aqueous layer was extracted 2a with 1.5 liters of dichloromethane, and the extracts were combined and washed with one liter of brine and dried over anhydrous sodium sulfate. Evaporation of the solvents on a rotary evaporator at 40 ° and finally at 40 ° under a vacuum of 1.0 mm for 1.5 hours gave 150.7 g of crude product as a yellow oil. The crude oil was distilled through a 12 inch Goodloe column (bath 150 ° C) collecting fractions as follows: 29 68833

Fraction kB. naino (gas chromatographic) - ~~ t ~~ —- purity_ 1 40-80 ° / p, 45 mm 7.9 g 4.6% 2 80-85 ° / 0.45-0.15 mm 6.2 g 50% 3 85-86 ° / 0.15 mm 21.2 g 92% 4 86-87 ° / 0.15 mm 99.4 g 100%

From the combined fractions 3 and 4, 120.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine were obtained as a colorless oil.

Analysis calculated for cuH 18 NO 2: C, 66.97; H, 9.71; N, 7.10.

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

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

A mixture of 15.6 g of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (79 mmol), 16.7 g of 2-isonitrosocyclohexanone (131 mmol), and 19.5 g g of zinc dust (300 mg atoms) in 300 ml of a 70% aqueous acetic acid solution, heated at reflux for 5 hours, cooled and filtered.

The filtrate was concentrated in vacuo and excess dioxane was added. The dioxane-acetic acid azeotrope was distilled off and the procedure was repeated until all the acetic acid had been removed. The residue was chromatographed on Alumina 111 eluting with 10% methanol in dichloromethane to give 10.7 g of crude 1,2,3,5,6,7,8,9-octahydro-2-Z * 2- (methylamino) ethyl / -4H-carbazol-4-one. The crude product was dissolved in methanol and treated with methanolic HCl and the solvent was evaporated to give 12.2 g of 1,2,3,5,6,7,8,9-octahydro-2-C2- (methylamino) ethyl7-4H- carbazol-4-one hydrochloride.

c) 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexyl] -5,7,7-pyrrolo [-2,3-b] g / Preparation of isoquinolin-11 (11H) -one

A mixture of 2.3 μl of 2,3,5,6,7,8,9-octahydro-2-ZO 2 - (methylamino) ethyl] -4H-carbazol-4-one hydrochloride (8.14 mmol) and 2.3 g of paraformaldehyde (76 mmol) in 100 mL of n-butanol was heated in a pressure flask immersed in an oil bath at 180 ° C at an internal pressure of 80 psi for 80 hours. The solution was cooled and the solvent removed in vacuo and the residue dissolved in water and washed with dichloromethane (discarded). The aqueous solution was made alkaline with ammonium hydroxide and extracted with dichloromethane. The extracts were dried over sodium sulfate, filtered and evaporated to a volume of 10 ml. The mixture was read with 10 grams of alumina, filtered, and evaporated to dryness. The residue was chromatographed on 80 g of Alumina III eluting with 10% methanol in dichloromethane to give crude 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro -4a, 11a-trans-1H, 6H-cyclohexa [4,57] pyrrolo [2,3-g] isoquinolin-11 (11H) -one with a small amount of the corresponding 4a, bicep isomer. Crystallization of the crude product from methanol -dichloromethane-ether gave 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa / 4,57pyrrolo (2,3-g) -isoquinolin-11 (11H) -one as an off-white solid The free base was treated with HCl in methanol and the hydrochloride was recrystallized twice from ethanol to give 0.46 g of pure 2-methyl-2, 3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, EH-cyclohexa / 4,5-7pyrrolo / 2,3-g7isoquinolin-11 (11H) -one, hydrochloride , 0.75 molar hydrate as crystals, mp 217-220 ° C (19% yield).

Analysis calculated for C 18 H 21 N 2 O.HCl.0.75 H 23: C, 62.33; H, 8.01; N, 9.09; Cl, 11.50; Found: C, 62.56; H, 8.11; N, 9.08; Cl, 11.59.

