Note: Descriptions are shown in the official language in which they were submitted.
2553
The present invention relates to octah~dro-lH-pyrrolo~2,3-g~
isoquinolines of the general formula
R~ $ R3 A
wherein Rl is hydrogen, alkyl, alkanoyl, arylcarbonyl or
arylalkyl; R2 and R3, independently, are hydrogen, alkyl,
~ycloalkyl, alkenyl, alkanoyl and arylcarbonyl, aryl or
arylalXyl; and R4 is hydrogen, alkyl, hydroxyalkyl, phenyl-
hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxy-
alkyl, alkoxyphenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-
hydroxyalkyl, alkoxy-hydroxyalkyl, alkanoyloxyalkyl and aryl-
carbonyloxyalkyl, al];oxycarbonylalkyl, arylalkyl, alkenyl,
cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, aryl-
carboxamido-alkyl, alkanoyl-alkyl and arylcarbonylalkyl,
cyclic-alkyloxoalkyl, cyclic-alkylhydroxyalkyl, alkenyloxy-
alkyl, arylalkenyl, aryloxyalkyl, N-alkyl-pyrrolidinylalkyl,
trifluoroalkyl o~ 2 to 6 carbon atoms, aryl-N-imidazolonyl-
alkyl, or R ~ N-alkyl, wherein R6 and R7, independently, ar~
hydrogen or lkyl, or taken together with the nitrogen, are
a morpholine, N-methyl-piperazine, piperazine or pyrrolidine
group and X is O or S;
with alkyl, alkoxy, alkenyl, alkynyl and alkanoyl having up
to 7 carbon atoms, cycloalkyl having 3 to 6 carbon atoms,
cyclic-alkyl being cycloalkyl, bornyl or adamantyl and with
aryl being phenyl or phenyl bearing one or more substituents
1~325S3
selected from the group consisting of halogen, trifluoro-
methyl, alkyl, alkoxy, nitro, amino, alkylamino and
dialkylamino;
optical and geometric isomers of these compounds and pharmaceut-
ically accepta~le acid addition salts thereof.
As used herein, the term "alkyl" denotes a straight or branched
chain saturated hydrocar~on containing 1 to 7 carbon atoms, for
example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neo-
pentyl, pentyl, heptyl, and the like. The term "alkoxy" denotes
an alkyl ether group in which the alkyl group is as described
above, for example, methoxy, ethoxy, propoxy, pentoxy and the
like. The term "alkenyl" denotes a straight or branched chain
unsaturated hydrocarbon containing 2 to 7 carbon atoms,for example,
vinyl, allyl, and the like. The term "alkynyl" denotes a straight
or branched chain unsaturated hydrocarbon containing 2 to 7 carbon
atoms, for example, ethynyl, propargyl, methylbutynyl, and the
like. The term "halogen" or "halo" denotes the halogens, bromine,
chlorine, fluorine, and iodine. The term "trifluoroalkyl of 2
to 6 carbon atoms" preferably denotes 2,2,2-trifluoroethyl and
the like. The term "aryl" denotes phenyl or phenyl bearing one
or more substituents selected from the group consisting of halogen
trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower
alkylamino, and di-lower alkylamino. The term "arylalkyl" pre-
ferably denotes benzyl and the like. The term "aryloxy" denotes
an aryl ether group in which the aryl group is as described
above, for example, phenoxy and the like. The ~ m "a~x~l" denotes a
group derived from an aliphatic carboxylic acid of 1 to 7 carbon
atoms, for example formyl, acetyl, propionyl, and the like. The
term "arylcarbonyl"denotes a group derived from an aromatic
....
1~3ZSS3
carboxylic acid, such as be~zoyl and the like. The term "alk-
anoyloxy" denotes a group derived from an aliphatic carboxylic
acid of 1 to 7 carbon atoms, for example, formyloxy, acetoxy,
propionyloxy, and the like. The term "arylcarbonyloxy" denotes
a group derived from an aromatic carboxylic acid, ~uch as benzo-
yloxy and the like. The term "cyclic-alkyl" denotes a cycloalkyl
group.of 3 to 6 carbon atoms, that is cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, bornyl or adamantyl.
Preferred compounds of formula A are those wherei~ is hydrogen, R2 and R3
are alkyl; R4 is alkyl, hydroxyaL~yl, phenyl-hydroxyaL~yl, halophenyl-hydroxy,alkyl,
~o~y~kyl, aryloxy~kyl, a~lcarbony~kyl, or arylalkyl: and X is 0.
Most preferred compounds of formula A of the invention wherein g is O are:
3-ethyl-2,6-dimethyl-4,4a,~,6,7,8,8a,9-octahydro-4a,8s-trans-lH-pyrrolo-
12,3-g3 isoquinolin-4-one;
(-~3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-
12,3-g3 isoquinolin-4-one;
(-)-3-ethyl-2,6-dimethyl-4,4a,5,~,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-
12,3-g] isoquinolin-4-one, hydrochloride, 0.25 molar hydrate;
2-methyl-3-ethyl-6-(2-hydroxy-2-phenylethyl~4,4a,5,6,7,8,8s,9-octahydro-
4a,8a-trans-1~-pyrrolo[2,3-g] isoquinoLi.n-4-one;
2,3,6-trimethyl-4,~a,5~6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolol2,3-g3 -
isoquinolin-4-one;
2,3,~trimethyl-4,4a,5,6,7,B,8a,~octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] -
isoquinolin-4-one, hydroc~doride;
113Z553
2-methyl-3-ethyl-6-benzyl-4,4a,5,~,7,8,8a,9-octanydr~4a,8a-trarl~lH-
2 pyrrolol2,3-g3 isoquinolin-4-one;
3 2-methyl-3-ethyl-6-benzyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-
4 pyrrolo[2,3~"] isoquinolin-4-one, hydrochloride;
S 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8~-
6 trans-lH-pyrrolo[2,3~] isoquinolin-4-one;
7 2-methyl-3-ethyl-6-(2-ethoxyethyl~4,4a,5,6,7,8,8a,9-octahydr~4a,8a-trans-
8 lH-pyrrolo[2,3-g] isoquinolin-4-one;
g 2-methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-
lH-pyrrolo[2,3~ isoquinolin-4-one,hydro~hloride;
11 2-methyl-3-ethyl-6-14-(4-fluorophenyl~4-oxobutyll -4,4a,5,6,7,8,8a,9-octahydro-
12 4s,8a-trans-lH-pyrrolo[2,3~3 isoquinolin-4-one;
13 2-methyl-3-ethyl-6-13-(4-fluorophenyl)-3-oxopropylJ -4,4a,5,6,7,8,8a,9-octahydro-
14 4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one;
lS 2-methyl-3-ethyl-6~3-phenoxypropyl~-4,4a,5,6,7,8,8a,9-octahydro-4a,8Q-trans-
16 lH-pyrrolo[2,3~ isoquinolin-4-one; -
17 2-methyl-3-ethyl-6~2-hydroxy-3-methylbutyl)-4,4a,5,6,7,8,8a,9-octahydro-
18 4a,8a-trans-lH-pyrrolo[2,3~] isoquinolin-4-one;
19 2-methyl-3-ethyl-6 (2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7,8,8a,9-octahydro-
4a,8a-trans-lH-pyrrolo[2,3-g]isoquinolin-4-one; and
21 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolol2,3~]-
22 isoquinolin-4~ne, hydrochloride, dihydrate.
23 .
24 .
27
_4_
1~3Z5S3
Il
1 ¦¦ Exemplary of the compolmds of formula A wherein X is O are:
2 !i 2-methyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3~ isoquinolin-
3 4-one;
4 3-ethyl-2,6~imethyl-4,4a,5,6,7,8,8a,9-octahydr~lH-pyrrolol2,3~ isoqu~nolin-
5 4-one;
6 3-ethyl~,2,6-trimethyl-4,4a,5,6,7,8,8a,9~ctahydro-lH-pyrrolol2,3~"] isoquinolin-
7 4-one;
B l-benzoyl-2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3~ -
9 isoquinolin-4-one;
3-ethyl-2-methyl-6~2-propynyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo-
11 ~2,3~] isoquinolin-4-one;
12 ~3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-
13 [2,3~] isoquinolin-4-one;
14 (~)-3-ethyl-2,6~imethyl-4,4a,5,6,7,8,8a,9-octahydr~4a,8a-trans-lH-pyrrolo-
~2,3-g] isoquinolin-4-one, hydrochloride, 0.25 molar hydrate;
16 3,6-dimethyl-2-(2-propyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo~2,3 gl-
17 isoquinolin-4-one, hydrochloride;
1~ 3,6-dimethyl-2~2-propyl)-4,4a,5,6,7~8,8a,9~ctahydro-lH-pyrrolo[2,3 g3-
19 isoquinolin-4-one;
2,6-dimethyl-3-butyl-4,4a,5,6,~,8,8a,9-octahydro-lH-pyrrdo[2,3~] isoquinolin-
21 4-one;
22 2-methyl-3-ethyl-6-[2-hydroxy-2-(4-chlorophenyl)ethyll -4,4a,5,6,7,8,8a,9-
23 octahydro-lH-pyrrolo[2,3~] isoquinolin-4-one;
24 2-methyl-3-ethyl-6-(2-hydroxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrol~
25 [2,3~] isoquinolin-4-one;
~6 2-methyl-3-ethyl-6-(2-propenyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo-
77 [2,3~3 oqu~nolin-4-one;
-- 5 --
r ~175 -
` ~ 1132553
1 1 2-methyl-3-ethyl-6~2-propenyl~4,4a,5,6,7,8,8a,9-octahydro-lH-p~rolo-
2 I2,3~ isoquinolin-4-one, hydrochloride, 0.5 molar hydrate;
3 ¦ 2-methyl-3-ethyl-6-(cyclopropylmethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-
4 ¦ pyrrolo[2,3~,~ isoquinolin-4~ne;
S 2-methyl-3-ethyl-6~cyclopropylmethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-
6 pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride, 0.2 molar hydrate;
7 2,6-dimethyl-3-ethyl-1~2,2~imethyl-1-oxopropyl)-4,4a,5,6,7,8,8a,9-octahydro-
-8 lH-pyrrolo[2,3~] isoquinolin-4-one;
- 9 ~,6-dimethyl-3-cyclopropyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3~-
isoquinolin-4-one;
11 3-ethyl-2-methyl-6~2-dimethylaminoethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-
12 pyrrolol2,3~] isoquinolin-4~ne;
13 1-benzyl-2,6~imethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydr~lH-pyrrolo~2,3 g3-
14 isoquinolin-4-one;
3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9~ctahydro-lH-pyrrolo[2,3~3 isoquinolin-
16 4-ox~6-aceti~ acid, ethyl ester; .
