NO811342L - PROCEDURE FOR THE PREPARATION OF PYRROLOKINOLIN DERIVATIVES - Google Patents

Description

Most of the compounds described here are new.

However, a few of the compounds have been described in the literature, but not as antipsychotic or analgesic agents (see Roy et al., J. Chem. Soc. C. 1969, 1886-1891).

According to the invention is produced. hexahydro-pyrrolo[3,4-c]quinolines of the formula:

where R 2 is hydrogen', C^-C^ normal alkyl, C^-Cg cycloalkyl, C^-Cg hydroxyalkyl, C^-C^ hydroxycycloalkyl, phenyl, benzyl

R is hydrogen, C 1 -C 4 alkyl or phenyl;

R 1 is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 cycloalkyl, acetyl, benzyl or CH 2 CF 3 ,

or when R 1 and R 1 - are alkyl, they may be linked together to form a 5-, 6- or 7-membered ring; and

R and R , which may be the same or different, are hydrogen,

x y

halogen, trifluoromethyl, C 1 -C 8 alkyl, C 1 -C 8 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3a J -alkylthio, hydroxy or cyano, or when R x and R y are alkoxy on neighboring carbon atoms. can they be bound

together to form a 5-membered methylenedioxy or a 6-membered ethylenedioxy ring,

with the proviso that

i) when R^ is hydrogen and R^ is methyl, R^ is hydrogen and R is hydrogen or methyl in the 8-position, R9 is not methyl or phenyl; and

ii) when R^ and R<- are bonded together to form a 5-membered ring and R and R are hydrogen, R 0 is not phenyl,

and the pharmaceutically acceptable acid addition salts thereof.

The compounds produced according to the invention,

can exist in different configurations, and according to the invention the individual stereoisomers (including optical isomers) can be prepared bg mixtures thereof. It must for-. it is stated that methods for resolving racemates to prepare the corresponding optical isomers are well known.

A preferred group of compounds of formula (I) has the (3) configuration with respect to the hydrogen atoms in positions 9b, 3a and 4 as shown in formula (II). A further preferred group has the (3) configuration and also has the following formula (II ):

where JJ^/ and have the meanings given above, and Rg is hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 6 alkoxy, hydroxy or cyano, and the acid addition salts thereof.

A particularly preferred subgroup of compounds produced according to the invention comprises compounds of formula (II) or acid addition salts thereof where R2 is hydrogen

or C₁-C₂ normal alkyl, R₂ is hydrogen or C₁-C₂ alkyl,

R1 is C1-C4 normal or branched alkyl, and Rg is C1-C- normal or branched alkyl, C1-C8 branched alkyl, C1-C3 alkoxy, halogen (especially fluorine, chlorine or bromine) or hydroxy.

The quinolines are preferably prepared as salts of citric acid, since these seem to be the easiest to

handle and are most stable. However, other pharmaceutically acceptable acid addition salts can also be prepared, e.g. the hydrochlorides, hydrobromides, phosphates, sulphates, acetates and maleates.

A particularly preferred compound is one having the 3-configuration shown by formula (II), where R 2 , R 1 and R 8 are each methyl, and R 1 is ethyl.

The R 2 ~ substituents in the above definition of formula (I) can be more particularly selected from the group of hydrogen;

C 1 -C 8 normal alkyl, preferably C 1 -C 6 normal alkyl, particularly preferably methyl or ethyl; C₁-C₁ cycloalkyl, preferably C₁-C₁ cycloalkyl, e.g. cyclopropyl and cyclopropylmethyl;

C^-Cg hydroxyalkyl, where the alkyl part is particularly C^-Cg normal alkyl or C^-C^ branched alkyl, preferably C^-C^ normal and C-j-C^j branched alkyl, e.g. methyl, ethyl and isopropyl; C 1 -C 8 hydroxy-cycloalkyl where the cycloalkyl part is preferably . is C 1 -C 3 cycloalkyl, e.g. cyclopropyl and cyclopropylmethyl;

phenyl; benzyl;.

R. is selected from the group of hydrogen; C-^-C^. alkyl.,

especially methyl and ethyl; or phenyl.

R 1 - is selected from the group of hydrogen; C 1 -C 8 alkyl,

in particular C₁-Cg normal alkyl and C₁-Cg branched alkyl, preferably C₁-C₆ normal and C₁-C₂ branched alkyl, e.g. methyl, ethyl, isopropyl, -CH 2 CH.(CH 3 ) 2 and -CH 2 C(CH 3 ) 3 ; C 3 -C 8 cycloalkyl-, preferably C 1 -C 3 cycloalkyl, e.g. cyclopropyl and cyclo-propyl Imety 1 ; acetyl; benzyl; and -CH 2 CF 3 .

When R^ and R<- are alkyl, they may be linked together to form a 5-, 6-, or 7-membered ring containing the nitrogen in the 5-position of pyrrolo[3,4-c]quinoline.

R and R , which may be the same or different, are chosen

x y

from hydrogen; halogen, especially fluorine, chlorine or bromine; trifluoromethyl; C^-Cg alkyl, especially C^-Cg normal alkyl and C-^-C^ branched alkyl, preferably C^-^ normal and C-^-C^ branched alkyl, e.g. methyl, ethyl, isopropyl and tert-butyl; C 1 -C 8 cycloalkyl, preferably C 1 -C 3 cycloalkyl, e.g. cyclopropyl and cyclopropyl-methyl; C 1 -C 3 alkoxy, especially methoxy; C 1 -C 3 alkylthio; hydroxy; and cyano.

When Rx or R is hydrogen and the other does not have this meaning, the substituent other than hydrogen may be in the 6-, 7-, 8- or 9-position of the pyrrolo[3,4-c]quinoline derivative.

When Rx and R are alkoxy, they may be bonded together for

to form a 5-membered methylenedioxy or 6-membered ethylenedioxy ring when they are on neighboring carbon atoms in the aromatic ring. E.g. can R^ and R^ mean -O-CP^-O- or -O-CP^-Cr^-O- where the oxygen atoms are bound to positions 6 and 7, 7 and 8 or 8 and 9 in pyrrolo[3,4 -c]quinoline deriv. However, they can be alkoxy on adjacent carbon atoms without being bonded together into a ring.

Particularly preferred compounds are the following three compounds: each of R 4 - 9 R 8 means a methyl radical and R 1 means an ethyl radical; each of R 2 9 R 8 represents a methyl radical and each of R 1 and R 2 represents an ethyl radical; and each of R 2 and R 8 represents a methyl radical, and R 1 and R 2 are alkyl and are bonded together to form a 6-membered ring.

The compounds can be produced in several ways. Among literature sites that illustrate synthetic methods for the preparation of useful intermediates for the preparation of the compounds of formula (I) or the compounds themselves, are e.g. W. Pftizinger, J. f ur Prakt. Chemie, 5j5, 283 (1897);

E. Campaigne and J.H. Hutchinson, J. of Heterocyclic Chem. 1_, 655 (1970) and Roy et al mentioned above. The following preparative methods shall illustrate the invention

In method (I) above, R and R are as defined for

x Y

formula (I). R^Q is methyl, ethyl or phenyl, R2 is as defined for formula (I) and R' is C^-C^alkyl, to obtain C2~C6 a^y^- in the 5-position; hydrogen to obtain methyl in the 5-position; or CF^to obtain.-CH2CF3i 5-position.

Among the reagents used in method I, it will

it is understood that different replacements can be made. For example, the ethyl ester R^^COCH2CO2E.t can be replaced by R10COCH2CO2CH3. KOH can be replaced by NaOH, acetic anhydride (Ac2O) can be replaced by another dehydrating agent such as dicyclohexylcarbodiimide, the compound NaBH^ can be replaced by KBH^, the compound BH^•tetrahydrofuran (THF) complex can be replaced by lithium aluminum hydride, and citric acid can be replaced by any other acid which forms pharmaceutically acceptable salts.

Compounds of formula (VI) can also be prepared as indicated by Ried and Weideman in Chem. Ber., 104, 3341-3349

(1971).