Example 2 a) Preparation of 3,4-dihydro-1H-6,8-dimethoxy-2-methyl-isoquinoline hydrochloride

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

b) Preparation of 1, 2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline and octahydro-2-methylisoquinoline-6,3-dione

Ammonia (150 mL) was condensed in a flask containing 5-butanol (9.1 g, 123 mmol) and diethyl ether (50 mL). To the solution was added 3,4-dihydro-1H-6,8-dimethoxy-2-methyl-isoquinoline hydrochloride (1.0 g, 4.1 mmol). After stirring for 2-3 minutes, lithium wire (0.57 g, 82 mmol) was added in short portions over 30 minutes. The blue solution was stirred at reflux for 2.5 hours and solid ammonium chloride (4.5 g) was added until the blue color disappeared. Ether (100 ml) was added and the ammonia was allowed to evaporate overnight. Ice water (100 ml) was added and the organic phase was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate, and evaporated to dryness to give 1,2,3,4,4a, 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58 g, yield 68 %) as a yellow oil.

The crude product (1.05 g) was boiled in 20 ml of 70% acetic acid solution for 5 hours and the acetic acid was removed on a rotary evaporator. The residue was dissolved in water and washed with chloroform. The aqueous phase was concentrated to a volume of 10 mL and chromatographed on Dowex AG 50WX3 eluting with 2 M aqueous pyridine to give 0.1 H

O

octahydro-2-methyl-isoquinoline-6,8-dione (yield 11.6%) as a yellow-yellow solid. Treatment with hydrochloric acid in methanol gave the hydrochloride, m.p. 193-106 °.

32 688 33 c) 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa [4,5] pyrroloZ ”2,3 -g / isoquinolin-11 (11H) - is the preparation of octahydro-2-methylisoquinoline-6,8-dione.

A mixture of 72 g of crude octahydro-2-methylisoquinoline-6,8-dione (purity about 30%, about 0.1 mol), 21.1 g of crude 2-isonitrosocyclohexanone (purity about 60%, about 0.1 mol) and 19.5 g of zinc dust (0.3 g atoms) in 500 ml of 70% aqueous acetic acid solution were boiled for one hour. A second portion of 10.5 g of 2-isonitrocyclohexanone and 6.5 g of zinc dust were added and the mixture was boiled for another 2 hours. The solution was cooled and evaporated to dryness in vacuo, and the residue was dissolved in water and washed with chloroform (discarded). The aqueous solution was made alkaline with ammonium hydroxide and extracted with chloroform. The extracts were washed with brine, dried over sodium sulfate and evaporated to dryness. Crude 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, Ha-trans-1H, 6H-cyclohexaZ4,57 pyrrolo [2,3-g] iso- quinolin-11, HH-one was chromatographed on silica gel (dry column) eluting the mixture prepared by shaking (in parts by volume) 9Q parts of chloroform, 30 parts of methanol, 10 parts of water and 6 parts of acetic acid with the organic phase to give 7.8 grams 2-methyl-2,3, H, 4a, 5,7,8,9, -1Γ, 11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexaZT 4,5, pyrrolo [2,3-g] ~ isoquinolin-1 (IIIH) -one, after slurrying with hot ethanol, as a white amorphous solid, mp 273-275 ° C (dec).

Analysis calculated for C, 7k, 38; H, 8.58; N, 10.84; Found: C, 74.21; H, 8.39; N, 10.61.

Example 3

Following the procedure of Example 2C, starting from 2-isonitrosocyclopentanone and octahydro-2-methyl-isoquinoline-6,8-dione, 2-methyl-1,2,3,4,4a, 5,7,8,9,10a were obtained. -decahydro-4α, 10α-trans-6H-cyclopentane Z'4,57ργΓΓθ1ο / 2,3-g7 isoquinolin-10 (10H) -one, m.p. 296-297 ° C (dec.), Crystallized from ethanol-methanol.

33 68833

Analysis calculated for c 15 H 20 N 2 O: C, 73.74; H, 8.25; N, 11.47; Found: C, 73.93; H, 8.41; N, 11.46.

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

Analysis calculated for ci5H2QN2O * HCl. 0.5H 2 O: C, 62.17; H, 7.65; N, 9.67;

Cl, 12.23; Found: C, 62.16; H, 7.71; N, 9.54; Cl, 12.37.