17 2-benzyl-3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3~,] isoquinolin-
1~ 4-one;
19 3,6-dimethyl-2-(2-propenyl)-4,4a,5,6,7,8,8a,g-octahydro-lH-pyrrolo~2,3~ -
isoquinolin-4-one;
21 2,6-dimethyl-3~2-propyl~4,4a,5,6,7,8,8a99-octahydro-lH-pyrrolo[2,3 g3-
22 isoquinolin-4-one;
23 3-ethyl-2-methyl-6-r2-hydroxy-3-(4-chlorophenoxy)propyll -4,4a,5,6,7,8,8a,9-
24 .octahydro-lH-pyrrolo[293~] isoquinolin-4-one;
3,6-diethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3~] isoquLnolin-
~6 4-one;
Z7
-6-
~ I
~ ` il3Zs53 il
. ~l
2-methyl-3-ethyl-6-propyl-4,4a,5,6,7,8,8Q,9~ctahydro~ -pyrrol~
2 ~2,3-~isoquinolin-4~ne;
3 ~-methyl-3-ethyl-6-butyl-4,4~,5,6,7,8,8a,9-octahydro-lH-pyrrolo-
l2,3-g] isoquinolin-4-one;
3 2-methyl-~ethyl-6-pentyl-4,4a,5,6,7,8,8a,g-octahydro-lH-pyrrolol2,3-g~-;
isoquinolin-4-one;
7 1 3,6-dimethyl-4,4a,5,6,7,8,8a,9-oct~hydro-lH-pyrrolo[2,3-g]-isoquinolin-
8 ~ 4-one;
~methyl-4,4a,5,6,7,8,8a79-octahydro-lH-pyrrolo[2,3-g~ isoquinolin-4-one;
~0 ~benzyl-4,4a,5,G,7,8,8a,9~ctahydro-lH-pyrrolo[2,3-g] isoquinolin-4-onej
11 2,~dimethyl-3-propyl-4,4a,5,6,7,8,8a,g-octahydro-lH-pyrrolo[2,3-s]-iso-
12 quinolin-4-one; . I
13 3-ethyl-2-methyl-6-[2-hydroxy-3-(4-t-butylphenoxy)-propyl)-4,4a,5,6,7,8,8a,9-
14 octahydro-lH-pyrrolc[2,3-g] isoquinolin-4-one;
lS 3-ethyl-2-methyl-6-[2-hydroxy-2-(4-chloro-3-trifluoromethylphenyl)ethyl]-
16 4,4as5,6,7,8,8a,9~ctahydro-lH-pyrrolo[2,3~] is.oquinolin-40ne;
17 . 3-ethyl-2-methyl-6-(2-hydroxy-2-adamantylethyl)-4,4a,5,6,7,8,8a,9-octa-
18 hydro-lH-pyrrolo[2,3-g] isoquinolin-4-one;
19 3-ethyl-2-methyl-6-[2-(4-morpholino)ethyl] -4,4a,5,6,7,8,8a,9~ctæhydro-1~-
2û pyrrolo~2,3-g] isoquinolin-4~ne;
21 ll 3-ethyl-2-methyl-6-[2-oxo-2~4-fluorophenyl)ethyll-4,4a,5,6,7,8,8a,9-octa-
22 ¦¦ hydro-lH-pyrrolo[2,3~] isoguinolin-4-one; ?
, . . . . . . .. , . . . . , . . _ . .. . _ . _ .. .. . .
2~ I . .
2 ~ ¦ .
26
27 1 . _
I . _ . . . . ...., . _ ...... .
i " '' ' ~.
- 7 - ~
I 113Z553
I .
1 3-ethyl-2-methyl-6-(2-methylpropyl)-4,4a,5,6,7,g,8a,9-octahydro-llI-
2 pyrrolo~2,3-g] isoguinolin-4-one;
3 3~thyl-2-methyl-6~yClobItylmethyl-4,4a,5,6,7,8,8a,9-octahydr~lH-
4 p~rrolo[2,3~ isoquinolin-4~ne;
3~thyl-2-methyl-6-hexyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g3-
-~i isoquinolin-4-one;
7 ~ethyl-2-methyl-6-heptyl-4,4a,5,6,7,8,8a,9-octahy~r ~ lH-p. ~ lor2,3 ~ 3--
8 isoquinolin-4-one;
9 3-ethyl-2-methyl-6-[2-(1-pyrrolidinyl)ethyl] -~,4a,5,6,7,8,8a,9-octahydro-lH-
lo pyrrolo~23-g3isoquinolin-4-one; ~ !
11 3-ethyl-2-methyl-6-(4-methoxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-
12 pyrrolo[2,3-g]isoquinolin-4-one;
13 2,6-dimethyl-3-ethyl-1-~-oxobutyl)-4,4a,5,6,7,8,~a,9~ctahydro-1~-pyrrolo-
14 12,3-g] iso~uinoIin-4~ne;
lS 3-ethyl-2-methyl-6-(4-1 chloro-2-phenylethyl~4,4a,5,6,7,8,8a,9-octahydr~lH-
16 pyrrolo[2,3-g] isoquinolin-4-one;
1~ ~~,~dimethyl-3-propyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-
18 pyrrolo[2,3~] isoquinolin-4-one;
19 2,3-dimethyl-6~2-phenylethyl)-4,4a,5,6,7,8,8a,9~ctahydro-4a,8a-
trans-lH-pyrrolo~2,3~] isoquinolin-4-one;
21 2,3-dimethyl-6-[4-(4-fluorophenyl~4-oxobutyl]-4,4a,5,6,7,8,8a,9-octa-
22 ¦ hydro-4a,8a-trans-lH-pyrrolo[2,3~] isoquinolin-4-one;
23 ¦ 3-ethyl-2-methyl-6~2,2,2-trifluoroethyl)-4,4a,5,6,7,8,8a,9-octahydro-
225 l4a8a-trans-lH-pyrrolo~23~]isoquinolin-4-one;
2,6~imethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-cis-1~-pyrrolo~2,3~]-
2S ~; isoquinolin-4-one;
27
,",.. ll
11325~i3
1 2-acetyl-3,6~imethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-
2 12,3 g3 isoquinolin~ne;
3 . 3-ethyl-2-methyl-6-[2-(2-thienyl)ethylJ-4,4a,5,6,7,8,8a,9~ctahydr~a,8a-
4 trans-lH-pyrrolo[2,3~] isoquinolin-4-one;
S 3-ethyl-2-methyl-6-[2~2-furyl)ethyl] -4,4a,5,6,7,8,8a,9-octahydro-4a,8s-trans-
6 lH-pyrrolo[2,3~] isoquinolin-4-one; and
7 3-ethyl-2-methyl-6-[2-(1,3-dihydro-2(2H)-benzoimidazolonyl)ethyl~ -4,4a,5,6,7,8,8a,~
.~ octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one.
,'g ..
Most preferred compounds of formula A of the invention wherein X is S are:
11 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,677,8,8a,9-octahydr~4a,8a-trans-
12 IH-pyrrolo[2,3 g3 isoqlLinolin-4-thione;
13 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrroloi2,~
14 gl isoquinolin-4-thione;
2-methyl-3-ethyl-6-~4~4-fluorophenyl)-4-oxobutyl] -4,4a,5,6,7,8,8a,9-octahydr~
16 4a,8a-trans-lH-pyrrolo[2,3~] isoquinolin-4-thione; and
17 2-methyl-3-ethyl-6~2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7,8,8a,9-octahydro-
~8 ~ 4a,8a-tr s-lEi-pyrrolo[2,3~] isoguinolin-4-tùione.
2l
225 '
26
_ 27
.....
113Z553
1 Exemplary of compounds of formula A wherein X is S are:
2 ~-methyl-3-ethyl-6 (2-hydroxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-o~tahydr~4a,8a-
3 trans-lH-pyrrolo~2,3~] isoquirlolin-4-thione;
4 2,3,6-trimethyl-4,4a,5,6,7,~,8a,g~ctahydr~4a,8a-trans-lH-pyrrolo[2,3~ is~
S quinolin-4-thione;
2-methyl-3-ethyl-6-benzyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pvrrolo-
~ [2,3-g] isoquinolin-4-thione;
.~ 2-methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-
g lH-pyrrolo[2,3-g3 isoquinolin-4-thione;
~0 2-~nethyl-3-ethyl-6-~3-(4-fluorophenyl)-3-oxopropyll -4,4a,5,6,7,8,Sa,9-octahydro-
11 4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-thione;
12 2-methyl-3-ethyl-6~3-phenoxypropyl)-4,4a,5,6,7,8,8a,9-oct~hydr~a,8a-trans-
13 lH-pyrrolo[2,3-g] isoquinolin-4-thione;
14 2-methyl-3-ethyl-6-(2-hydroxy-3-methylbutyl~4,4a,5,6,7,8,8a,9-octahydr~
lS 4a,8a-trans-lH-pyrrolo[2,3 gl isoquinolin-4-thione; and
16 .2-methyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolol2,3~] isoguinolin-4-
17 thione. .
~8 . ................ . .
19 The compounds of the invention may exist as the 4a,8a-trans or 4a,8a-cis isomers
or mixtures thereof; the 4a,8a-trans isomers are preferred.