In Method II, the compounds of formula (X) can be prepared by Method I up to formula (VIII) with the given definitions of R. n and R', or by combinations of Method I with Methods III, IV, V and VI. R 2 i Method II is as defined for formula (I), and X is a replaceable group such as bromine or chlorine. The dimethylformamide with sodium carbonate can be replaced with toluene and triethylamine.

In Method III above, formula (VHIb) denotes compounds of formula (Villa) with the exception that R^Q is below the plane of the molecule as shown and is therefore of α-configuration. As will be seen from the above, Method III is primarily a modification of Method I where it is desired to change the R2 substituent. Compounds of formula (XII) can thus be prepared by reacting the compounds of formula (V) with NH3i Method I..

By modifying Method I, the intermediate product with formula (VI) can be prepared as shown in Method IV:

In Method IV, C 1 -C 4 is alkyl or phenyl. The reaction leading to formula (XV) is carried out under reflux for 5 hours. The conversion of (XV) to (XVI) is carried out on a steam bath for approx. 1.5 hours. R2X above is as defined in Method II.

R and R are as defined for formula (I). Formula (XXVI) has x y

the same structure as formula (.VI), except that Rj^ replaces R^Q.

By Method V, R oq ^ R y as defined for formula (I),

with the exception that both cannot be in the ortho position to the nitrogen atom in formula (XVII) if both are different from hydrogen. R 2 in formula (XVIII) is as defined for formula (I). The reaction leading to the compound of formula (XIX) can be carried out at about 10°C under nitrogen or at room temperature.

R.2 and R.sub.1 are methyl or ethyl. R.sub.2 may be different from methyl or ethyl, e.g. H, C 1 -C 4 alkyl or benzyl, but a mixture may occur and such requires separation of the products, e.g. by chromatograph i. In formulas (XIX) and (XX). R^ is hydrogen if R^ was methyl and is methyl if R^ 2 was ethyl. The reaction with the BH^•tetrahydrofuran complex leading to the compound of formula (XX) can also be carried out with the aid of lithium aluminum hydride.

By method VI, the compounds of formula (XXVI) can be prepared by method I, III or IV. The compound of formula (XXVI) is hydrogenated with PtCl 2 in ethanol or a similar neutral solvent. The reaction of the compound of formula (XXI) to the compound of formula (XXII) takes place in toluene with triethylamine or can be carried out with toluene and 10% NaOH.

The subsequent BH ^ • TH F reaction can be replaced by lithium aluminum hydride to form the compound of formula (XXIII). Alternatively, a compound of formula (XXI) can be reacted with an alkyl halide, such as CH^Br, to give alkyl in the 5-position. The addition of acid chloride to the compound of formula (XXIV) to give the compound of formula (XXV) can be carried out in toluene with 10% NaOH in water or with a toluene-triethylamine mixture.

With the methods described above, modifications can be made to arrive at the desired compounds. If the prepared compound of formula (I) e.g. has a bromine atom on the aromatic ring and cyano is desired, a conversion can be made with a reagent such as CuCN as exemplified later.

As shown in Methods I and IV, the starting materials are isatins with the formula

where R x e.g. is CH3 0 and R y is H, as in 5-methyl J-isatin:

These isatins are commercially available, or they can be prepared by following the method set forth in Org. Sight. Coll. Vol. I, page 329:

According to the invention, a method is thus provided for the preparation of the compounds of formula I, where R 2 , R 5 , R 5 , Rx and R 5 have the above meanings, and pharmaceutically acceptable acid addition salts thereof, by

(a) reduction of a compound of the formula:

to form the corresponding compound of formula I;

(b) reacting a compound of formula I, wherein

at least one of R and R means a methoxy radical, with bromohydrogen-x y

acid;

. (c) debenzylation of a compound of the formula:

by catalytic hydrogenolysis; (d) reaction of a compound of the formula:

with a compound of the formula R 1 X where R 2 has the meaning given above except for hydrogen, and X means a replaceable group, e.g. bromine or chlorine;

(e) reaction of a compound of the formula:

with an acetic acid halide, e.g. acetyl chloride or acetic anhydride; or

(f) resolving a racemate of formula I, wherein

1*2 r / ; Rx and R have the meanings given above.

Illustrative compounds are shown in the following Table I where R 2 /R 1 , R 1 , R 1 , and the specified production method refers to the previously described methods:

The following examples further illustrate the invention. Unless otherwise stated, all temperatures are in °C, and NMR data are in deniers per million relative to tetramethylsilane as an internal standard:

Example 1 (Method I)

2, 6- dimethylquinoline- 3, 4- dicarboxylic acid ( i)

To a 2 liter three-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser, N,, inlet tube and dropping funnel was added 73 g (0.45 mol) 5-methylisatin, 300 g KOH and 1100 ml H 2 O under a N 2 atmosphere. The dark solution was maintained at 55° while 164 g (1.26 mol) of acetic acid ester was added dropwise over a period of 3 hours. When the addition was complete, the internal temperature was raised to 85° and held there for 45 minutes. The reaction mixture was then stirred at ambient temperature for 2 days.

Acidification of the reaction mixture by dropwise addition of 400 ml of concentrated HCl over a period of 2.25 hours while the internal temperature was maintained at approx. 20°C, gives a light brown solid which is collected by filtration, washed with H,,0 and

dried in vacuum; yield 99.8 g (90% of the theoretical).

2, 6- dimethylquinoline- 3, 4- dicarboxylic acid anhydride ( ii)

A 2 liter round bottom flask equipped with magnetic stirrer, reflux condenser and drying tube was charged with 70 g (0.285 mol) of (i) and 1 liter of reagent grade acetic anhydride.

The light brown suspension was stirred under reflux for 23 hours.

Ac 2 O was removed in vacuo using a rotary evaporator, and the resulting; dark, solid matter was smeared

with 500 ml of ether. The solid was collected on a filter and dried; yield 5'8g (89.4%).

The ether filtrate was concentrated on a rotary evaporator to give an additional 5.4 g (8.3%) of product, total yield 63.4 g (97.7%).

w^q 1825, 1775 cm"<1.>

1, 3- dioxo- 2, 4, 8- trimethyl- 2H- pyrrolo[ 3, 4-c] quinoline (iii)

A 2 liter round bottom flask equipped with a magnetic stirrer,

reflux condenser and drying tube were added 59 g (0.26 mol)

of (ii), 1 liter of dry pyridine and cooled with an ice bath. To the cool mixture was added a small excess of reagent grade dry methylamine (9.3 g required). The dark mixture was warmed to room temperature and then refluxed for 20 hours with efficient stirring. The reaction mixture was allowed to cool, and the pyridine was removed in vacuo on a rotary evaporator. The dark solid thus obtained was triturated with toluene and evaporated in vacuo to remove them

last traces of pyridine. Toluene treatment was followed by trituration with ether, and the solid was filtered; yield 56 g. Concentration of the ether filtrate gave a further 4 g, total yield 60 g (96%).

1755, 1690 cm"<1>

1, 3- dioxo- 5- ethyl- 3aa, 4a, 5, 9ba- tetrahydro- 2, 4, 8- trimethyl-2- H- pyrrolo[ 3, 4-c] quinoline (iva) and

1, 3-dioxo-5-ethy 1-3aa, 43,5,9ba-tetrahydro-2,4,8-trimethyl-2-H-pyrrolo[3,4-c]quinoline (ivb)

15 g (0.0624 mol) of (iii) and 550 ml of glacial acetic acid (glacial HOAc) were introduced into a 1 liter 3-necked flask equipped with a thermometer, reflux condenser and magnetic stirrer. The brown solution was cooled to 15°C, and 23.7 g (0.624 mol) of reagent grade NaBH 2 was added portionwise over a period of 1.5 hours while maintaining the internal temperature between 15 and 20°. The reaction mixture was stirred overnight at room temperature and then refluxed for 1 hour.

The reaction mixture was cooled, transferred to a

2 liter beaker, diluted with 1 liter cold H20 and regulated

to pH 10-12. with approx. 500 ml of 50% NaOH. The suspension was extracted with 3 x 250 mL portions of ether and 3 x 250 mL portions of ethyl acetate (EtOAc). The organic extracts were combined, dried (Na 2 SO 4 ) and evaporated to dryness in vacuo to give 14.8 g of a reddish brown oil which partially solidified on standing at room temperature.