Example 4

Following the procedure of Example 2C, starting from 2-isonitrosocycloheptanone and octahydro-2-methyl-isoquinoline-6,8-dione, 2-methyl-1,2,3,4,4a, 5,7,8,9, 10,11,12α-dodecahydro-4α, 12α-trans-6H-cyclohepta [4,57] pyrrolo] -2,3-g7 isoquinolin-12 (12H) -one, m.p. 293-296 ° C, crystallized from ethanol.

Analysis calculated for C 18 H 18 N 2 O 2: C, 74.96; H, 8.88; N, 10.28; Found: C, 74.79; H, 8.74; N, 10.33.

Example 5

Following the procedure of Example 2C, starting from 2-isonitrosocyclooctanone and octahydro-2-methylisoquinoline-6,8-dione, 2-methyl-2,3,4,4a, 5,7,8,9,10, -11,12,13a-dodecahydro-4a, 13a-trans-1H, 6H-cyclooctaZ4,5-7pyrrolo [7,3-g] isoquinolin-13 (13H) -one, m.p. 298-300 ° C, crystallized from water-dimethylformamide.

Analysis calculated for cpgH26N2O: C} 75> 1 + 8; H, 9.15; N, 9.78; Found: C, 75.29; H, 9.04; N, 9.70.

Example 6 a) 2,3,4,4a, 5,7,8,9,10,11a-Decahydro-4a, 11a-trans-1H, 6H-cyclohexA, 5jpyrrolo [2,3-g] isoquinoline-11 (11H ) is manufactured

A mixture of 1.9 g of 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa-4,5-7pyrrolo / 2,3-g7-isoquinolin-11 (11H) -one, 2.6 g of ethyl chloroformate and 3.2 g of 34,68833 potassium hydrogen carbonate in 100 ml of dioxane, were heated to reflux for 6 hours, cooled and filtered. The filtrate was evaporated to dryness in vacuo, dissolved in chloroform, and extracted with 5% aqueous hydrogen chloride, washed with water, brine, and dried over sodium sulfate. Evaporation of the solvent gave 1.4 g of carbamate, 2-ethoxycarbonyl-2,3,4,4a, 5,7,8,9,10, 11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexane / 4,5,5-pyrrolo [2,3-g] isoquinolin-11 (11H) -one. From the aqueous extracts, 0.45 g of the starting material was recovered by treatment with ammonium hydroxide and extraction with chloroform.

The crude carbamate (1.4 g) was heated at reflux for 24 hours with 15 ml of 30% aqueous sodium hydroxide in a mixture of 15 ml of ethanol and 5 ml of dioxane. The mixture was evaporated to dryness in vacuo and the residue was dissolved in 5% aqueous hydrogen chloride solution and washed with chloroform. The aqueous solution was made alkaline with ammonium hydroxide and extracted with chloroform. The extracts were washed with brine, dried and evaporated to dryness to give 0.65 g of 2,3,4,4a, 5,7,8,9,10, 11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexane / 4 , 5 (pyrrolo [2,3-g] isoquinolin-11 (11H) -one and m.p. 250-251 ° C.

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

A mixture of 0.68 g of 2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa [4.5-7pyrrolo] 12, 3- g / isoquinolin-11 (11H) -one, 1.68 g of N-chloro-p-fluorobutyrophenone and 1.55 g of potassium carbonate in 15 ml of diethyl ketone were heated at reflux for 24 hours. The mixture was cooled, filtered and evaporated to dryness. The residue was chromatographed (dry column) eluting with a mixture of the organic phase prepared by shaking (by volume) 90 parts of chloroform, 30 parts of methanol, 10 parts of water and 6 parts of e-diacid to give 0.85 g of crude amine, which was crystallized. again from ethanol to give 0.42 g of pure 2- [4- (4-fluorophenyl) -4-oxobutyl] -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a 11a-trans-1H, 6H-cyclohexa [4,57] pyrrolo [2,3-g] isoquinolin-11 (11H) -one as a crystalline solid, m.p. 220-222 ° C.