21
22 The oo~pounds of the formLla A above, the~r optical and geometric iso-
23 mers and their pharmaoe utically acoepta~le acid addition salts can be prepa- :
red in accordan oe with the invention ky a prooess which ocmprises
26
27
113Z553
a) for preparing a compound of the formula A above wherein R1 is
hydrogen, R4 is alkyl, alkGxyalkyl or cycloalkyl-alkyl and
X is O and R2 and R3 are as described above, i.e. a compound
of the general formula
O
R~ ~ R3
~ H R2
wherein R4" is alkyl, alkoxyalkyl or cycloalkyl-alkyl and
R2 and R3 are as described above;
treating a compound of the general formula
4 ~ NH ~ ~ R3
N ~ ~ R
H 2
wherein R2, R3 and R4" are as described abo~e, with formalde-
hyde, or
b) for preparing a compound of the formula Ia above, treating a
compound of the general formula
R4"-N ~ XII
o
-- 11 --
~l13;~5S3
wherein R4" is as desc~ibed abo~e, with a compound of the
general formula
O ~ R3 in the presence
of a reducing O ~ / R3
~ agent or with
HO~'~ ~ R a c~mpound of
2 the general ~ ~
~II fon~la H2N VITT
wherein R2 and R3 are as described above, or a ketal or
hydrochloride precursor thereof, or
c) for preparing a compound of the formula A above wherein Rl
and R4 are hydrogen and X is O and R2 and R3 are as described
above, i.e. a compound of the general formula
HN ~ ~3
~ N ~ ~ Ib
H ~2
wherein R2 and R3 are as described above,
N-demethylating a compound of the formula Ia above wherein R4" is
methyl, or
d) for preparing a compound of the formula A above wherein R2
and R3, independently, are hydro.gen, alkyl, cycloalkyl,
alkenyl, aryl or arylalkyl, R4 is hydrogen, alkyl, alkoxy-
alkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-
alkyl, furyl-alkyl, alkenyloxyalkyl, arylalkenyl, aryloxy-
alkyl or trifluoroalkyl of 2 to 6 carbon atoms and X is S and
Rl is as described above, i.e. a compound of the general
formula
- 12 -
... . . . . . . . . .
~13~553
4 ~ N ~ R3
IIc"
3R
wherein R2' and R31, independently, are hydrogen, alkyl,
cycloalkyl, alkenyl, aryl or arylalkyl, R4" is hydrogen,
alkyl, alkoxyalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl,
alkynyl, thienyl-alkyl, furylalkyl, alkenyloxyalkyl, aryl-
alkenyl, aryloxyalkyl or trifluoroalkyl of 2 to 6 carbon
atoms and Rl is as described above,
treating a compound of the general formula
o
R''l ~ R3
~ IN 1 R2
wherein Rl, R2', R3' and R4''' are as described above,
with phosphorus pentasulfide, or
0 e) for preparing a compound of the formula A above, wherein R4
is hydroxyalkyl, phenylhydroxyalkyl, halophenyl-hydroxyalkyl,
alkylphenylhydroxyalkyl, alkoxyphenyl-hydroxyalkyl, aryloxy-
hydroxyalkyl, alkoxyhydroxyalkyl, alkanoyloxyalkyl and aryl-
carbonyloxyalkyl, alkoxycarbonylal];yl,
arylcarboxa~idoalkyl, alkanoylalkyl and aryl~arbonylalkyl,
cyclic-alkyloxoalkyl, cyclic-alkylhydroxyalkyl, N-alkyl-
pyrrolidinylalkyl, aryl-N-imidazolonylalkyl or
R
R ~ N-alkyl, wherein R6 and R7, independently, are hydrogen
or alkyl or taken together with the
D - 13 -
~325~3
nitrogen, are a moxpholine, N-methyl-piperaæine, piperazine
or pyrrolidine group and X iS S and Rl, R2 and R3 are as
described above, i.e. a compound of the general formula
IV
4 ~ N ~ R3
R2
Rl
wherein R4V is hydroxyalkyl, phenylhydroxyalkyl, halophenyl-
hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-
hydroxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxyalkyl,
alkanoyloxya~cyl and arylcarbonyloxyaU;yl, alkoxy~onxlaL~yl, aryl-
carboxamidoalkyl, alkanoyl-alkyl and arylcarbonylalkyl,
cyclic-alkyloxoalkyl, cyclic-alkylhydroxyalkyl, N-alkyl-
pyrrolidinylalkyl, aryl-N-imidazolonylalkyl or
~ -alkyl, wherein R6 and R7, independently, are hydrogen
or alkyl or taken together with the nitrogen, are a morpho-
line, N-methyl-piperazine, piperaæine or pyrrolidine group,
and Rl, R2 and R3 are as described above,
splitting off the ketal and/or ether protecting group or groups in a
compound of the general formula
N ~ R3
~ I ~ R
R
- 14
- - ^ , . . . .. .
113~5S;~
wherein R2" and R3" have the same meaning as R2 and R3
except in case R2 and R3 are alkanoyl and axylcarbonyl,
R2" and R3" are alkanoyl and arylcarbonyl protected as ke~al,
and RV has the same meaning as RIV, but protected as
ketal or ether and Rl is as described above,
or
f) for preparing a compound of the formula A above, wherein R
is alkyl, alkanoyl, arylcarbonyl or arylalkyl and R4 is
alkyl, alkoxyalkyl or cycloalkyl-alkyl, and R2, R3 and X are
as described above, i.e~ a compound of the general formula
R4 ~ ~ Ac
Rl3
wherein Rl' is alkyl, alkanoyl, arylcarbonyl or arylalkyl
and R2, R3, R4" and X are as described above,
substituting a compound of the general formula
4~N~ - R3
N ~ \ Aa
H R2
wherein R2, R3, R4" and X are as described above,
at the pyrrole nitrogen atom, by formation of the p~le
anion with a strong base followed by quenching with an alkyl
alkanoyl or arylcarbonyl halide, or
- 15
l~J32553
g) for preparing a compound of the formula A above, wherein
Rl is hydrogen and R4 is alkyl, hydroxyalkyl, phenyl-
hydroxyalkyl, haiophenyl-hydroxyalkyl, alkylphenyl-hydroxy-
alkyl, alkoxyphenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-
hydroxyaikyl, alkoxy-hydroxyalkyl, alkanoyloxyalkyl and
arylcarbonyloxyalkyl, alkoxycarbonylalkyl,
arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl,
furyl-alkyl, arylcarboxamidoalkyl, alkanoylalkyl and arylcar-
bonylalkyl, cyclic-alkyloxoalkyl, cyclic-alkylhydroxyalkyl,
alkenyloxyalkyl, arylalkenyl, aryloxyalkyl, N-alkyl-pyrroli~
dinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atoms, aryl-N-
imidazolonylalkyl or
/N-alkyl, wherein R6 and R7, independently, are hydrogen
or alkyl, or taken together with the nitrogen, are a
morpholine, N-methyl-piperazine, piperazine or pyrrolidine
group, and R2, ~3 and X are as described above, i.e. a
compound of the general fbrmula
X
4~N~ ,~R3
N ~ ~ Ad
H R2
wherein R4' is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl,
halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxy-
phenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl,
alkoxy-hydroxyalkyl,alkanoyloxyalkyl and arylcarbonyloxyalkyl, alkoxy-
carbonylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl,
thienyl-alkyl, furylalkyl, arylcarboxamidoalkyl, alkanoyl-
alkyl and arylcarbonylalkyl, cyclic-alkyloxoalkyl, cyclic-
alkylhydroxyalkyl, alkenyloxyalkyl, arylalkenyl, aryloxy-
alkyl, N-alkyl-pyrrolidinyl-alkyl, trifluoroalkyl of 2 to 6
- 1 6
~13~553
carbon atoms, aryl-N-imidazolonylalkyl or / N-alkyl,
wherein R6 and R7, independently, are hydrogen or alkyl, or
taken together with the nitrogen, are a morpholine, N-methyl-
piperazine, piperazine or pyrrolidine group, and R2, R3 and
X are as described above,
substituting a compound of the general formula
H-N ~ R3 Ab
N ~ R2
H
wherein R2, R3 and X are as described above,
at the isoquinoline nitrogen atom, by treating with an alkyl,
alkenyl, cycloalkylalkyl or an arylalkyl halide or with an
epoxide or a haloalkylamine, or
h) for preparing a compound of the formula A above, wherein R
is alkyl, alkanoyl, arylcarbonyl or arylalkyl and R4 is
alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-
hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-
hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-
hydroxyalkyl, alkanoyloxyaIkyl and aryl~arbonyloxyalkyl, alkoxy-
carbonylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl,
alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl,
alkanoyl-alkyl and arylcarbonylalkyl, cyclic-alkyloxoalkyl,
cyclic-alkylhydroxyalkyl, alkenyloxyalkyl, arylalkenyl,
aryloxyalkyl, N-alkyl-pyrrolidinyl-alkyl, trifluoroalkyl
of 2 to 6 carbon atoms, aryl-N-imidazolonylalkyl or
R \ N-alkyl, wherein R6 and R7, independently, are hydrogen
- 17 -
.. .... , ., . ,,,, . .. -: -
~32SS3
or alkyl, or t~ken together With the nitrogen, are a
morpholine, N-methyl-piperazine, piperazine or pyrrolidine
~roup, and R2, R3 and X are as described above, i,e. a
compound of the general formula
R4 ~ ~ R3
N ~ ~ R
Rl
wherein Rl', R2, R3, R4' and X are as described above,
substituting a compound of the formula Ae hereinbelow at the
isoquinoline nitrogen atom, by treating with an alkyl, alkenyl,
cycloalkylalkyl or an arylalkyl halide or with an epoxide or
a haloalkylamine, or
i) for preparing a compound of the formula A above, wherein R
is alkyl, alkanoyl, arylcarbonyl or arylalkyl and R4 is
hydrogen and R2, R3 and X are as described above, i.e. a
compound of the general formula
X
H - N R3
~ ~ R
wherein Rl', R2, R3 and X are as described above,
splitting off the protecting group by hydrolysis or hydro-
genolysis, in a compound of the general formula
- 18
D
. . . - . . . .