The crude material was purified by column chromatography on

300 g of silica gel using ether/hexane and gradient elution. The epimer (iva) that was eluted first (10% ether),

were isolated as brown-yellow needles; yield, 7.1 g (42%)

NMR (CDCl 3 ) 0.81 [d, J = 6.5 Hz, 4-CH.j]; KBr C=0 1760, 1675 cm"<1.>

A mixture of (iva) and (ivbj) was then eluted;

yield, 1.25 g (7.35%).

Epimer (ivb), 1 g (5.8%), eluted with 20% ether was isolated as a bright red solid; NMR (CDCl 3 ) 0.96-1.24 [m, 4-CH 3 , 5-ethyl-CH 3 ]; KBr C=0 1775, 1690 cm"<1.>

5- ethyl- 1, 3, 3aa, 4g, 5, 9ba- hexahydro- 2, 4, 8- trimethyl- 2H- pyrrolo-[ 3, 4-c] quinoline (va) (compound 3 in Table I)

A solution of 7 g (0.0257 mol) of (iva) in 50 ml anhydrous reagent grade THF was added to a 500 ml 3-necked flask equipped with a thermometer, reflux condenser, N 2 ~ inlet tube and magnetic stirrer. The apparatus was supplied with N2

and cooled to 0° using an ice bath while 270 mL of a 0.94M solution of BH 2 THF in THF was added dropwise over 20 minutes. The ice bath was removed and the reaction mixture was refluxed for 18 hours under N 2 .

About 100 ml of THF was distilled off at atmospheric pressure,

and the reaction mixture was cooled with an ice bath. The reaction was quenched by the addition of 100 mL of cold H 2 O followed by 120 mL of 6M HCl over 10 minutes. The remaining THF was distilled off at atmospheric pressure. The aqueous phase was made alkaline (pH 10-12) with 20% NaOH, and the white mixture was extracted with 5 x 150 mL portions of ether. The extracts were combined, dried (Na 2 SO 4 ) and evaporated in vacuo to give 6.3. g of the raw material as a yellow oil. Flask-to-flask distillation of the crude yielded 5.8 g (93%) of a colorless oil, b.p. 110-115°/0.1 mm Hg.

NMR (CDCl 3 ) 0.99-1.19 [m, 4-CH 3 , 5-CH 2 CH 3 J, 2.20 [s, 8-CH 3 ],

. 2, 29' [s, 2-CH3] ; M/e+, 244.

citrate of (va)

A solution of 5.7 g (6.0209 mol) of (va) in 100 mL of reagent grade anhydrous ether was treated portionwise with 4.03 g (0.021 mol) of citric acid in 800 mL of ether with vigorous stirring. The precipitated citrate salt was filtered, washed with ether and dried in vacuo at 50°C, yield 9.2 g (95%), melting point (m.p.) 129-131°C (dec.)

Analysis for c^gH24N2"<C>6<H>8°7

Calculated: C 60.53, H 7.39, N 6.42

Found: C 60.67, H 7.33, N 6.19

5- ety1- 1, 3, 3aa, 4a, 5, 9ba- hexahydro- 2, 4, 8- trimethy1- 2H-pyrrolo[ 3, 4- c] quinoline ( vb)

(ivb) was transferred to (vb) in 84% yield by the procedure described above for (va).

citrate of (vb)

The citrate salt of (vb) was prepared by the method described above for the preparation of the citrate salt of (va), m.p. 152-153°.

Analysis for C16H24N2*C6H8°7

Calculated: C 60.53, H 7.59, N 6.42.

Found: C 60.75, H 7.33, N 6.16.

Example 2

3- cyano- 2, 6- dimethyl- quinoline- 4- carboxylic acid (vi)

A hot solution of 5-methylisatin (25 g, 0.155 mol) in 400 mL of H 2 O containing 6.2 g (0.155 mol) of NaOH was treated with 12.7 g (0.155 mol) of 3-amino-crotononitrile in 3 approximately equal portions. The reaction mixture was refluxed for 5 hours and then stirred at ambient temperature overnight.

The reaction mixture was cooled and acidified to pH 3 with 25 mL of 12% HCl. The precipitate was filtered, washed with H 2 O and dried in vacuo; yield 16.4 g (47%) .

• KBr _1 KBr tvr\^ —1

vCN 2200 cm, vC00H 1690 cm.

1, 3- dioxo- 4, 8- dimethyl- 2H- pyrrolo[ 3, 4-c] quinoline (vi i)

A mixture of 16.4 g (0.07 mol) of (vi) and 175 g of polyphosphoric acid was heated on a steam bath with periodic mechanical stirring for 1.5 hours. The hot reaction mixture was poured onto 1 liter of ice/water with stirring. After standing overnight, the mixture was clarified by filtration through Celite, and the filtrate was adjusted to pH 4 with NaOH pellets. The resulting solid was filtered, washed with H 2 O

and dried in a vacuum oven at 50°C.

KBr ->,-s~ — 1 KBr —1

h.7„ 300 cm , h,,- 1760, 1720 cm

Nn C—U

Preparation of compound ( iii) from compound ( vil)

To a stirred suspension of 6.6 g (0.029 mol) of (vii) and 4.0 g (0.029 mol) potassium carbonate in 75 ml anhydrous dimethylformamide (DMF) was added in one portion 20.6 g (0.145 mol) CH^ IN. The reaction mixture was protected from atmospheric moisture and stirred for 24-28 hours.

The solid was ■ filtered, washed with H 2 O and dried in a vacuum oven at 50°C. Yield, 5.1 g, m.p. 159-162C.

w^q- 1775, 1690 cm"<1>.

This spectrum was identical to the spectrum for (iii) produced by Method I in example 1.

Example 3

6- bromo- 2- methylquinoline- 3, 4- dicarboxylic acid (viii)

A 1 liter 3-necked flask equipped with a magnetic stirrer, reflux condenser, thermometer and dropping funnel was charged with 50 g (0.221 mol) 5-bromisatine, 150 g KOH and 540 ml H 2 O. The dark solution was kept at 60° while 80.8. g (0.621 mol) of acetic acid ester was added dropwise over 2 hours. When the addition was complete, the internal temperature was raised to 90°C and the mixture was refluxed for 1 hour. The solution was cooled and stirred at room temperature for 2 days.

The reaction mixture was poured into 1 liter of crushed ice and acidified over a period of 1 hour with 200 ml of concentrated HCl. The resulting suspension was diluted with 1 liter of H2O,

and the solid was filtered off, washed with H 2 O and dried, yield.66.04 g (96.0%).

6- bromo- 2- methylquinoline- 3, 4- dicarboxylic anhydride (ix)

A 1 liter round-bottomed flask with magnetic stirrer, reflux condenser and drying tube was charged with 16 g (0.0516 mol) of (viii)

and 250 mL of reagent grade Ac20. The mixture was stirred at reflux for 18 hours.

Excess Ac 2 O was evaporated in vacuo on a rotary evaporator and the remaining material was triturated with ether, filtered and dried in vacuo to give 14.7 g of the crude product.

1, 3- dioxo- 2, 4- dime byI- 8- bromo- 2H- pyrrolo[ 3, 4- c] quinoline (x)

14.7 g of the anhydride (ix) was added to 350 ml of dry pyridine

in a 3-necked flask equipped with a reflux condenser, drying tubes, magnetic stirrers and a thermometer. The flask was cooled with an ice/t₂O bath and reagent grade dry CH₂₆NH₂ was introduced into the mixture. The flask was then allowed to warm to room temperature and refluxed for 20 hours.

The pyridine was evaporated in vacuo. It obtained darkness

syrup was triturated with ether, and the solid filtered off

to give 15.2 g of the product.