Analysis calculated for C, 73.50; H, 7.16; N, 6.86; F, 4.65; Found: C, 73.46; H, 7.08; N, 7.16; F, 4.61.

35 68833

Example 7

Following the procedure of Example 6b, alkylation of 2,3,4,4a, 5,7,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa-Z-4,5,7-pyrrole [7, 3-g7isoquinolin-11 (11H) -one (2-bromoethyl) benzene, gave 2- (2-phenylethyl) -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexaZA, 57pyrroloZ-2,3-g-isoquinolin-11 (HH) -one, m.p. 250-256 ° C (decomposed), as a crystalline solid after recrystallization from ethanol.

Analysis calculated for C 23 H 29 N 2 O: C, 79.27; H, 8.10; N, 8.04; Found: C, 79.29; H, 8.40; N, 7.97.

Example 8

Following the procedure of Example 6b, alkylation of 2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11α-trans-1H, 6H-cyclohexa-Z4,5, pyrroloZ "2,3-g7 isoquinolin-11 (11H) -one with benzyl chloride gave 2-benzyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H , 6H-cyclohexaZ4,5Jpyrrolo Z2,3-g7isoquinolin-11 (11H) -one, mp 256-258 ° C, as a crystalline solid after recrystallization from ethanol.

Analysis calculated for ^ 22 ^ 26 ^ 2 ^ 1 C, 79.00; H, 7.84; N, 8.38; Found: C, 79.27; H, 8.03; N, 8.60.

Example 9 a) Following the procedure of Example 6a, starting from 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZT4,57pyrrolo / f2 1,3-g7isoquinolin-10 (10H) -one, via carbamate gave 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ- 4,5-pyrrolo [2,3-g] isoquinolin-10 (10H) -one, m.p. 242-245 ° C (dec.), Crystallized from ethanol-ethyl acetate.

Analysis calculated for C 18 H 18 N 2 O 2: C, 73.01; H, 7.88; N, 12.16; Found: C, 72.84; H, 7.78; N, 12.30.

b) Following the procedure of Example 6b, alkylation of 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [4,5] pyrroloZ

2,3-g7isoquinolin-10 (10H) -one with benzyl chloride gave 2-benzyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H -cyclopentaZ-4,5-pyrroloZr2,3-g7isoquinolin-10 (10H) -one, m.p. 2 5 8-2 6 0 ° C (decomposed), as a crystalline solid after recrystallization from ethanol.

36 68833

Analysis calculated for C, 78.71; H, 7.55; N, 8.74; Found: C, 78.97; H, 7.54; N, 8.63.

Example 10

Following the procedure of Example 6b, alkylation of 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta / 4,57-pyrrolo / * 2,3-g7isoquinoline-10 (10H) -one with {'' '- -chloro-p-fluorobutyrophenone, gave 2-N- (4-fluorophenyl) -4-oxobutyl-1,2,3,4,4a, 5,7 , 8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta / 4,5-pyrrolo [2,3-g] isoquinolin-10 (10H) -one, mp 225-227 ° C, as a crystalline solid from ethanol after recrystallization.

Analysis calculated for C 2-7; C, 73.07; H, 6.90; N, 7.10; F, 4.82; Found: C, 72.76; H, 6.86; N, 7.24; F, **, 71.

Example 11

Following the procedure of Example 6b, alkylation of 1,2,3,4, 4a, 5, 7, 3, 9, 10a-decahydro-4a, 10a-trans-6H-cyclopenta [4,5-a] pyrrolo [2,3-g] isoquinoline-10 (10H) -one (2-bromoethyl) benzene gave 2- (2-phenylethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H -cyclopenta [4,5-b] pyrrolo [2,3-g] isoquinolin-10 (10H) -one, m.p. 2 51-2 54 ° C (decomposed), as a crystalline solid after recrystallization from ethanol.

Analysis calculated for ^ 22 ^ 26 ^ 2 ^ 'C, 79.00; H, 7.84; N, 8.38; Found: C, 78.68; H, 7.72; N, 8.28.