1132S53
~ N ~ R3
. I I 11 11 Ah ,
~ N ~ ~ R
wherein Z is a protecting group and Rl', R2, R3 and X are as
described above,
or
-j) for preparing a compound of the formula A above, wherein R
is alkyl, alkanoyl, arylcarbonyl or arylalkyl and R4 is
hydrogen, alkyl, alkoxyalkyl, alkanoyloxy-alkyl and aryl-
carbonyloxyalkyl, alkoxycarbonylalkyl,
arylalkyl, alkenyl, cycloalkylalkyl, alkynyl, thienyl-alkyl,
furylalkyl, arylcarboxamidoalkyl, alkanoylalkyl and aryl-
carbonylalkyl, cyclic-alkYloxoalkyl, alkenyloxyalkyl,
arylalkenyl, aryloxyalkyl, N-alkyl-pyrrolidinyl-alkyl,
trifluoroalkyl of 2 to 6 carbon atoms or aryl-N-imidazolonyl-
alkyl and R2, R3 and X are as described above, i.e. a compound
of the general formula
X
VI ~ R3
N ~ ~ R
¦; 2
wherein R4I is hydrogen, alkyl, alkoxyalkyl, alkanoyloxy-
alkyl and arylcarbonyloxyalkyl, alkoxy-
carbonylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl,
thienyl-alkyl, furyl-alkyl, arylcarboxamido-alkyl, alkanoyl-
""" -- 1 9
.. . ..... ..
~13;2553
alkyl and axylc~bonylalkyl, cyclic-alkyloxoalkyl, alkenyl-
oxyalkyl, arylalkenyl, aryloxyalkyl, N-alkyl-pyrrolidinyl-
alkyl, trifluoroalkyl of 2 to 6 carbon atoms or aryl-N-
imidazolonylalkyl and Rl', R2, R3 and X are as described
above,
substituting a compound of the general formula
VI Xl
4~N--~R3
~ I R~
wherein R2, R3, R~I and X are as described above,
at the pyrrole nitrogen atom, by formation of the pyrrole anion
with a strong base followed by quenching with an alkyl, alkanoyl
or arylearbonyl halide, or
k) for preparing a compound of the formula A above, wherein R
is alkyl, alkanoyl, arylcarbonyl or arylalkyl and R4 is
hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl,
alkylphenyl-hydroxyalkyl, alkoxyphenyl~hydroxyalkyl, aryloxy-
hydroxyalkyl, alkoxyhydroxyalkyl, cyclic-alkylhydroxyalkyl
R6\
or / N-alkyl, wherein R6 and R7, independently, are
hydrogen or alkyl, or taken together with the nitrogen, are
a morpholine, N-methyl-piperazine, piperazine or pyrrolidine
group, and R2, R3 and X are as described above, i.e. a
compound of the general formula
X
VII ll
4 ~ N ~ R3
N ~ R
Rl
D - 20
~132553
wherein R4II is h~dxoxyalkyl, phenyl-hydroxyalkyl, halo-
phenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-
hydroxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxyalkyl,
cyclic-alkyl-hydroxyalkyl or R6> N-alkyl, wherein R6 and R7
independently, are hydrogen or alkyl, or taken together with
the nitrogen, are a morpholine, N-methyl-piperaæine, pipera-
zine or pyrrolidine group, and Rl~, R2, R3 and X are as
described above,
splitting of the protecting group by acid hydrolysis in a corres-
ponding compound of the formula Af" above, but wherein R4II isprotected, i.e. in a compound of the general formula
X
VIII 11
4 ~N ~'~--R3
R
wherein R4III has the same meaning as R4II, but in a pro-
tected form, and Rl', R2, R3 and X are as described above,
or
1) isomerizing the mixture of the cis and trans isomers obtained
to a final ratio which comprises predominantly the trans
isomer, or
m) separating the trans isomer from the mixture obtained, or
n) resolving a racemic mixture obtained into the optical anti-
podes and
o) if desired 9 converting a compound obtained or a non phaxmao
ceutically accepthble acid addition salt into a pharmaceuti-
cally acceptable acid addition ~alt thereof.
;~ - 21 -
1132553
More specifically, the compounds of formula A above, their
optical and geometric isomers and their pharmaceutically
acceptable acid addition salts as well as various lntermed-
iates therefor can be prepared as illustrated hereinbelow in
more detail.
- 22 -
~3Z553
1 Thus, for exanple, the compounds of formula A wherein X is O are characterized2 by the formula
J \ ~ R3
,9 wherein Rl, R2, R3 and R4 are as hereinbefore described,
13 and can be ~ ar~ as set forO~ in ~cheAI 1,11, m and IV and fur her dQcribed.
lG
22
24 . .
26
- 113Z553
.
FORr~lULA SC~EME I
OCH3 OCH3
N~ ~ C2RS
4 .- ~ OCH3
S , XIY I / III OCH3
7 OCH3 / wherein R " is CH
~14" 9 ,~ > 4 ~`` OCHJ
11 , /
12
3 R4 ~O HO~ R2 H N ~ R
16 ' VII or VIII
, .
18 \ ~ = _ )
19
~ L/ 11
21 , R,~ >R4" - N~ R3
22 ; I R2 7 2
23 IX H Ia H
26 wherein R2, R3 ar.d R4" are as previously described.
27
,
24
~.,
113Z553
In accordance with Formula Scheme I, compounds of formula IV wherein
R4" is methyl, are prepared by reacting the primary amine of formula XIV
with ethyl chloroformate to yield the urethane of formula III, which is
reduced with lithium aluminum hydride to yield the N-methylamine of
formLla IV. In a broader aspect, the ccmpounds of the formula IV can be
prepared by reductive alkylation of the compound of formula XIV, utilizing
the corresponding aldehyde, for example, acetaldehyde, and the like, and
sodium cyanoborohydride under known conditions (see, for example, R. F.
Borch, J. Am. Chem. Soc., 93, 2897 (1971)). Birch reduction of the amine
of formula IV with lithium in ammonia containing t-butanol yields the
dihydroamine of formula V. Other modifications of the Birch reduction may
also be employed. Thus, the 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 the boiling point of the solvent or below, for example, from
-78 to 15C. If ammonia is used, the reaction is run at reflux. Optionally,
cosolvents such as diethyl ether or tetrahydrofuran may be added.
The hydrolysis of the dihydroamine of formula V is readily acccmplished
by the usual methods for hydrolysis of enol ethers, for example, with aqueous
acid. Exemplary of acids which may be used are hydrochloric acid, hydro-
bromic acid, formic acid, acetic acid, p-toluenesulfonic acid and perchloric
acid. These may be used in aqueous solutions or mixed solvents. At least
tw~ equivalents of water per mole of dihydroamine and more than 1 equivalent
of acid are needed. Tetrahydrofuran, benzene, diethyl ether, acetone,
toluene, dioxane or acetonitrile are exemplary of the solvents which may be
employed. For example, hydrolysis of the dihydroamine of formula V wherein
R4" is methyl in 2N hydrochloric acid at roam temperature or above or in
aqueous acetic acid at between 40 and re~lux leads to the diketone of
formula VI, wherein R4" is methyl.
- 25 -
~L13Z~53
The diketone of fosmula VI is condensed in a Knorr condensation to give the
dihydroindolone-et11ylamine of formula IX. The l~norr condensation is a well-l~nown
method for the preparation of pyrroles and the proccss mny be used in any of the well-
known modifications [see, for exemplary conditions, J. M. Patterson, Synthesis, 281
~976) and references therein]. For e~ample, the reaction of an isonitroso!cetone of
formula YII in the presence of a reducing agent, for e~amplc with zinc in aqueous acetic
acid or hydrochloric acid, is thought to proceed via the aminocarbollyl compound of
formula VIII which then condenses with the diketone of formula VI to gi~e the product
dihydroindolone-ethylamine of formula IX. Alternatively, the condensation can becarried out with an aminocarbonyl compound formula VIII or pr~-
cursor thereof, such as an aminoketone hydrochloride salt, or an
acetal derivative of an aminoketone or aminoaldehyde. The use of
a precursor of the aminoketone or aminoaldehyde is preferred, since
such substances are prone to self-condensation. They may be best be
utilized in situ where the aminocarbonyl component is liberated in the presence of the
diketone of formula VI. The aminocnrbonyl componcnt immediately reacts to.fGrm the
dihydroindolone-ethylamine of formula IX. It is not necessary to isolate the diketone OI
formula Yl prior to carrying out the Knorr condensation since the reaction conditions
20 employed are sufficient to hydrolyze the dihydroamine of formuia V to the diketone of
formula ~,1. The Knorr condensation is best carried out at a pH of frorn about pH 2 to
pH 6. Much above i~I~ 6, there is a considerable loss in yield due to the formation of
self-condensation products of the aminocarbonvl compound of formula VIII.
Preferably, an isoni~rosol~etone of formula VII and zinc dust in a~ueous acctic
acid is condensed with .~ diketone of formulu VI wherein R L" is methvl to Eive the
30 product dihydroindolone-ethylamine of formula IX wherein R4" is methyl.
-- 26 --
113ZS53
1 The Knorr condensation is preferably carried out at a temperature range of from
2 about room temperature to refl~ 12 isonitrosoketones of formula VII are lalown
3 ~ompounds [see, for instance, Ferris, J. Org. Chem., 24,1726 (1959)] or can re dily be
4 prepared by nitrosation of the corresponding ketones, for example, with an alkyl nitrite,
~i or in the case of highly acidic ~-diketones or ~-ketoesters, with sodium nitrite.
7 ~3xemplary of isonitrosoketones which may be used in the Knorr condensation are~
2-isonitroso-3-pentanone;
9 2,3-butanedione monoxime;
2-isonitroso-4-methyl-3-pentanone;
i 1 2-isonitroso-3-hexanone;
12 2-isonitroso-3-heptanone;
13 3-isonitros~4-methyl-2-pentanone;
14 2isonitroso-1-cyclopropyl-1-propanone;
lS 3isonitroso-5-hexen-2-one;
16 cyclopropyl-2-isonitroso-1-propanone; and -
17 3-isonitroso-4-phenyl-2-butanone.
18
19 Fxemplary of aminocarbonyl precursor compounds which may be used in the
Rnorr condensation are:
21 aminoacetaldehyde dimethyl acetal; and
22 2-amino-3-pentanone hydrochloride.