8- bromo- 2, 4- dimethyl- 1, 3- dioxo- 5- ethyl- 3aa, 4a, 5, 9ba- tetrahydro-2H- pyrrolo[ 3, 4-c] quinolin (xi)

A 1 L 3-necked flask equipped with magnetic stirrer, reflux condenser and N 2 T tubing and thermometer was charged with 22.1 g (0.0724 mol) of (x) in 750 mL of ice-HOAc. The flask was cooled using an ice/water bath and N2 was passed through. NaBH^

(28 g, 0.724 mol) was added portionwise over 1 hour with vigorous stirring, an internal temperature of 15-20° and a constant N 2 gas flow. was maintained. The thick red-brown mass was stirred at room temperature for 20 hours and refluxed under N2i for 2 hours. HOAc, 250 mL was distilled off, the flask was cooled in an ice/water bath, and

the mixture was neutralized with 200 ml of 50% NaOH. The thick mixture was extracted with EtOAc. The EtOAc extract was washed with H 2 O, dried (Na 2 SO 4 ) and evaporated to dryness to give (xia) and (xib).

20 g of a red-brown syrup was obtained which was purified

over silica gel by gradient elution with ether/hexane (7 to 30%) to give 11 g of (xia) as a beige solid.

8-bromo-2,4-dimethyl-5-ethyl-1,3,3aa,4a,9ba-hexahydro-2H-pyrrolo[3,4-c]quinoline (xiia) (compound 8 in Table I)

A 1 liter 3-necked flask equipped as above and through which N2 was passed was charged with 11 g (0.0305.mol) of (xia)

and 240 mL of dry THF. A 360 ml solution of 0.9M BH^•THF

(0.325 mol) was added dropwise over 15 minutes with vigorous stirring. The mixture was refluxed for 60 hours under N 2 , cooled in an ice/water bath and the reaction quenched with 125 mL H 2 O and 75 mL 6M HCl. THF was distilled off at

atmospheric pressure. The remaining aqueous phase was made alkaline with 50% NaOH (ice cooling) and extracted with ether.

The combined ether extracts were washed with H 2 O, dried (Na 2 SO 4 )

and evaporated in vacuo to give 12.4 g crude oil. Flask-to-flask distillation of the oil gave 8.51 g (85%) of a yellow oil.

8- cyano- 2, 4- dimethyl- 5- ethyl- 1, 3, 3aa, 4a, 5, 9ba- hexahydro- 2H-pyrrolo[ 3, 4-c] quinoline. (xiiia) (compound II in Table I)

A mixture of 3.09 g of (xiia) (0.01 mol) 1.95 g (0.021 mol) CuCN and 50 mL dry reagent grade N-methyl-2-pyrrolidone was refluxed with stirring under N 2 i for 8 h. The flask was cooled, the mixture filtered and the filtrate poured into 400 ml. 5M NaCN/H 2 O. The aqueous phase was extracted several times. times with EtOAc and the extracts were combined and dried (MgSO 4 ). Evaporation and flask to flask distillation gave 1.53 g (60%) of an oil (b.p. 160-165°, 0.1 torr). Conversion of the oil to its citrate salt in ether gave a pale yellow powder, m.p. 93-96 (split.).

Analysis for C^5<H>21<N3>'C6<H>8°7

Calculated: C 59.05, H 6.53, N 9.39

Found: C 59.38, H 6.43, N 9.42.

Example 4

6- methoxy- 2- methylquinoin- 3, 4- dicarboxylic acid (xiv)

A solution, of 59.4 g (0.335 mol) of 5-methoxysatin and

225 g KOH in 800 ml H 2 O was treated dropwise with 121.4 g (0.932 mol) acetic acid ester at 55° over a period of 2 hours. The solution was refluxed for 45 minutes and stirred

at room temperature for 2 days. Acidification with 300 ml of concentrated HC1 while maintaining the temperature_ at ambient conditions,

gave a tan solid which was filtered, washed with H 2 O and dried; yield 60.8 g (69.4%).

2, 4- dimethyl- 1, 3- dioxo- 8- methoxy- 2H- pyrrolo[ 3, 4-c] quinoline (xv)

A solution of 60.8 g (0.233 mol) of (xiv) in 1 liter of reagent grade Ac 2 O was refluxed for 6 h. Distillation of excess Ac.,0, trituration of the residue with ether and filtration gave 59.2 g of the anhydride.

A mixture of 40 g (0.164 mol) of the anhydride and 75.0 ml of dry xylene was cooled, and CH 2 N 1 - 2 was bubbled into the stirred suspension for 20 minutes. The reaction mixture was then slowly heated to reflux temperature (1 hour), and. reflux treatment was continued for 24 hours. The reaction mixture was filtered while hot and the filtrate was evaporated to dryness to give 21 g of the product (xv).

2, 4- dimethyl- l., 3- dioxo- 5- ethyl- 8- methoxy- 3aa, 4 a, 5, 9ba- tetrahydro-2H- pyrrolo [ 3, 4- c] quinoline ( xvia)

To 9 g (0.035 mol) pyrrolo [3,4-c]quinoline . (xv) in 250 ml of ice-HOAc and 24 ml of dry THF under N,,, with ice-cooling and efficient stirring, 13.25 g (0.35 mol) of NaBH^ were added portionwise at such a rate that the internal temperature of 10-15 C was maintained. The mixture was stirred at ambient temperature for 72 h, refluxed for 1 h and finally

alkaline with 50% NaOH while maintaining the temperature at 20°C.

The resulting mixture was extracted with several portions of ether and the extracts combined, dried (Na 2 SO 4 ) and evaporated in vacuo to give 8.3 g of the product after trituration with hexane.

2,4-dimethyl-5-ethyl-8-methoxy-1,3,3aa,4g,5,9bg-hexahydro-2H-pyrrolo[3,4-c]quinoline (xviia) (compound 4 in Table I)

To a solution of 8.3 g (0.0288 mol) of the dioxo intermediate (xvia) in 200 ml of dry THF under N2 was added 305 ml (0.29 mol) of a 0.94 M solution of BH^•THF in THF with effective ■ stirring and external ice cooling. The solution was refluxed under N 2 for 20 hours, cooled and the reaction was quenched by dropwise addition of 175 mL H 2 O and 125 mL 6M HCl. Excess THF was distilled off at atmospheric pressure, the aqueous residue was adjusted to pH 9 with 15% NaOH

and the suspension was extracted with ether. The ether phase became

dried (Na2S0^), evaporated in vacuo and the crude oil purified by flask to flask distillation at 125-130 and 0.1 torr.

2,4-dimethyl-5-ethyl-1,3,3act,4g,5,9bg-hexahydro-8-hydroxy-2H-pyrrolo[3,4-c]quinoline (xviiia) (compound 7 in Table I)

A solution of 2.14 g (0.0082 mol) of the 8-methoxy compound (xviia) in 40 mL of 48% HBr was refluxed under N 2 in 24 h. The cooled solution was basified to pH 9 with conc. NH 4 OH, and the cloudy mixture was extracted several times with EtOAc (9 x 100 mL). The combined extracts were dried (Na 2 SO 4 ) and reduced to dryness to give 1.57 g of a tan syrup. Conversion to the citrate salt with 1.2 g of citric acid in THF/ether/methanol (MeOH) (1:4:0;05) gives 1.75 g of the product, m.p. 65-70° (split.).

Analysis for C15H22N2° ' C6H8°7 * 1// 2 H2°

Calculated: C 56.36, H 6.98, N 6.26

Found: C 56.65, H 7.20, N 6.10

Example 5 (Method II)

4,8-dimethyl-5-ethyl-1,3,3aa,4a,5,9ba-hexahydro-2H-pyrrolo-[3,4-c]quinoline (xix) (compound 20 in Table I)

A mixture of 6 g (0.0187 mol) of (xx) with formula (Villa) where R2benzyl, RiQ= methyl, R1■= methyl, Rx = H and Ry = methyl in the 8-position prepared by Method (I), 1.5 g of 10% Pd/C and 180 ml of absolute ethanol were shaken in an atmosphere of H 2 at an initial pressure of 3.5 kg/cm 2 at 40° for 17 hours. The catalyst was removed by filtration and the filtrate concentrated to dryness in vacuo on a rotary evaporator. The resulting yellow oil was Kugelrohr distilled at 105-115° and 0.2 torr, yield 3.85 g.

y-(4,8-dimethyl-5-ethyl-1,3,3aa,4a,5,9ba-hexahydro-2H-pyrrolo-[3,4-c]quinolin-2-yl)-p-fluorobutyrophenone ( xxi ) ( connection 29

in Table I)

A mixture of 1.5 g (6.5 mmol) of (xix), 1.34 g (6.7 mmol)

γ-Chloro-p-fluorobutyrophenone, 0.66 g (6.5 mmol) of triethylamine and 75 mL of dry toluene were refluxed for 47 hours under N' 2 .