Example 12 2-Methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-5H-cyclopenta [4,5] pyrrolo [d]? Preparation of 3-g7 isoquinoline-10 (10H) -t ion

A mixture of 244 mg (1.0 mmol) of 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ4,57pyrrolo / 2,3-g7 isoquinolin-10 (10H) -one and 222 mg (1.0 mmol) of phosphorus pentasulfide in 15 ml of dixane were stirred and boiled for 17 hours. The dioxane solution was decanted off and water (20 ml) and enough ammonium hydroxide were added to the residue to bring the pH to between 8-9. The mixture was extracted with chloroform, and the extracts were washed with brine, dried and evaporated to dryness. The crude thion was chromatographed as described in Example 12 to give 65 mg of pure solid thion, which was recrystallized from acetonitrile to give 2-methyl-1,2,3,4,4a, 5,7,8,9 , 10α-decahydro-4α, 10α-trans-6H-cyclopenta [5,5] pyrrolo [2,3-g] isoquinoline-10 (10H) -thione, m.p. 224-227 ° C (dec.).

37 6 8 8 3 3

Analysis calculated for C 15 H 20 N 2 S: C, 69.19; H, 7.74; N, 10.76; Found: C, 68.97; H, 7.59; N, 10.97.

Example 13 2-Methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexyl-4,5-pyrrolo A, 3-g7isoquinoline For the preparation of the 11 (11H) -1 ion, the procedure of Example 12 starting from 2-methyl-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a, 11a-trans-1H, 6H-cyclohexa [4,5-pyrrolo] [2,3-g] isoquinolin-11 (11H) -one.

Example 14 1,2,3,4,4a, 5,7,8,9,10a-Decahydro-4a, 10a-trans-6H-cyclo-Penta A, 5,7,7-pyrrolo [2,3-g] isoquinoline-10 (10H) -t ion ready The method of Example 12 starting from 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta A, 5_ / pyrroloZ2 is used. , 3-g7 of isoquinolin-10 (10H) -one.

Example 15 2-A- (4-Fluorophenyl-N-oxobutyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10-trans-6H-cyclopenta A, 57pyrrolo / For the preparation of--2,3-g-7isoquinoline 10 (10H) -thione, the procedure of Example 6b is used starting from 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans- 6H-cyclopenta A, 5-7pyrrolo [2,3-g] isoquinoline-10 (10H) -t ion and Ά-chloro-p-fluorobutyrophenone.

Example 16 2- (2-Phenylethyl) -1A, 3,4,4at5,7,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ4, Sjpyrrolo A, 3% Isoquinoline-10 (10H ) -ionion is prepared according to the procedure of Example 6b starting from 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta A, 5,7-pyrroloZ "2,3 -g7isoquinoline-10 (1OH) -thion and (2-bromoethyl) -benzene.

Example 17 2- (2-Hydroxy-3,3-dimethylbutyl) -2,3,4,4a, 5,7,8,9,10,11-decahydro-4a, 11a-trans-1H, 6H-cyclohexane Preparation of A, 5,7,7-pyrrolo [2,3-g] isoquinolin-11 (11H) -one

A solution of 488 mg (2.0 mmol) of 2,3,4,4a, o, 7,8,9,10,11a-decahydro-4α, 11α-trans - 1H, 6H-cyclohexa A, 5 -7pyrrolo [1,3-g7 isoquinolin-11 (11H) -one and 300 mg (3.0 mmol) of 3,3-dimethyl-1,2-38 6 8 8 3 3 epoxyburan in 15 ml of methanol, boiled for 24 hours. and evaporated to dryness. The residue was chromatographed, and the crude product (350 mg) was crystallized from ethanol to give 200 mg of 2- (2-hydroxy-3,3-dimethylbutyl) -2,3,4,4a, 5,7,8,9,10, decahydro-4α, 11α-trans-1H, 6H-cyclohexaZ,5,5-pyrrolo [2,3-g] isoquinolin-11 (11H) -one, m.p. 276-2 7 8 ° C (dec.).

Analysis calculated for ^ 21Η32 ^ 2 ° 2: C, 73.22; H, 9.3 δ; N, 8.13; Found: C, 73.39; H, 9.31; N, 8.15.