225 '
26
27
113Z553
m e am me of the formwla IX is converted to the compound of the
formLla Ia via an intramolecular Mannich reaction. The Mbnnich reaction
is usually performed startLng with a ketone and a dialkylamine salt, for
example, dimethylamine hydrochloride and formaldehyde (for example, as an
aqueous solution, as paraformaldehyde or as trioxane) in an alcoholic
solvent such as ethanol, at reflux. In the modification herein described,
an acid addition salt of the dihydroindolone-e~hylamine of formula IX is
reacted with formaldehyde, added in the form of paraformaldehyde, trioxane,
or as aqueous formaldehyde in a solvent. For example, a high boiling
hydroxylic solvent, such as amyl alcohol, octanol, ethylene glycol or
diethylene gly~ol m~noe thyl ether, a high boiling polar aprotic solvent,
such as dimethylformamide, N-methylpyrrolidinone or diethylene glycol
dimethyl ether; a lower boiling polar solvent, such as ethanol, butanol
or 2-propanol under pres Æ e, or a lower boiling aprotic solvent under
pressure, such as dioxane or tetrahydrofuran, may be used at a temperature
in the range of from about 135 to about 200 to yield the pyrroloC2,3-g~
isoquinolines of formula Ia. The reaction, especially when run at tempera-
tures below 150 leads to a ~ixture of cis and trans isomers, i.e., for
example, when R4" is methyl, oom~ounds of the formulas
- 28 -
553
C~ ~ ¦ ~ ~ ~ R3 ~ ~ ~ ~ R3
H I R2 N R2
H H H
trans cis
I'a~ r'a~
Longer heating of the reaction mixture or separate heating of the
iscmeric muxture of hydrochloride salts of formulas I'a and I"a, for
example, in ethylene glycol at reflux for 2 hours can be used to equilibrate
the cis and trans isomers to a final ratio which comprises predominantly
the trans isomer, which is readily isolated by crystalliza~ion or by
chrcmatographic separation.
Preferred is the reaction of the hydrochloride salt of the dihydro,
indolone-ethylamine of formula IX whereinR4" is methyl with paraformalde-
hyde in octanol at 180 for 2 hours, wherein the product is isolated as
almDst exclusively the trans isomer I'a.
- 29 -
~.
113'~553
FDRMUL~ SCHEME II
CH3-N~
H \~
\
\
O ' ' ~1 0
'J ~ I R2 CH3-N~Rp32
XIII Ic~ ~
". '
,_ . "~ - i
. .
: ~ R3
H -N ~ N ~ R2 Ib
H
- whereLn ~ and R3 are as previously described, and Rl is
alkyl, alkanoyl, aroyl or araIkIyl~
- 30 -
'3D
1~L32553
l In accordance with Formula Scheme II, compounds of formula Ic~ are
~ prepared by alkylation or acylation of the pyrrole nitrogen of a compound of formula Ia'
3 and other N-6-alkyl derivatives by formation of the pyrrole anion with stron~T base, for
4 example, sodium amide, potassium hydride, sodium methylsulfinylcarbanion, or butyl- !
5 lithium, or with an alkali metal followed by quenching with an alkyl or acyl halide in a
6 solvent such as tetrahydrofuran, dioxane, ethyl ether, dimethylformamide or dimethyl-
7 sulfoxide. For example, treatment of a compound of formula Ia' wherein R2 is methyl
8 and R3 is ethyl, with sodium in liquid ammonia followed by quenching with methyl
g iodide affords the l-methyl derivative, i.e., a compound of formula Ic~wherein R2 is
10 methyl, R3 is ethyl, and Rl' is methyl. Similarly, reaction of a compound of formula Ia ', i
ll ¦ wherein R2 is methyl and R3 is ethyl, with butyllithium in tetrahydrofuran at -30
12 I followed by quenching with benzoyl chloride affords the l-benzoyl derivative, i.e., a
13 compound of formula Ic~wherein Rl' is benzoyl, R2 is methyl and R3 is ethyl.
141
N-Demethylation of the compound of formula Ia'can be accomplished by standard
16 N-dealkylation procedures, such as the von Braun method [H. A. Hageman, Org.
17 Reactions, 7, 198 (1953)], or via acid or base hydrolysis of a urethane derivative such as
18 those listed in K. C. Rice [J. Org. Chem., 40, 1850 (1975)]. One procedure for the
l9 dealkylation of the cornpound of formula lal is via the urethane of formula XIII and
20 acid hydrolysis to give the secondary amine of formula Ib. For example, a compound of
21 formula Ia' ,wherein R2 is methyl and R3 is ethyl is refluxed in diethyl ketone with
22 excess ethyl chloroformate and potassium bicarbonate for 3 hours to give a compound of
23 formula XIII, wherein R2 is methyl and R3 is ethyl. Hydrolysis of the foregoing
24 compound with concentrated hydrochloric acid in acetic acid at reflux for 24 hours ~ives
25 a compound of formula Ib, wherein R2 is methyl and R3 is ethyl. The same compound
26 is obtained by hydrolysis of the urethane of formula XIII with sodium hydroxide in !
27 refluxing ethanol.
` ~ 113Z553
ORnl ~ LA SCHE:~I E 111
, r
18 Rl , R2 ~ R3 and R4 ' are as previous ly
~0 described .
1~32553
~ accordance with Formula Scheme m, the compounds of formulas Ic, Idend le
are prepared from the secorldary amine of formuls Ib, the starting material for the
preparation of numerous derivatives encompassed by formula 1, by wbstitution at the
bssic amine nitrogen (N-6) and/or the pyrrole nitrogen (N-l~. For example, treatment of
~ compound of formula Ib with an alky1 hslide, such as ethyl bromide, Qn alkenyl halide,
such as allyl bromide, a cycloalkyl-alkyl-halide, such as chloro-
methylcyclopropane, or an ælylalkyl halide, such as benzyl bromide,
in the presence of a base, for example, potassium carbonate, in
10 acetone, 2-propanone or dimethylfc)rmamide, yields the correspond-
ingly substituted compound of formula Id, that is, wherein Rl 4 is
~lkyl, alkenyl, cycloalkyl-alkyl or arylalkyl, respectively. With
reactives halides, the reaction may be run at room temperature; wi th
less reactive halides, reflux temperatures are used, and in some
cases, the reaction rate can be enhanced by the addition of an
iodide salt, such as lithium iodide, to the reaction mixture.
Reaction of a compound of formula Ib with epoxyaL'csnes gives the hydroxyalkyl
20 substituted compound of formula Id. Treatment with a substituted epoxyalkane gives
the 2-substitute~2-hydroxyaL~cyl analogs of a compound of formula Id, for example,
reaction of a compound of formula Ib with styrene oxide gives a compound of formula
Id, wherein R4' is 2-phenyl-2-hydroxyethyl. The reaetion is ususlly csrried out in the
presence of an alcoholic solvent such as methanol, st from sbout room temperature to
the reflux temperature of the mixture. The expoxyaL'canes are either commercially
availab1e or are prepared by epoxidation of the corresponding olefins, or by
methylenation of a ketone with a sulfoniummethylide or sulfoxonium methylide reagent,
for example, dimethylsulfonium methylide. Thus, for example, treatment of benzPlde-
30 hyde with dimethylsulfonium methylide gives styrene oxide.
-- 33 --
V
- i ~ ~ l
113Z553
1 I The compound oi ~ormula lb mny be con~c.ted to the eompound of rormul~i Ic by
2 ! a process in which, succcssively, tllc basic aminc nitrogen (N G) of the compound of
3 I formula Ib is protected with a hydrolyzable or hydrogcnolyzable protccting group,
I substitutcd at the pyrrole nitrogen (N~ and deprotected. Typical protecting groups
5 are acetyl, t-butox~carbonyl, benzenesulfonyl, or bcnzyl. The reaction of the protected
6 I intermediate is carricd out substantially as described for the conversion of the
7 I compound of formula Ia to the compound of formula Ic~. The substituted intermediate is
8 I deprotected by base or acid hydrolysis or hydro~enolysis methods appropriate to the i
g ¦I protecting group. For example, the compound of formula Ib ~here R~ is methyl and R3
10 is ethyl, is treated with formic acetic anhydrlde to yield the 6-formyl derivative.
11 I Treatment of the derivative with sodium hydride in dimethylsulfoxide followed by
12 ¦ treatment with methyl iodide and acid hydrolysis yields the compound of formula Ie
13 I where Rl' is methyl, R2 is methyl, and R3 is ethyl.
14
Treatment of a compound of formula Ib wit]l a haloalkylamine in the presence of
16 i a base, for example, potassium carbonate, or an aziridine yields amine-substituted
17 ¦ analogs of a compound of formula Id, respectively. The reaction conditior.s are as
18 described for the preparation of ~lkyl derivatives.
19
In some cases, where R4' in the compound of formula Id does not contain
21 functional groups capable of undergoing alkylation or acylation, the procedures outlined
22 in Formula Scheme III can be used directly to prepare N-l substituted analogs of formula
23 ¦ I c. Alkylations can occur in cornpounds wherein R4' is hydroxynlkyl, phenyl-
24 ¦ hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-h~iroxy-
25 alkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxyalkyl, cyclic-alkylhydroxyalkyl, or /N-
26 alkyl, wherein R~; and R7, independently, are hydrogen or alkyl, or taken together with
27 the nitrogen, are mDrpholine, N-methyl-piperazine, piperazine or pyrrolidine
3ro~. ~e funcUonal g~ups ~erein,
34 _
113~553
1 1I for example, hydroxyl or secondary amino, must be protectcd with a base-stable
2 protecting group, such as tetrahydropyranyl. After N-l alkylation, the protecting group
3 is removed by acid hydrolysis.
The compound of formula Ie is converted to the compound of formula Ic using
6 substantially the same procedure used in the conversion of the compound of formula Ib
7 to the compound of formula Id.
8 .
9 In the reactions described in Formula Schemes I, II and III, both the trans isomers
of the formula
11
~ I L ~ ~ 1~ ~ ~ R3
17¦~ wherei Rl,R~,R3rrdR4rrerspreviouslydescribed,
18 and cis isomers of the formula
19 _ .
~ R,L~ 3 1"
25 j wherein Rl, R2, R3 and R4 are as previously described,
26 ¦ of the compounds of formula I may be formed, with the trans isomer predominating.
27 I The pure trans isomer may be separated by chromatography or crystallization. In
28 1 addition, the mixture may be isomerized as described for the isomerization of the trans
29 and cis isomers of the oxo compound of formula I'a' and l"a'
-- 35 --
Z5,S3
~ FORMllL~ SC~IEUE IV
s ~ CI~ ~ OCH3
73 l ~ ~ X
8 ¦ j)CH3
l3 ~ R4~ ~OcN3 Xl
12 1 /
~ R4~ -N~ + ~ 3 O R3
ll NON R N N~R
VII or VIII
18
19 ~ R3
23- 1 .