The toluene was cleared by filtration and evaporated in

vacuum on one rotary evaporator. The remaining brown oil was dissolved in ether and extracted with 10% HCl. The watery one

extract was made alkaline with aqueous NaOH and extracted with ether. The ether phase was dried (Na 2 SO 4 ) and reduced to dryness on a rotary evaporator in vacuo, yielding 2.1 g of a brown oil.

The brown oil was filtered through a column of neutral alumina in 1:1 ether/hexane to give 1.05 g of pure material. Conversion to the citrate salt as described above gave 1.3 g of product, m.p. 65-70°.

Example 6 (method III)

4,8-dimethyl-1,3-dioxo-2-(2-morpholinoethyl)-2H-pyrrolo[3,4-c]-quinoline (xxii)

A mixture of 5 g (0.022 mol) of 1,3-dioxo-4,8-dimethyl-2H-pyrrolo[3,4-c]quinoline (vii) (also known as 2,6-dimethylquinoline-3,4-dicarboximide ), 4.65 g (0.025 mol) N-(2-chloroethyl)-morpholine, 6.9 g (0.05 mol) K 2 CO 3 and 50 mL dry DMF were stirred and heated at 50 for 18 h. The dark mixture was poured into r 2 O with stirring and the solid filtered,

yield 6 g after drying in vacuum.

4,8-dimethyl-1,3-dioxo-5-ethyl-2-(2-morpholinoethyl)-3aa,4a,5,9ba-tetrahydro-2H-pyrrolo [3,. 4- c] quinoline (xxiii)

To a cooled solution of 6 g (0.0177 mol) of the pyrrolo-[3,4-c]quinoline (xxii) in 140 ml of ice-HOAc under N2 was added 6.7 g (0.177 mol) of NaBH^ at such a rate that the internal temperature did not rise above 20°. The reaction mixture was stirred for 18 hours at ambient temperature and then refluxed for 1.5 hours under N2. Excess HOAc was removed in vacuo on a rotary evaporator, and the resulting syrup was treated with ice-water and 30% NaOH solution until strongly basic.

The aqueous mixture was extracted with CH 2 Cl 2 .

The CH 2 Cl 2 extracts were washed with H 2 O, dried (Na 2 SO 4 ) and evaporated in vacuo to give 4.3 g of a dark gum.

The dark gum was chromatographed on silica gel

(Woelm, activity grade III) eluting with 30% ether/hexane and ethyl acetate, yield 2.6 g of a red-brown syrup.

4,8-dimethyl-5-ethyl-1,3,3aa,4a,5,9ba-hexahydro-2-(2-morfolino-ethyl)-2H-pyrrolo[3,4-c]quinoline' ( xxiv) (connection 26 in table I)

A cold solution of 40 ml of 0.94M BH^THF, under N2ble

added dropwise to a cold, stirred solution of 2.6 g of the pyrrolo-[3,4-c]quinoline (xxiii) above in 40 mL of dry THF. The solution was refluxed under N 2 in 4 hours. Excess BH 2 was eliminated by adding 20 mL cold H 2 O and 50 mL 6M HCl to the cooled solution under N 2 .Excess THF was distilled off at atmospheric pressure.

The aqueous mother liquor was made strongly alkaline with 50% NaOH solution and extracted with ether. The ether extracts were washed with H2O, dried (Na2SO4) and reduced to dryness in vacuo at

a rotary evaporator to give 1.85 g of a syrup.

The crude syrup was converted to the citrate salt (1.03 g citric acid) in ether as described above.

The crude citrate salt was crystallized from absolute ethanol/ether; yield 2.2 g, m.p. 6 5° (split.).

Example 7 (Method V)

2, 9- dimethyl- 1, 3- dioxo- 3aa, 3ba, 6a, IQba- tetrahydro- pyrrolo-[ 1, 2- a]- 2H- pyrrolo[ 3, 4- c] quinoline ( xxv)

A solution of 7.65 g (0.0316 mol) of benzoyl peroxide i

150 ml dry. CHCl^ was added dropwise (3 hours) to a stirred solution of 11.35 g (0.0704 mol) N-(p-tolyl)-pyrrolidine and 3.17 g (0.0285 mol) N-methylmaleimide under N 2 and cooled to -10°.

After storage at -10°C for 15 hours, 125 ml of a

25% NaOH solution added over 20 minutes and the mixture stirred 1/2 hour at 0°. Another 100 mL of H 2 O was added and the CHCl 3 phase was separated. The aqueous mother liquor was extracted with CHCl 2 and the combined CHCl 2 extracts were backwashed with H 2 O and dried (Na 2 SO 4 ). Removal of CHCl^

in vacuo on a rotary evaporator gave 14 g of crude oil.

The crude oil was chromatographed on silica gel (Woelm, activity grade III, distributed by ICN Pharmaceuticals, Cleveland, Ohio) eluting with 25% ether/hexanes.

The desired material obtained (1.5 g) was contaminated with a small amount of 2-benzoyloxy-N-(p-tolyl)pyrrolidine.

Conventional rules of nomenclature dictate that the products of Examples 7 and 8 be designated 2,9-dimethyl-derivatives instead of 2,8-dimethyl-derivatives, due to the presence of an additional fused ring in the system as R₁ and R₂ are bonded together. The 9-position in this system corresponds to the 8-position in the formula in Table I.

Example 8

2, 9- dimethyl- 1, 3, 3aa, 3ba, 6a, 1Oba- hexahydro- pyrrolo[ 1, 2- a]-2H- pyrrolo[ 3, 4- c] quinoline ( xxvi)

A cold solution of 57 ml of 0.94M BH^ • THF in THF was

during 10 minutes under.N 2 was added to a cold solution of 1.46 g (0.0054 mol) of the imide (xxv) prepared according to Example 7 in 75 ml of dry THF. The solution was stirred and refluxed under N2i for 24 hours. Excess BH 2 was eliminated by dropwise addition of 25 ml H 2 O and 50 ml 6M HCl. The THF was distilled off at atmospheric pressure and the remaining aqueous phase was made strongly alkaline with 15 ml of 50% NaOH solution. The aqueous layer was extracted with ether. The ether extracts were dried (Na 2 SO 4 ) and reduced to dryness in vacuo on a rotary evaporator to give 1.5 g of a brown oil. Flask to flask distillation of the oil (b.p. 107-111° at 0.3 mm) gave 0.86 g of a pink-colored oil. Transfer to the citrate salt gave 1.48 g of solid, m.p. 104-108°.

Example 9

4 , 8- dimethyl- l., 3- dioxo-5- ethyl- 3aa, 4a , 5 , 9ba- tetrahydro- 2H-pyrrolo[ 3, 4-c] quinoline (xxvii)

Sodium borohydride (19.6 g) was added portionwise under N 2

to a stirred solution of 11.75 g of 2,6-dimethylquinoline-3,4-dicarboximide in 400 ml of ice-HOAc. The internal temperature was maintained at or below 20°. The dark mixture was refluxed for 4 hours and then excess HOAc was distilled off in vacuo. The remaining syrup was treated with 80 ml of cold H 2 O and made alkaline with 30% NaOH solution. A thick precipitate formed which was extracted into 175 ml of Cl 2 Cl 2 . The CH 2 Cl 2 phase was separated, washed with H 2 O and dried (Na 2 SO 4 ). Removal of CH2C1'2 in vacuum on a rotas ion evaporator gave a

dark gum which was chromatographed on silica gel (Woelm,

act.degree III) by gradient elution with 1-25% EtOAc/hexane, yield 5 g.

( xxviii)

A solution of 3.64 g (19.8 mmol) of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride in 10 ml of DMF was added to a stirred mixture of 5 g (19.8 mmol) of the compound of formula ( Vila) where R2 = H, R4= -CH3, R' = -CH3> Rx = ~CH3 in C-8

and.R = H, 4.24 g (40. mmol) Na-CO- and 50 ml of dry DM F.

yz o

The reaction mixture was stirred at ambient temperature i

20 hours and then at 90° for 2 hours.