Example 18 2- (2-Hydroxy-2-phenylethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [b, 5,7-pyrrolo] -2,3 The method of Example 17 starting from 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta-Z 4 is used to prepare -g7isoquinolin-10 (10H) -one. 5_? pyrroloZ "2,3-g7isoquinolin-10 (10H) -one and styrene oxide.

Example 19

By the method of Example 6b, 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ4,5-7pyrroloZ2,3-g7-isoquinolin-10 (10H) was alkylated. -one with 4-methoxybenzyl chloride to give 2- (4-methoxybenzyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [4], 57pyrroloZ2,3-g-isoquinolin-4-one, m.p. 236-238 ° C (dec.), As a crystalline solid recrystallized from ethanol.

Analysis calculated for ^ 22 ^ 20 ^ 02: 7 5, 40; H, 7.48; N, 7.99 Found: C, 75.39; H, 7.41; N, 8.03

Example 20

By the method of Example 6b, 1,2,3,4,4a, 5, -7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ4,5,7-pyrrolo [2,3-g] iso- were alkylated. quinolin-10 (10H) -one with 4-chlorobenzyl chloride to give 2- (4-chlorobenzyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans 6H-cyclopenta [4,5] pyrrolo [2,3-b] isoquinolin-10 (10H) -one as a crystalline monohydrate, m.p. 254-256 ° C recrystallized from ethanol.

Analysis calculated for C 21 H 23 N 2 O 1 H 2 O: C, 67.63; H, 6.22; N, 7.51;

Cl, 9.51 Found: C, 67.86; H, 6.38; N, 7.50; Cl, 9.92 39 6 8 8 3 3

Example 21

By the method of Example 6b, 1,2,3,4,4a, 5,7,7,9,9,10a-decahydro-4α, 10α-trans-6H-cyclopenta [4,5] pyrrolo [2,3-b] isoquinol was alkylated. -10 (10H) -one with allyl bromide to give 2- (2-propenyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaA , 57pyrroloZ-2,3-gisisoquinolin-10 (10H) -one, m.p. 257-259 ° C (dec.) Recrystallized from ethyl acetate / ethanol.

Analysis calculated for C, 75.52; H, 8.20; N, 10.36 Found: C, 75.25; H, 8.17; N, 10.36

Example 22

By the method of Example 6b, 1,2,3,4, -4a, 5,7,8,8,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ4,5] pyrrolo [2,3-g] isoquinoline-10 (10H) was alkylated. -one with 2-bromoethyl ether to give 2- (2-ethoxyethyl) 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaA, bX7, 3 -g7isoquinolin 10 (1OH) -one, m.p. 236-238 ° C (dec.), As a crystalline solid recrystallized from ethanol.

Analysis calculated for C, 71.49; H, 8.67; N, 9.26 Found: C, 71.35; H, 8.47; N, 9.23

Example 23 a) By the method of Example 6a using 2-methyl-2,3,4,4a, 5,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-ΙΗ, 6H- cycloocta [4,5-b] pyrrolo [2,3-g] isoquinolin-13 (13H) -one was obtained via the carbamate 1,2,3,4,4a, 5,6,7,8,9,10,11,12,13a tetra-decahydro-9α, 13α-trans-cyclooctaZ, 4,5-7 pyrrolo [2,3-g] isoquinolin-4-one, mp 283-285 ° C recrystallized from ethanol.

Analysis calculated for C, 74.96; H, 8.88; N, 10.28 Found: C, 74.71; H, 8.65; N, 10.24 b) 1,2,3,4, -4a, 5,7,8,9,10,11,12,13a-dodecahydro-4a, 13a-trans-1H, 6H were alkylated by the method of Example 6b -cycloocta [4,5-b] pyrrolo [2,3-g] isoquinolin-13 (13H) -one with ethylene ketal of gamma-chloro-p-fluorobutyrophenone, followed by acid hydrolysis to give 2-Z-4- (4 (fluorophenyl) -4-oxobutyl-1H-2,3,4,4a, 6,7,8,9,10,11,12,13a-tetradecahydro-4a, 13a-trans-cyclooctaZT4,5J pyrroloZ Β-3-isoquinolin-13 (13H) -one, m.p. 2 4 8 -

2 50 ° C

K

4o 6 8 8 3 3

Example 24

By the method of Example 17, 1,2,3,4,4-4a, 5,7,7,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ * 4,5,5-pyrrolo [2,3-g] isoquinoline-10 ( 1 OH) -one with ethylene oxide at room temperature to give 2- (2-hydroxyethyl) -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H- cyclopentaZ-4,57pyrroloZ,2,3-g7 isoquinolin-10- (1OH) one, m.p. 237-239 ° C (dec.), As a crystalline solid recrystallized from ethanol.