24 l 2 ~ 3 and R4 are as previously described
2~
-- 36 --
i
1132553
1 An alterllative synthcsis of the compounds of formula Ia is described in ~ormula
2 Scheme IV, in which the isoquinoline ring is formed prior to the formation of the pyrrole
3 ring. In acco~dance witll Formula Scheme IV, the (3,5-dimethoxyphenyl)-ethylamine of
4 formula IV is refluxed with agueous formaldehyde to give the tetrahydroisoquinoline of
5 formula X. Birch reduction of the tetrahydroisoquinoline of formula X with lithium in
6 liquid ammonia containing t-butanol under conditions substantially the same as
7 described for the Birch reduction of the compound of formula IV yields the hexa-
8 hydroisoquinoline of formula XI. Hydrolysis of crude hexahydroisoquinoline of formula
9 XI under conditions substantially the same as described for the hydrolysis of the
10 dihydroamine of the formula V yields the diketone of formula XII. The compound of
11 formula XII is reacted in a Knorr condensation, as described in the preparation of the
12 dihydroindolone-ethylamine of formula IX with the isonitrosoketone of formula VII or;
13 with the aminocarbonyl compound of formula VIII to give the pyrroloisoquinoline of !
14 formula Ia. Preferred is the sequence of reactions in accordance v~ith Formula Scheme
15 IV starting with the amine of formula IV, wherein R4" is methyl, giving the correspond-
16 ing N-methyl-pyrroloisoquinoline of formula Ia' as a mixture containing the trans isomer
17 I'a~and the cis isomer of formula I"a~
18
19 The same procedures for isomerization of the mixture of pyrroloisoquinolines of
20 formulas I'a~ and I"a' as described previously may be employed to yield mainly the trans
22 isomer of :~o mule l'a~
24
26
27
113Z553
The compounds of formula A wherein X is S are charncterized by tl~e formula
S II
4 ~ ~N~ R 3
R2
Rl `
wherein Rl, R2, R3 and R4 are as hereinbefore described,
10 and cRn be prepared as set forth hereinafter.
Thione compounds of formula II are generally prepared by reaction of phosphorus
pentasulfide on keto compounds of formula I. When the compound of formul~ I has no
functional groups capable of reacting with phosphorus pentasulfide besides the 4-oxo
group, then the compound of formula I may be converted to the compound of formula II
directly by heating with phosphorus pentssulfide in an inert organic solvent. On the
other hand, when the compound of formula I does contain functional groups capable of
reacting with phosphorus pentasulfide, for exsmple, when R4 is other than hydrogen,
alkyl, alko~yalkyl, araIkyl, aIkenyl, cycloaIkyl-alkyl, aIkynyl, thienyl-aIkyl,
furyl-aIkyl, alkenyloxyalkyl, arylalkenyl, aryloxyaIkyl, or trifluoxoalkyl of
2 to 6 carbon atoms or when R2 or R3 is alkanoyl or arylcarbonyl, these
groups m~st be protected before the reaction and deprotected thereafter. For
example, keto groups may be protected as a ketal such as ethylene ketal and
alcohol grDups may be protected as an ether derivative, such as a benzyl
ether. Alternatively, thiones of formula II may be made by suitable proced-
27 ures described in Formula Scllemes V and VI.
- 38
` 113Z553
EOI:~ UL ` SC; I' ~ L V
~1
R4~ ~N Ra
22 ~
24 wherein R~ 2 ~ R3 and Rd~" are as hereinbefore described.
-- 39 --
1132553
1 In Formula Scheme V, the compound of formula Ia is converted to the compGund
2 I of formula IIa by heating in an inert organic solvent with phosphorus pentasulfide.
3 Preferred solvents are tetrahydrofuran, benzene, and dioxane, and the reaction is
4 generally run at reflux temperature. The compound of formula IIa may then be
5 alkylated or acylated to the compound of formula IIc~in the same manner described in
6 Formula Scheme II for the conversion of the compound of formulaIa' to the compound of
7 formula Ic
. 9 Additional compounds of formula II can be made as described in Formula Scheme
O Vl:
18 _
21
22
23
_40_
,,~,,
~
1~ 1132553
1 I FOR~IULA SCHEi~IE VI
2 !
4 H~ 3
~: 17 ~R2 R2
18 IIe \ Rl' IId / H
29 \~1 ' L/
21 R4~,~R3
24
. .
26 wherein R2, R3, Rl' and R4' are as previously described.
~1 113Z553
~ ~ I
1 1 In Formula Scheme VI, the compound of formula Ib is reacted with phos?norus
2 ~ tasulfide as above described, to afford the thione of formula IIb. Subsequent trans-
-3 formations of the compound of formula IIb to the compounds of formulas IIc, IIdand Ile
4 .are performed in the same manner as described in Formula Scheme III for the analogous
S oxo compound Ib in its conversions to the compounds of formulas Ic, Id and Ie.
8 ~ In esc resctions, both the trsns isomers of the iormuls
0 3 ~ ~ R3
wherein Rl, R2, R3 and R4 are as previously described,
16 and cis isomers of the formula
l9 ] ~ ~R nr
22
2S wherein 1~, R2, R3 and RdL are as previously described,
26
5S3
of the compounds of formula II may be formed, with the trans isomer
predominating. The pure trans isomer may be separated by chromatography
or crystallization. Ln addition, the mixture may ke isomerized as
described for the isomerization of the trans and cis isomers of the oxo
compound of formula I'a~and I"a~.
- 43 -
` I . 11325~3
...
. -.
l The compounds of formula Aform acid addition salts with inorganic or organic
2 j a- ds. Thus, they form pharmQceutic~ly acceptablc acid addition salts with both
3 pharmaceutically acceptable organic and inorganic acids, for example, with hydrohalic ~
4 acid, such as, hydrochloric acid, hydrobromic acid, hydroiodic acid, other mineral acid -
salts, such as sulfuï ic acid, nitric acid, phosphoric acid, or the like, alkyl- and mono-aryl
6 sulfonic acids, such as ethanesulfonic acid, toluenesulfonic acid, benzene;,ulfonic acid,
7 or the like, other organic acids such as acetic acid, tartaric acid, maleic acid, citric
8 acid, benzoic acid, salicylic acid, ascorbic acid, and the lil;e. Non-phfirmaceuticaliy
acceptable acid addition salts of compounds of formula Acan be converted into pharma-
ceutically acceptable acid addition salts via conventional metathetic reactions whereby
ll the non-pharmaceutically acceptable anion is replaced by a pharmaceutically accept-
12 able anion; or alternatively, by neutralizing the non-pharmaceutically acceptable acid
13 addition s~1t and then reacting the so obtained fr.ee base with a reagent yielding 8,
14 pharmaceutically acceptabIe acid addition salt. The acid addition salts may also form
l 5 hydrates.
16- ¦ The compounds of formula Aand their pharmaceutically acceptable acid addition
17 salts exhibit neuroleptic activity. Significantly, however, they laclc hypotensive
18 activity, and demonstrate only weak cataleptic activity. Accordingly, the compounds of,
19 formula A sre useful as antipsychotic agents, for instance, in the treatment of
~0 sahizopl1renia. The activity of the compounds of formulaA which makes them useful as
21 antipsychotic agents can be demonstrated in warm-blooded animals, in accordance '
22 with Icnown rocedures.
27
'.
I -44 -
3Z553
.~ 11 ' ' ' ' ' ~
¦¦ For example, by onc procedure, trained rats are placed in e2cperimental chambers
, e~;ipped with a response lever, a steel grid floor for delivery of electric shock and a
3 loudspeaker for presentation of auditory stimuli. Each trial consists of a fifteen~econd
warning tone, (conditioned stimulus), continuing for an additional fifteen seconds
accompanied by electric shock tunconditioned stiMulus; 1.0 mA, 350 V.A.C.). The rats
6 can terminate a trial at any point by depression of the response lever. A response
7 during the initial fifteen-second warning tone ends the trial before shock delivery and is
8 considered an avoidance response, while a response occurring during shock delivery is an
9 escape response. Trials are presented every two minutes during a one-hour test session
(30 trials per session).
~ 11 .
12 'rrained rats maintain a reliable control baseline of avoidance behavior (zero to
13 three avoidance ~ailures per session). Compound~ are administered at appropriate
14 pretreatment times to a minimum of three tc four rats at each dose level ove- a range
of doses. l~ats receive vehicle alone, during control sessions. One control and one
16 experimental session are alternated during each weelc; each animal serves as his own
17 controL
18
19 The session is divided into three consecutive twenty minute (ten trial) segments.
2~ Respo-se nts ere su nmd ~ve rll subjects rt r given dose within e~-h ~egment.
-- ~5 --
113~53
1 The number of triaLs in which the rats fa,led to e~hibit an avoidance response
2 (_~oidance block; AB) or failed to exhibit an escape respcnse (escape block; EB) is
3 determined for the segment displaying the maximum such effect at each dose. This
4 number is e2cpressed as a percentage of the total trials within the segment. The dose
calculated to produce a 50% block of avoidance (AB 50) is obtained from the dose-
6 effect regression line fitted by the Method of Least Squares. The lowest dose which
7 produced a 20% block of escape responding (EB 20) is read from a graphic dose-effect
8 plot. In obtaining these values, percent effect is plotted against the log dose.
: -9 .
Antipsychotic agents can be distinguished from other types of drugs, which
11 affect the behavior of rats in this procedure, by the larger separation between doses
12 which block avoidance responding and doses which block escape responding. The clinical
13 potency of antipsychotic drugs with known therapeutic uses and properties is
14 significantlv and highly coirelated with their potency in this procedure. Consequently,
the compounds of formula A may be used therapeutically in dosage ranges consistent
16 with their potency in the test procedure~ -
17
18 When 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8~a,9-octahydro-4a,8a-trans-lH-pyrrolo-
19 [2,3-g] isoquinolin-4-one, hydrochloride, which has demonstrated an LD5~ of, for
20 example, 350 mg/kg p.o. in mice, is utilized as the test substance, neuroleptic activity
21 is observed at an AB50 of 0.7 mg/kg p.o. and 0.095 mg/kg s.c. In the (-)-enantiomer of
22 the foregoing compound, neuroleptic activity is observed at an AB50 of 0.48 mg/kg p.o.