Inorganic salts were filtered off, and the filtrate was reduced to dryness in vacuo on a rotary evaporator to give 8 g of a red gum. The gum was chromatographed on neutral alumina (Woelm, act. grade III) by gradient elution with EtOAc/hexane to give the desired material as a syrup.

4,8-dimethyl-5-ethyl-1,3,3act,4a,5,9ba-hexahydro-2-(N-methyl-pyrrolidin-2-ylethyl)-2H-pyrrolo[3,4-c]quinoline (xxiii)

(compound. 28 in Table I)

A cold solution of 75 ml of 0.94M BH3-THF was added dropwise to a cold solution of the pyrrolo[3,4-c]quinoline (xxviii) above in 50 ml of dry THF under N,,. The solution was stirred and refluxed for 18 hours. Standard acid/H 2 O work-up as described for corresponding compounds gave 0.8 g of a golden syrup which was transferred to the dicitrate from an EtOAc solution of the syrup and 0.8 g of citric acid. A cream-colored solid was obtained, m.p. 140° •

(column.).

Example 10 (Method VI)

1, 3-di oxo-3aa , 4a , 5 , 9ba-tetrahydro^- 2 , 4 , 8- trimethyl 1- 2H-pyrrolo-[ 3, 4-c] quinoline (xxx)

A mixture of 13.7 g (0.057 mol) of (iii), 1.04 g

(7.6 wt%) PtO 2 and 250 mL of reagent grade MeOH were added to a nickel-plated flask on a Parr shaker. The reactor was supplied with H2 and shaken until the H2 absorption ceased. The catalyst was removed by filtration through a celite pad. The pad was washed with 400 mL of acetone which was mixed with the MeOH filtrate. The combined filtrate was evaporated

N

to dryness to give a peach-colored solid, m.p.•147-148°.

5- benzoyl- 1, 3- dioxo- 3aa, 4a, 5, 9ba- tetrahydro- 2, 4, 8- trimethy1-2H- pyrrolo[ 3, 4-c] quinoline (xxxi)

Benzoyl chloride (1.14 g, 0.008 mol) in 25 mL of dry toluene

was added in one portion to a mixture of 1.8 g (0.0074 mol) of (xxx), 0.82 g (0.008 mol) triethylamine and 25 ml dry toluene.

The resulting mixture was stirred and refluxed

for 5 h, and after cooling it was diluted with 200 mL of EtOAc and transferred to a separatory funnel. The organic layer

was washed with 100 ml saturated NaHCO 3 solution and U 3 O and then dried (NaSO 3 ). Removal of the solvent in vacuo on a rotary evaporator gave a tan semi-solid. Trituration with ether gave a cream-coloured solid, m.p. 204-205°.

5-benzy1- 1, 3, 3aa, 4a, 5, 9ba- hexahydro- 2, 4, 8- trimethyl- 2H-pyrroloph3, 4- c] quinoline (xxx. ii) (compound 39 in Table I)

A solution of BH^ *THF (55 ml of a 0.98M solution)

was added under N2 to a stirred solution of 1.8 g

. (0.0052 mol) of (xxxi) in 50 mL of dry THF. The mixture was refluxed for 18 hours under N 2 , cooled and quenched with 30 ml H 2 O and 60 ml 6M HCl. The THF was distilled off at atmospheric pressure and the remaining aqueous layer was made alkaline with 25 mL of 50% aqueous NaOH and then extracted with ether. The ether extract was dried (Na 2 SO 4 ) and evaporated to dryness on a rotary evaporator, and the resulting oil was flask to flask distilled; k.p. 140-145° at 0.25 mm Hg. Conversion to the citrate salt in ether gave a white solid,

sm.p. 88-90°.

Example 11

1,3,3aa,4a,5,9ba-hexahydro-2,4,8-trimethyl-2H-pyrrole o[3,4-c]-quinoline (xxxiii) (compound 40 in Table I)

To a solution of (xxx) (7.33 g, 0.03 mol) in 300 ml

dry THF was gradually added 9.1 g (0.225 mol) of lithium aluminum hydride under N 2 , and the mixture was stirred and refluxed overnight.

The reaction flask was then cooled in an ice bath, and the reaction was quenched by the addition of saturated aqueous Na 2 SO 4 solution. Inorganic salts were filtered off, and the filtrate brought to dryness on a rotary evaporator to

give a viscous brown oil. Flask to flask distillation gave a pure product, b.p. 100-110° at 0.35 mm Hg.

Example 12

5-acetyl-1,3,3aa,4a,5,9ba-hexahydro-2,4,8-trimethyl-2H-pyrrolo-[3,4-c]quinoline (xxxiv) (compound 43 in Table I)

A solution of 1.5 g of acetyl chloride in 20 ml of toluene was added dropwise to a rapidly stirred mixture of 2.6 g (0.012 mol) of (xxxiii), 100 ml of toluene and 50 ml of 10% aqueous NaOH. The reaction mixture was stirred and heated at 45° under N 2 overnight.

The toluene layer was separated, mixed with toluene washing liquid

from the aqueous layer, backwashed with H 2 O and dried (Na-jSO^). The toluene solution was evaporated in vacuo and the resulting oil was distilled flask by flask,

k.p. 110-120° at 0.15 mm Hg. The oil was transferred to the citrate salt in ether, m.p. 75-80°.

Example 13

A solution of 5.4 g of the compound (va) in 100 ml dry. ether was vigorously stirred and treated dropwise with a solution of 8.91. g of di-p-toluoyl-l-tartaric acid in 200 ml of dry ether. Stirring was continued for 2 1/2 hours. The white solid was filtered, washed with ether and dried.

The salt was dissolved in 2:1 ether/MeOH (300 mL) and allowed to stand at ambient temperature. White crystals were filtered off and washed with ether, yield 4.22 g. The filtrate was cooled in a refrigerator. An additional 0.65 g of crystals was collected, total yield, 4.87 g, [α]D+45° (H 2 O) C, 0.1.

The tartrate salt was dissolved in H 2 O and made strongly alkaline with 10% NaOH solution. The free base was extracted into ether, washed with H 2 O, dried (Na 2 SO 4 ), and the ether was removed in vacuo on a rotary evaporator, yielding 2.15 g of a colorless oil, [a].D-86 , 63° (EtOH ) C, 0.105.

The oil was converted to a citrate salt in the same manner as described above in Example 1, yield 2.8 g,

[α]D-38.75° (H 2 O), C, 0.1.

The above MeOH/ether filtrate was reduced to dryness.

The resulting salt was triturated with EtOAc, ether and dried, yield, 6.6 g, [α]D + 85°, c, 0.1.

The salt was transferred to it. free base as described above to give 2.65 g of an oil, [α]D+43.65° (EtOH),

C; 0.12.

Conversion to the citrate salt as described above gave

3.25 g solid, [ot]D+ 16.25° (H 2 O), c, 0.1.

Example 14

2- ethyl- 6- methylquinoline- 3, 4- dicarboxylic acid (xxxv)

A stirred solution of 0.45 mol of 5-methylisatin, 300 g of KOH and 1.1 liter of r₂O was heated to 55° and 1.26 mol of ethyl propionyl acetate was added dropwise over 3 hours.

The internal temperature was raised to and maintained at 85° i

45 minutes after the addition was complete. The reaction mixture was then stirred at ambient temperature i

2 days.

Acidification of the reaction mixture, which was maintained at 20°, by the dropwise addition of 400 mL of concentrated HCl gave a tan solid which was collected, washed with water and dried.

2- ethyl-6-methyl- quinoline- 3, 4- dicarboxylic uric anhydride (xxxvi)

A mixture of 0.285 mol of (xxxv) and 1 liter of Ac 2 O was stirred and refluxed for 23 hours.

Ac 2 O was removed in vacuo using a rotary evaporator and the dark solid obtained was triturated with 500 mL of ether and filtered. Concentration of the filtrate gave a small amount of additional product.