Analysis calculated for C 18 H 22 N 2 O 2: C 'H, - 8.08; N, 10.21 Found: C, 69.66; H, 8.17; N, 10.19

Example 25

By the method of Example 17, 1,2,3,4, -4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [-4,5,5-pyrrolo] [2,3-g] was alkylated. .? isoquinolin-10 (1OH) -one with 3,3-dimethyl-1,2-epoxybutane to give 2- (2-hydroxy-3,3-dimethylbutyl) -1,2,3,4,4a, 5, - 7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [4,57] pyrrolo [2,3-g] isoquinolin-10 (10H) -one, m.p. 284-286 ° C as a crystalline solid recrystallized from ethanol.

Analysis calculated for C 18 H 19 N 2 O 2: C, 72.69: H, 9.15; N, 8.48 Found: C, 72.80; H, 9.02; N, 8.55

Example 26

To a solution of 2.35 g of racemic 2-methyl-1,2,3,4,4a, -5,7,3,9,10a-decahydro-4a, 10a-trans-6H-cyclopentaZ4, 57pyrrolo [.2] , 3-g of isoquinolin-10 (10H) -one in 20 ml of methanol, a solution of 3.62 g of (+) - dibenzolyl- (D) -tartaric acid monohydrate in 20 ml of methanol was added. The mixture was concentrated and crystallized from methanol three times and converted to the free base with ammonium hydroxide. Recrystallization of the base from ethanol gave 0.18 g of (-) - 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta [57] pyrrole. roloZ2,3-gisoquinolin-10 (1OH) one, m.p. 270-272 ° C (dec.). The hydrochloride disalt salt was -101.17 ° in methanol (1%).

Example 27 a) Preparation of crj- (3-chloropropyl) -4-fluorobenzenemethanol

A mixture of 2 g (10 mmol) of N, N-chloro-p-fluorobutyrophenone and 1.5 g (40 mmol) of sodium borohydride in 80 ml of ethanol was stirred at room temperature for 3 hours. The mixture was cooled in an ice-water bath, and 20 ml of 2N hydrochloric acid was slowly added thereto.

41 68833

The solvent was removed in vacuo, and 20 ml of water was added to the residue. The mixture was extracted with chloroform several times, the chloroform extracts were combined and dried over sodium sulfate, filtered and concentrated to an oily residue. The residue was chromatographed on silica gel using a mixture of hexane and ethyl acetate (9: 1) as eluent to give - (3-chloropropyl) -4-fluorobenzenemethane.

b) 2-14- (4-fluorophenyl) -4-hydroxybutyl-1,2,3,4,4a, 5, -7,8,9,10a-decahydro-6H-4a, 10a-trans-cyclopenta [4 Preparation of .alpha.-pyrrolo [2,5] S-p-isoquinolin-10 (10H) -one

A mixture of 115 mg (0.5 mmol) of 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cyclopenta (* 4, 57pyrrolo) , 3-g7 isoquinolin-10 (10H) -one and 138 mg (1.0 mmol) of potassium carbonate in 10 ml of n-butanol were heated to 100 ° C with stirring, and a solution of 121 mg (0, 6 mmol) of- (3-chloropropyl) -4-fluorobenzenemethanol in 8 ml of n-butanol. The mixture was then refluxed with stirring for 20 hours. The solvent was removed in vacuo, and 15 ml of chloroform was added to the residue. The solution was extracted with 2N hydrochloric acid several times, the acid extracts were combined and made alkaline with ammonium hydroxide. The mixture was extracted with chloroform several times, the extracts were combined and concentrated to a solid residue. The residue was chromatographed on a dry column of silica gel using a lower phase mixture of 90 ml of chloroform, 30 ml of methanol, 10 ml of water and 6 ml of acetic acid as eluent to give 14 mg of a solid, which was then boiled in ethanol for a few minutes, then cooled and filtered. to give 2- [4- (4-fluorophenyl) -4-hydroxybutyl] -1,2,3,4,4a, 5,7,8,9,10a-decahydro-6H-4a, 10a-trans-cyclopenta [ 4,57pyrrolo [2,3-b] isoquinolin-10 (10H) -one, m.p. 4 7-249 ° C.