23
24 Similarly, when 213,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydr~4a,8a-trans-lH-pyr-
rolo[2,3-g] isoquinolin-4-one, hydrochloride is utilized as the test substance, neuroleptic
26 activity is observed at an AB50 of 0.48 mg/kg p.o.
27
a~ss3
1 Similarly, when N-[2(3-ethyl-4,4a,5,G,'.',8,8a,9-octahydro-2-methyl-4-o~o-~a,8a-
- 2 trans-lH-pyrrolo[2,3~e,] isoquinolin-6-yl)2thyl~ -4-fluorobenzamide is utilized as the test
3 suDstance, neuroleptic activity is observed at an AB50 of 3-5 mg/kg p.o.
S Similarly, when 3-ethyl-2-methyl-6-[4-(4-fluorophenyl)-4-oxobutyl]-4,~a,~,6,7,-
6 8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one is utilized as the tes~
7 substsnce, neuroleptic activity is observed at an AB50 of 0.19 mg/kg p.o.
9 Similarly, when 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-tr&ls-lK-
pyrrdo[2,3-g] isoquinolin-4-thione is utilized as the test substance, neuroleptic activit~;
I l is observed at an AB50 of 0.9~ mg/kg p.o.
12
13 The compounds of formula A and their pharmaceutically acceptable acid addition
14 salts have antipsychotic effects which are qualitatively similar to those of hAIoperidol,
trifluoroperazine and molindone, known for their therapeutic uses and properties. Thus,
16 the compounds of formula A demonstrate a pattern of activity associated with
17 antipsychotic drugs of known efficacy and safety.
18
19 The compounds of formula A and their pharmaceutically acceptable acid addition
salts can be used in the form of conventional pharmaceutical preparations. By ~ay of
2i exemplification, suitable oral dosage units comprise or are in the range of from 0.05 to ~0
22 mg., and suitable oral dosage regimens in warm-blooded animals comprise or are in the
23 range of from about 0.001 mg/kg per day to about 10 mg/kg per day. However, for an~
24 particular warm-blooded animal, the specific dosage regimen may be variable and
should be adjusted according to individual need and the professional judgment of the
26 person administering or supervising the administration of a compound of formula ~ or a
27 pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency
2~ with which any such dosage form will be administered will varyj depending upon the
29 quantity of active medicament present therein and the needs and requirements of the
pharmacological situation.
- 47-
, .....
~3Z553
¦¦ For the disclosed use, the compounds of formula A and their pharmaceutically
2 .~ acceptable acid addition salts are formulated, using conventional inert pharmaceutical
3 adjuvant materials, into dosage forms which are suitable for oral or parenter~l
4 administration. Such dosage forms include tablets, suspensions, solutions, and the li~;e.
Furthermore, the compounds of formula Acan be embodied into, and administered in the
6 form of, su~table hard or soft capsules. The identity of the inert adjuvant materials
7 which are used in formulating the compounds of formulaA and their pharmaceutically
8 acceptable acid addition salts into oral and parenteral dosage forms will be immediately
9 apparent to persons skilled in the art. These adjuvant materials, either inorganic or
organic in nature, include, for example, water, gelatin, lactose, starch, magnesium
11 stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. Moreover, preservatives,
12 stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure,
13 buffers, or the like, can be incorporated, if des~red, into such formulations.
~`
17
18 _
19 . '. ~ '
21 ;` : ~
22
24
27 - ~8 -
113Z5~3
. .
. 1 .
1 Since the compounds of formula Aand their pharmaceutically acceptable acid
2 : addition salts possess ~n ~symmetric carbon atom, they are ordinarily obtained as
3 racemic mixtures. The resolution of such racemqtes into the optically active isomcrs
4 can be carried out by known procedures. Some racemic mixtures can be precipitated as
eutectics and can thereafter be separated. Chemical resolution is, however, preferred.
6 By this method, diastereomers are formed from the racemic mixture with an optically
active resolving agent, for example, an optically active acid, such as (+)-tartaric acid to
8 form a diastereomeric salt. The formed diastereomers are separated by fractional
9 crystallization and can be converted to the corresponding optical isomer base. Thus,
the invention covers the optically active isomers of the compounds of formula A as
ll well as their racemates. -
12 - .
13 Furthermore, due to the possible different spatial arrangements of their atoms,
14 it is to be understood that the compounds of this invention may be o~tained in more
than one possible ~eometric isomeric form. The compounds of formula A,as described
16 and claimed, are intended to embrace all such isomeric forms. Accordingly, the
1~ examples included herein are to be understood as illustrative of particular mix~tures of
18 geometric isomers or sing~le geometric isomers and not as limitations upon the scope of
19 the invention. `
21 The Examples which follow further illustrate the inYention. All temperatures are
23 in degrees Centigrade, unless otherwise stated
24
26
2~
~ - 49 -
Z~53
. ' ' `.' " ' ' '- , . . .
- ' "~'" ' .' ' . ' .
-2 ii Pre3aration of N-2-(3.5-dimethox~Tphcnyl)^ethyl carbamic acid. ethyl ester
3 ' In a 51. 3-neck round-bottom flask fitted with a mechanical stirrer and addition
4 funnel were placed 32.63 g. of (3,5-dimethoxyphenyl)-ethylamine hydrochloride, 600
. ml. of water, 600 ml. of dichloromethane and 150 ml. of lN sodium hydro~:ide solution.
6 The mixture was stirred and cooled in an ice bath while 16.28 g. of ethyl chloroformnte
7 in 60 ml. of dichloromethane was added dropwise over 30 min. During the addition. a
8 total of 150 ml. of lN sodium hydro~;ide solution was added in 8 portions tc keep the pH
9 between 8 ~nd 9. After the addition was complete, the mixture was stirred in the ice
bath fol 1 hour. The mixture was transferred to a separatory funnel and the organic
11 layer was separated. The aqueous solution was extracted with 200 ml. of dichlorometh-
12 ane and the organic solutions were combined and washed with 100 ml. of water and 100
13 ml. of brine and dried over anhydrous sodium sulfate and filtered. The filtrate was
14 concentrated on a rotary evaporator to give 3~.1 g. of crude N-2-(3,5-dimethoxyphenyl)-
ethyl carbamic acid, ethyl ester as a colorless oil.
17
~0 . ,
I
21
223. . ' . , .
I
26
a~ .
~ ~ !
,
113Z553
1 ¦¦ Exam~?le la
2 1I Pre~aration of N-methyl~3,5-dimethoxyphenyl~-ethylamine hydrochloride
3 In a 3 1. 3-neck roun~bottom flask equipped with a mechanical stirrer, addition
funnel, and condenser were placed 180 ml. of 70~6 sodium dihydrobis(2-methoxyethoxy~ i
aluminate solution and 700 ml. of dry tetrahydrofuran. The solution was cooled in an
6 ice bath and a solution of 37.1 g. of crude N-2-(3,5-dimethoxyphenyl)-ethyl carbamic
7 acid, ethyl ester in 100 ml. of dry tetrahydrofuran was added over 15 minutes. After the
8 addition, the mixture was heated to reflux for 1 hour and then was cooled in an ice bath.
9 Excess hydride was decomposed by the dropwise addition of 100 ml. of 5% sodium
hydroxide solution. After all the base had been added, the organic layer was separated
11 and the aqueous extracted with 100 ml. of ether. The combined organic solutions were
12 concentrated to an oil on a rotary evaporator and the oil was dissolved in 300 ml. of
13 ether. The ether solution was washed with 50 ml. of water, 50 ml. of brine, dried over
14 anhydrous sodium sulfate, and filtered. To the filtrate was added 70 ml. of ethereal
hydrogen c~oride to precipitate the amine hydrochloride. The solid was collected on a
16 Buchner funnel and was crystallized from 180 ml. of absolute ethanol and 270 ml. of
17 ether to give 28.9 g. of N-methyl~3,5-dimethoxyphenyl)-ethylamine hydrochloride as a
white, crystrl i le solid, mp 160-164D.
24
26
-51-
...... ~ ~
11 113~553
~ . '.
-.~ . . .
Example 2
2 Pre~aration of N-methyl-l?S~imetho~ycyclohexa-1.4-diene-3-ethvlamine
3 18j.2 g. of N-methyl-(3,5-dimethoxyphenyI)-ethylamine hydrochloride was dissol-
4 ved in 1600 ml. of water and the solution was made alkaline with lG0 ml. of ammonium
hydroxide. ~he mixture was extracted with 3 x 1000 ml. of dichloromethane and the
6 combined extracts were ~vashed with 1000 ml. of brine and dried over anhydrous sodium
7 sulfnte. Evaporation of the solvent on a rotary evaporator at 35-40 gave 156.0 g. of
8 free base.
9 ., .~
In a 12 1. 3-neck flask equipped with a mechanical stirrer and two dry ice
11 condensers, one fitted with a gas inlet and the other with a soda-lime drying tube was
12 condensed 4.0 l. of anhydrous ammonia. To the ammonia was added a solution of 15G.0
13 g. of the free base in 400 ml. of t-butanol and 400 ml. of anhydrous ether over 15
14 minutes. To the stirred solution was added over 50 min. a total of 33.6 g. of lithium
wire cut into 2.5 in. lengths. The addition rate was controlled so that S in. of wire v~as
16 added per minute. After all the lithium had been added, the deep bIue mixture was
17 stirred under reflux for 2 hours. Then 2.8 1. of anhydrous ether was added- to dilute the
lB mixture, the drying tube was removed to allow the hydrogen to vent, and a tot~1 of 2~0
l9 g. of ammonium chloride powder was added slowly over 30 minutes until the blue color
23 had dissipated. The dry ice condenser was removed and the mixture was stirred and the
21 a.nmonia allowed to e~;aporate overnight. To the residue was added 2.8 1. OI ice water.