1, 3- dioxo- 2, 8- dimethyl- 4- ethyl- 2H- pyrrolo[3, 4-c] quinoline

(xxxviii)

To a cooled mixture of 0.26 mol of (xxxvi) and 1 liter of dry pyridine was added a small excess of reagent grade dry methylamine. The dark mixture was warmed to room temperature with stirring and refluxed for 20 hours. The reaction mixture was cooled and the pyridine removed in vacuo on a rotary evaporator. The resulting dark solid was triturated with toluene and evaporated in vacuo. Trituration with ether gave the product which was used further without further purification.

4, 5- diethyl- 2, 8- dimethyl- 1, 3- dioxo- 3aa, 4a, 5, 9ba- tetrahydro-2H- pyrrolo[ 3, 4-c] quinoline (xxxix)

To a cooled, stirred solution of 0.0624 mol of (xxxiii) and 550 ml of ice-HOAc under N 2 , 0.624 mol of NaBH^ was added portionwise while the internal temperature was maintained between 15 and 20 . The reaction mixture was stirred overnight at ambient temperature, followed by 1 hour reflux. The reaction mixture was cooled, diluted with 1 liter of H 2 O and made alkaline (pH 11-12) with 50% NaOH. The resulting mixture was extracted with EtOAc. The organic phases were collected,

dried (Na-jSO^) and evaporated to dryness in vacuo to give a reddish-brown oil.

The pure epimer was obtained by gradient elution with ether/hexane over a column of silica gel.

4,5-diethyl-2,8-dimethyl-1,3,3aa,4a,5,9ba-hex. ahydro-2H-pyrrolo-[3,4-c]quinoline (xl) (compound 15 in Table I)

To a cooled, stirred solution of 0.025 mol of (xxxix)

in 50 ml. anhydrous reagent-grade THF was added under N 2 to 270 ml of a 0.94 molar solution of BH 2 /THF over a period of 20 minutes. The reaction mixture was refluxed under N2i for 18 hours. About. 100 mL of THF was distilled off at atmospheric pressure, and the reaction in the remaining solution was quenched with 100 mL of H 2 O and 120 mL of 6M HCl. The remaining THF was distilled off at atmospheric pressure and the resulting aqueous phase was made strongly alkaline with 20% NaOH. The milky suspension was extracted with several portions of ether. The extracts were combined, dried -(Na^O^) and evaporated in vacuo to give a crude yellow oil. Flask to flask distillation gave a colorless oil. Conversion to the citrate salt in ether gave a white solid, m.p. 99-101°.

Example 15

2, 10- dimethyl- 1, 3- dioxo- 3aa, 3ba, 7a, llbg- tetrahydro- piperidino-[ 1, 2- a]- 2H- pyrrolo[ 3, 4- c] quinoline ( xli)

A solution of 0.0316 mol of benzoyl peroxide in 150 ml of dry CHCl 2 was added dropwise over the course of 3 hours to a stirred solution of 0.07 mol of N-(p-tolyl)piperidine and 0.028 mol of N-methyl-maleimide under N2 and cooled to -10°.

After standing at -10° for 15 hours, 125 ml of 25% aqueous NaOH solution were added over 20 minutes, and the mixture was stirred for half an hour at 0°. A further 100 ml of H₂O was added and the CHCl₂ phase separated. The aqueous mother liquor was extracted with CHCl 2 , and the combined CHCl 2 extracts were washed with H 2 O and dried (Na 2 SO 4 ). Evaporation of CHCl 2 gave a dark crude oil which was purified on a silica gel column eluting with 25% ether/hexane.

2, 10- dimethyl- 1, 3, 3aa, 3ba, 6a, 11ba- hexahydro-piperidino[ 1,2-a]-2H- pyrrolo[ 3, 4-c] quinoline (xlii) (compound 46 in Table I)

A cold solution of 57 ml of a 0.94 M BH 2 /THF solution was added during 10 minutes under N 2 to a cold solution of 0.0054 mol of (xli) in 75 ml of dry THF. The solution was refluxed and stirred for 24 hours under N2. Excess BH 2 was eliminated by dropwise addition of 25 ml H 2 O and 50 ml 6M. HC1. The THF was distilled off at atmospheric pressure and the remaining aqueous solution was made strongly alkaline with 15 ml of a 50% NaOH solution. The aqueous layer was extracted with ether. The ether extracts were dried (Na 2 SO 4 ) and reduced to dryness in vacuo to give a brown oil. Flask to. flask distillation gave an oil which was converted into the citrate salt, m.p. 156-160°.

As indicated in example 7, correct nomenclature is indicated

that the product according to this example is designated the 2,10-dimethyl derivative and not the 2,8-compound, the latter numbering system following from the general formula given in Table I.

The compounds produced according to the invention are

has been found to have antipsychotic properties, as will be shown by favorable comparisons with certain known antipsychotics, notably, thioridazine and clozapine in standard experimental pharmacological and biochemical investigations.

Compounds produced according to the invention counteract, for example, apomorphine-induced climbing in mice, they counteract a,4-dimethyl-3-hydroxyphenethylamine hydrochloride-induced hyperactivity in rats, they counteract apomorphine-induced hyperactivity more than apomorphine-induced biting in rats, they have a very weak cataleptic effect on rats and they antagonize hyperactivity induced by injection of dopamine into the nucleus accumbens in rats. They also increase dopamine flow in the limbic area of the rat brain, which is measured by an increase in homovanillic acid levels. These results indicate that the pyrrolo[3,4-c]quinoline derivatives prepared according to the invention are antipsychotic agents that are relatively free of extrapyramidal side effects (EPS) and by implication that they do not induce tardive dyskinesia in humans. Compounds prepared according to the invention are also useful in alleviating side effects, such as tardive dyskinesia, of other antipsychotic agents.

Antagonism of apomorphine-evoked climbing in mice as a test for antipsychotic agents is described in Puech et al, European Journal of Pharmacology, 50, 291-300

(1978); Costall, et al., European Journal of Pharmacology,

50, 39-50 (1978); Ther et al. Arch. Int. Pharmacodyn.. CXXXVIII, 302-310 (1962); and Vonvoightlander et al., The Journal of Pharmacology and Experimental Therapeutics, 193, 88-94, (1975). The known clinically effective antipsychotic agents can counteract the tendency to climb depending on the dosage. Compared to known antipsychotic compounds, the compounds produced according to the invention are advantageous, as will be seen from the results summarized in the following Table II:

In investigations on antipsychotic activity with

the above-mentioned tests on rats, the compounds produced according to the invention exhibit activity when administered intraperitoneally in a dose from approx. 2.5 mg/kg body weight to 20 mg/kg body weight.. A preferred compound of formula (II) with the (3-configuration wherein , R^ and Rg are each methyl and R,, is ethyl) showed activity against apomorphine -induced hyperactivity when administered intraperitoneally in an amount of approximately 5 mg/kg body weight.

The new compounds also show effective analgesic-anti-inflammatory action in the standard inflamed rat paw test when carrageenan was used as an irritant. The analgesic activity of the new compounds is. beneficial compared to a reference standard such as aspirin. In the paw-press test, a preferred compound of formula (II) with the (3-configuration where R^, R^ and Rg. are each methyl and R^ is ethyl) raises the pain threshold by 73.2% in an oral dose of 100 mg/kg body weight; and in addition, this compound also showed significant anti-inflammatory activity (74.1% reduction in foot volume) at the same dose, a favorable result compared to reference standards.

In general, the compounds produced according to the invention exhibit analgesic effects on mice in laboratory experiments when they are administered orally in a dose of from approx. 5 to 100 mg/kg body weight.

Analgesic action has also been shown for the compounds produced according to the invention by the acetic acid-induced writhing test in mice, see R. Koster et al., "Acetic Acid for Analgesic Screening", Fed. Pro. 18:412 (1959). In this study, 10 ml/kg of 0.6% aqueous acetic acid was injected intraperitoneally into groups of six male Swiss-Webster mice (18-22 grams) 30 minutes after oral administration of the test compound. The mice were then placed in a plexiglass chamber for observation, and the number of writhes in each animal was counted over a period of 10 minutes starting 3 minutes after the acetic acid treatment. Comparison of the total number of writhes with the number observed for placebo-treated control groups on the same day was used to determine the activity of the test compound.