Claims (5)

68833 42 Claims A process according to patent application 793 183 for the use of therapeutically useful cycloalkaZ 4,5-pyrrolo [2,3-g] isoquinolines of the general formula XR -N - / " , C 1-4 hydroxyalkyl, aryl-C 1-7 hydroxyalkyl, alkoxy-C 1-7 alkyl, arylcarbonyl-C 1-7 alkyl, aryl-C 1-7 alkyl or C 2-7 alkenyl, X is O or S; n is 3, 4, 5 or 6, wherein aryl is phenyl optionally substituted by halogen or C 1-7 alkoxy, for the preparation of optical and geometric isomers of these compounds and their pharmaceutically acceptable acid addition salts, characterized in that a) a compound of general formula is X X H 2 wherein X and N are as defined above, a substituent is attached to the isoquinoline nitrogen atom, or b) to prepare a compound of general formula 43 6 8 8 3 3 o rk X JvJyCH:?) n Ia i H wherein R 1 is C 1-6 alkyl or C 1-4 alkoxy-C 1-6 alkyl and n is as defined above, a compound wherein the general formula is RkNH .A __ ^ [III Wn IX H wherein and n are as defined above, is treated with formaldehyde, or c) to prepare a compound of the above general formula Ia, a compound of the general formula 0.i R1-f * J XII o wherein Rj is as defined above, is treated with a compound of the general formula YAn vii ΗΟγΑ "ν - ^ in the presence of a reducing agent, or a compound of the general formula - 68833 V- ', ^ H2> n VIII or a precursor thereof, wherein n is as defined above, or d) for the preparation of a compound of general formula f, R "1 'K v N>, -, / ·' ^! I (CH) Ile H wherein R "^ is C 1-7 alkyl, C 1-7 alkoxy-C 1-7 alkyl, aryl-C 1-7 alkyl or C 2-7 alkenyl, and n is as defined above, of general formula III II (CH2> n Ie i »H where R" ^ and n have the same meaning as above, is treated with phosphorus pentasulfide, and if desired e) isomerizing a mixture of the cis and trans isomers obtained until the final ratio of isomers is obtained, that the mixture contains predominantly the trans isomer, and / or f) the trans isomer is separated from the resulting mixture, and / or g) the resulting racemic mixture is separated into optical antipodes and / or II 1.5 68833 h) the compound obtained or a non-pharmaceutically acceptable acid the addition salt is converted into a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that the compounds are prepared with C 1-6 alkyl, hydroxyalkyl, aryl C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, arylcarbonyl-C 1-6 alkyl C 1-7 alkyl or aryl-C 1-4 alkyl, X is 0 and n is 3 or 4, and the compounds are isolated as trans isomers. Process according to Claim 1, characterized in that 2-methyl-1,2,3,4,4a, 5,7,8,9,10a-dechydro-4a, 10a-trans-6H-cyclopenta Z is prepared. .4,5,7-pyrrolo [2,3-g] isoquinolin-10 (iGH) -one. Process according to Claim 1, characterized in that 2- [4- (4-fluorophenyl) -4-oxobutyl] -1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a , 10α-trans-6H-cyclopentaZ,4,5, (pyrrolo) [2,3-g] isoquinolin-10 (10H) -one. Process according to Claim 1, characterized in that 2- [4- (4-fluorophenyl) -4-oxobutyl] -2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a 11a-trans-1H, 6H-cyclohexa [4,5,7] pyrrolo [2,3-g] isoquinolin-11 (11H) -one. 1.6 68833