Antidepressant activity has also been shown for various compounds prepared according to the invention, e.g. compounds 11 and 28 in Table I. A suitable study on antidepressant activity is the muricidal rat study where it has been shown that the rats' tendency to kill mice can be selectively counteracted with antidepressants. All clinically effective antidepressants, e.g. tricyclic compounds such as impramine and amitriptyline, iprindole and mianserin, selectively antagonize muricid propensity in rats. References for this investigation are Z. P. Horovitz et al., Int. J. .Neuropharmacol. , 5:405-411 (1966) and J.B. Malick, Pharmacology Biochemistry and Behavior, 3:697-699 (1975).

In the muricid study, Long-Evans black-headed rats weighing 200-250 grams were isolated one in each cage and given food and water ad libitum. The rats were examined for muricide. propensity by placing a male Swiss-Webster mouse gently in front of the rat's cage, observing whether it was killed within a 5-min period.

Only rats that consistently killed mice during this 5-min period were used in the experiment. During the examination, the rats were tested in the morning (same day control) and then given the test compound or a placebo preparation intraperitoneally in the afternoon, and then tested/again if they killed 30 and 60 minutes after administration of the preparation.

Immediately after the second trial of mouse killing, all rats were examined for neurological disorder (ataxia) on a 45° inclined plate. As with the acetic acid twist test, the activity of the test compound was determined by comparison with the placebo results.

When used as antidepressants, the compounds produced according to the invention can be administered in an amount of from approx. 5 to 100 mg/kg body weight per day, preferably in a single dose at bedtime. Alternatively, the dose can be divided into equal parts and administered 3 to 4 times per day. day. Probable usual doses for the treatment of clinical depression would be approx. 100 to 300 mg/day. In the rat study for muricid activity, imipramine, a known antidepressant, is effective at 10 mg/kg administered intraperitoneally, and the usual dose range for humans is between 75 and 300 mg in total.

In consideration of the stated antipsychotic, antidepressant and analgesic effect of the compounds produced according to the invention, a pharmaceutical preparation can be prepared which comprises as active ingredient, an effective amount of the pyrrolo[3,4-c]-quinoline or the substituted pyrrolo[3, 4-c]-quinoline of formula (I) or (II) without . the caveats i) and ii) stated for the compounds of formula (I) together with a non-toxic, pharmaceutically acceptable diluent or carrier.

The pharmaceutical preparation may be in a form suitable for various uses, including oral, parenteral or rectal administration. For example the preparations can be prepared by known methods into tablets, capsules > aqueous or diaper-like solutions, suspensions or emulsions, or sterile injectable aqueous or diaper-like solutions or suspensions, dispersible powders or suppositories.

It will be clear to those skilled in the art that the pharmaceutical preparations, in addition to the active pyrrolo-quinoline derivative, may also contain one or more known drugs, such as an analgesic or antidepressant, or any other suitable drug. E.g. can any of the compounds prepared according to the invention

induce vomiting to some extent, and the compound can thus be administered simultaneously with an anti-emetic agent.

Preferred pharmaceutical preparations include such as

is suitable for oral administration in unit dose form, e.g.

tablets and capsules which may contain between 1 and 600 mg of the active ingredient, or which are suitable for intravenous, intramuscular or subcutaneous injection, e.g. a sterile aqueous solution containing between 1 and 50 mg/ml active ingredient, depending on e.g. the effectiveness of the relevant pyrrolo-quinoline derivative.

By administering an effective amount of a pyrrolo-[3,4-c]quinoline prepared according to the invention to a host animal, such as a human in need of such treatment, an antipsychotic, antidepressant or analgesic effect is thus achieved.

Based on the effect that the pyrrolo[3,4-c]quinolines show in standard animal experiments and a comparison of these with the effect of antipsychotic and analgesic agents currently used in the same experiments, the preparations are generally administered to humans, to achieve antipsychotic or analgesic effects in an oral dose of between approx. 300 mg and 600 mg of active ingredient, or in an intramuscular or subcutaneous dose of between 75 and 150 mg of active ingredient, the preparation being administered 1 or 2 times per day. However, it will be understood that the amount of pyrrolo[3,4-c]quinoline administered will depend on the particular compound used and the degree of treatment required.

Claims (7)

1. Procedure for the preparation of therapeutically active compounds of the formula: where R2 means hydrogen or 'a C^-Cg normal-alkyl-, C3-Cg cycloalkyl-, C^-Cg hydroxyalkyl-, C3-Cg hydroxycycloalkyl-, phenyl-, benzyl-, 2-morpholinoethyl-, 2-[ N-methylpyrrolidin-2-yl]- ethyl or 3-p-fluorobenzoylpropyl radical, R 4 means hydrogen or a C 1 -C 3 alkyl or phenyl radical, R5 means hydrogen or a C1-C6 alkyl, C3-C8 cycloalkyl, acetyl, benzyl or CF3 CH3 radical, or when R4 and R1- mean alkyl, they may be bonded together to form, together with the adjacent ring atoms in the pyrroloquinoline nucleus, a 5-, 6- or 7-membered ring, and R 1 and R 2 , which may be the same or different, represent hydrogen or a halogen atom, or a trifluoromethyl, C 1 -C 8 alkyl, C3" Cg cycloalkyl-, C-^ -C^ - alkoxy-, C^ -C-j alkylthio-, hydroxy- or cyano radical, or when Rx and R^ are alkoxy bonded to neighboring carbon atoms, they can be linked together to form a methylenedioxy-. or ethylenedioxy radical,' or a pharmaceutically acceptable acid addition salt thereof, with the proviso that i) when R. is hydrogen, RR is methyl, R is hydrogen and R is hydrogen or methyl in the 8-position, R2 is not methyl or phenyl, and ■ ii) when R^ and R,- are bonded together to form a 5-membered ring together with the adjacent ring atoms, and R^' and is hydrogen, R2 is not phenyl, characterized by (a) reduction of a compound with the formula: to form the corresponding compound of formula I; (b) reacting a compound of formula I, wherein at least one of Rx and R^ means a methoxy radical with bromohydropgenic acid; (c) debenzylation of a compound of the formula: by catalytic hydrogenolysis; (d) reacting a compound of the formula: with a compound of the formula R 2 X where R 2 has the above indicated meaning except for hydrogen, and X means a substituted . bar group, e.g. bromine or chlorine; (e) reaction of a compound of the formula: with an acetic acid halide, e.g. acetyl chloride; or acetic anhydride; or (f) resolving a racemate of formula I where R^ r R4 / R5 in Rx°9 Ry have the indicated meanings, and optionally converting the produced compound into a pharmaceutically acceptable salt. 2. Method as set forth in claim 1, characterized in that compounds are produced where R2 means hydrogen or one c^~ cg normal-alkyl-, 2-morpholinoethyl-, 2-[N-methylpyrrolidin-2-yl]ethyl- or 3- p-fluorobenzoylpropyl radical, means hydrogen or a C^-C^ alkyl radical, R^ means hydrogen or a C-^-C^ alkyl, acetyl or benzyl radical, or R^ and R,- are alkyl and are bonded together to form with the adjacent ring atoms of the pyrroloquinoline nucleus, a 5-, 6- or 7-membered ring, R₁ means hydrogen and R₂ means a halogen atom or a C₁ -C₁ alkyl, C₁ -C₁ alkoxy, hydroxy or cyano radical. 3. Method as stated in claim 1 or 2, characterized in that a compound is produced where the hydrogen atoms in positions 9b, 3a and 4 are cis to each other.. 4. Method as specified in claim 1, 2 or 3, characterized in that a compound with the formula is produced: where R,,, R. and R,- have the meanings specified in claim 2, R 8 means a halogen atom or a C 1 -C 8 alkyl, alkoxy, hydroxy or cyano radical. 5. Method as set forth in claim 4, characterized in that a compound is prepared where R 2 , R 4 and R 8 each means a methyl radical, and R 1 means an ethyl radical. 6. Method as set forth in claim 4, characterized in that a compound is prepared where R2 and Rg each mean a methyl radical and R^ and R1- each mean an ethyl radical. 7. Method as set forth in claim 4, characterized in that a compound is prepared where R^ and Rg each means a methyl radical, and R^ and R^, are alkyl and are bound together to form a 6-membered ring.