22 The mixture was transferred to a separatory funnel, rinsing Wit]l 800 ml. of ether, and
23 the layers were separated. The aqueous layer was extracted with 2 x l.S 1. of dichlo; o-
24 methane and the extracts were combined and washed with 11. oî brine and dried over
anhydrous sodium sulfate. Evaporation of the solvents on a rotary evaporator at 40
26 and finally at 40/1.0 mm. for 1.5 hours afforded 150.7 g. of crude product as a yellow
27 oil. The crude oil was distilled through a 12-in. Goodloe column (bath 150) collecting
28 fractions as follows: ¦
-52-
113Z5~3
Fracticn ~e wt gc purity
2 1 40-80/0.45 mrn. 7.9 g. 4.6%
3 2 80-85/0.45 to û.15 mm.6.2 g. 50%
4 3 85-86/O.lS mm. 21.2 g. 92%
6 4 86-87/0.15 mm. 99.4 g. lOO~S
? ~ractions3 and 4 combined afforded 120.6 g. of N-methyl-1,5-dimethoxycyclo-
~ hex~-1,4-dien 3-ethylamine es e colorless oi~.
. , ' ' .'
11
14
~1^o
~2'ô
"2223, . ,,', . I
24
226 . ' ' ' ''
-- 53 --
I 113Z553
¦ Prep~rstion of 6-[2-(~-methvlamino)ethvl~-2-methyl-3-ethyl-6,7-dihydro~5H)-4(1H,SH~
3 ~ in~olone
4 Ln a 1 1. 3-neck rounc~bottom flask equipped with a mechanical stirrer and con-
5 denser was placed a solution of 60.0 g. of distilled N-methyl-1,5-dimethoxycyclohexa-
6 1,4-diene-3-ethylamine in 700 mL of 70% aqueous acetic acid. The reaction mixture
7 was refluxed for 13 minutes and 59.5 g. of zinc dust was added in five portions over 10
8 minutes and then the mixture was refluxed for another 15 minutes. To the refluxin~ !
9 solution was added a solution of 42.1 g. of 2-isonitroso-3-pentanone in 175 ml. of 70%
10 aqueous scetic acid over a period of 1 hour. After the addition, the mixture was
11 refluxed for 2.5 hours and cooled to room temperature. The precipitated zinc acetate
12 was removed by filtration and the filter c~ce was washed with 500 ml. of I
13 dichloromethane. The filtrate was concentrated on a rotary evaporator and the residue
14 hested at 100/1.0 mm. for 30 minutes to remove last traces of acetic acid. The residue
was dissolved in 500 ml. of water and the solution was extracted with a x 150 ml. of
16 dichloromethane. The dichloromethane extracts were discarded and the aqueous layer
17 was made basic (pH 8-9) with 165 ml. of ammonium hydroxide and 500 ml. of brine was
18 added. The mixture was extracted with 3 x 200 ml. of dichloromethane and the
19 combined extract was washed with lD0 ml. of brine and was dried over anhydrous sodium
20 sulfate. Evaporation of the solvent afforded 56.0 g. of crude tetrahydroindolone which
21 was dissolved in 90 ml. of 2:1 toluene-ethyl acetate. The solution was stirred j
22 magnetically and was seeded and allowed to crystallize overnigm with stirring. The ¦
23 first crop of 20.8 g. was collected by filtrati~n and the mother liquor was concentrated
24 and crystallized again from a stirred solution to give 10.0 g. in the second crop. The
mother liquor was dissolved in 75 ml. of methanol and a solution of 15.0 g. of oxalic acid
26 in 50 ml. of methanol was added. The mixture was warmed 10 minutes on the steam
27 bath and cooled. The solid oxalate salt was filtered off and washed with 10 ml. of
Il . , I
1 1132553
1 ¦ methanol and dissolved in 50 ml. of water. The solution was made basic with ammonium
I hydroxide and extracted with 2 x S0 ml. of dichloromethane. The extracts were washed
3with 1 x 20 mL of brine and dried over anhydrous sodium sulfate and concentrated on a
rotary evaporator to give 4.5 g. of additional crude product. Crystallizatïon from 2:1
5toluene-ethyl acetate afforded 2.6 g. of additional crystalline product. The two crops
6and oxalate-derived crystals were combined and dried at 25/1 mm. for 2 hours to give
733.4 g. of 6-[2-(N-'methylamino)ethyl]-2-methyl-3-ethyl-6,7-dihydro~5H)-4(1H,5H)-indo-
lone ss a 11 ~ht 1 w solid, mp 114-120, hicll w. ho A-ge ~ous by TLC.
lG
23.
~5
26
27
.'' ; . ' ,
1132553
1 Exarnple 4
2 P~raration of 3-ethyl-2.6-dimethYl-4.4a,~.6,7,8,8a,9-octahydro-4a,8a-trans-lH-p~rrol~
3 12,3-~] -isoq~nolin-4-one, hydro_hloride -
4 In a S00 ml. round-bottom flask w~s plac~d li.0 g. of 6-[2-(N-methvlamino)eth~
S 2-methyl-3-ethyl-6,7-dihydro~5H~4(1H,SH)-indolone and 170 ml. of methanol. To the
6 solution was added 20 ml. of 4N hydrogen chloride in diethyl ether (made by bubbling HCl
7 gas into diethyl ether in an ice bath and titrating). The solvent was removed on a rotary
8 evaporator and the residual solid was dried at 50U/1 mm for 2 hours to give 19.7 g. of
9 crude hydrochloride salt.
~ a 3-1. 3-neck round-bottom flask equipped with a mechsnical stirrer, therm~
11 meter and distilling head were placed the 19.7 g. of hydrochloride salt, 21.8 g. of para-
12 - formaldehyde and 1000 ml. of octanol. The reaction mixture was heated to reflux and
13 water which was liberated was removed by distillat.on until the temperature of the
14 octanol solution in the flask reached 175-180, whereupon the distilling head was
removed and replaced by a reflux condenser. The reaction mixture was heated at 17i
16 180 for 1 hour and 6.54 g. of paraformaldehyde was added in three portions over 5
17 . minutes. Water was distilled out as before until the temperature reached ;75-i80 and
18 the mixture was heated at 175-1~0 for an additional 1 hour. The dark brown so!ution
19 was cooled and poured into 1000 ml. of water. The layers were separated and the
organic layer was extraeted with 2 x 400.ml. of 5% hydrochloric acid. The combined
21 aqueous extract wns washed with 2 x 150 ml. of chloroform and the chloroform solutions
22 were discarded. To the aqueous layer were added 120 ml. of ammonium hydroxide and
23 400 ml. of chloroform. The layers were separated and the aqueous solution w~s
24 extracted with 4 x 200 ml. of chloroform. The combined chloroîorm extracts ~vere
washed with 200 ml. of brine and dried over anhydrous sodium sulfate. Evaporaticn of
26 the solvent afforded 12.0 g. of crude pyrrolo[2,3-g] isoquinoline as a 4a,8a-trans, 4a,8a-
27 cis mixture (about 8:1~ as a dark tan solid. The crude solid was dissolved in 100 ml. of 9:1
~ - 56 -
113~553
1 ¦I dichloromethane-meth~nol and 300 ml. of diethyl ether was added. The fine solid
2 j precipitate, predominantly the 4a,8a-trans isomer, was collected by filtration and the
3 fntrate was concentrated and crystallized to give second and third crops of tan solid.
4 The combined material was dried at 25 /1 mm. for 1 hour to give 8.20 g. of a light grey
S solid, 3-ethyl-2,6-dimethyl-~,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3~3-
6 isoq,uinolin-4-one, mp 203-226. The partially-purified grey solid was
7 suspended in 80 ml. of methanol and 12 ml. of 4N hydrogen chloride in diethyl ether was
8 added. The solvent was removed and the residue was crystallized from 25 ml. oî hot
9 sbsolute ethanol. The first crop was collected by filtration and the mother liquid was
concentrated and crystallized to give second and third crops of crystals. The combined
11 solid was dissolved in 120 ml. of methanol and 2.4 g. of activated carbon (Darci~G-60) was
12 added. The mixture was warmed on a steam bath for 10 minutes and the carbon filtered
13 off through OELI~EThe filtrate was concentrated and recrystallized from lS ml. of t
14 ¦ ethanol to give three crops of white crystals. The combined solid was dried under
lS ¦ vacuum at 80/0.05 mm. for 18 hours to give 5.4 g. of 3-ethyl-2,6~imethyl-4,4a,5,6,7,8,-
16 ¦ Ra,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride as a white
17 ¦ solid, mp 196-198; Oxime, semihydrate, mp 131-133 .
181 . I
20 ~
2231
22sl .. ,
261
27 l
1:132553
`; ,'., . ~ - '', , ' ' '
l Examples 4a~
2 Following the procedures of Examples 3 and 4, the compounds listed in Table I
3 were prepared from the appropriate isonitrosoketor.e with variations as noted. Each
4 compound displayed spectral characteristics which were consistent with the descr.bed
structure. Melting points are for the free base or hydrochloride salt (.HCl) as indicated.
6 Isonitrosoketones ~rere prepared as described in the literature [e.g., I~erris et al., J.
7 Org; Chem., 24,1726 (1959)] by nitrosation of the appropriate ketone. The isolated
8 ~ ~ compounds athe 4a,8~-trans Isomers.
10 ' : .
11 . ' ' .
I
1~
2,8 ~ ' ~
21 - . -
23
24
26
-58-
.113Z553
2 1I P~ sS
6 o . ~ ¦ E
8 ~ ~ ' . ~ ~3 o
Il ~ ~ u~ ~
12 ~ ~I V::~zlc) V~Z
13 ~ / \
14 D O
'P: ~
~o I ~ el o
22 ~ ~ "` o
~ ' C ~ 2 c
S I ~ 5 C ' i
0~ ~ ~
~ _59_
ilJZ5S3
3 ~ ~ ~ s .--
4 jcSI ~
8 .
~1 C-~~
~ -
1~ ~
~. ' d
27
` ~
- 1 1132553
I Example S
2 Pie?a;ation of 2-methyl-3-cthyl-4~4a~s~6~7~8~8~9-octahydro-4a78a-trans-lH-pyrrolo[2~3
3 g] isosuinolin-4-one
A mixture of 3-ethyl-2,6-dimethyl-4,4a,5,G,7,8,8a,9-octahydro-lH-pyrrolo[2,3-
S g]isoquinolin-4-one prepared as in Example 4 (4.92 ~., 20 mmol), ethyl chloroformate
6 (19~55 g., 180 mmol~, and potassiurn bicarbonate (6.0 g.j 60 mmol) in diethyl ketone tlOO
7 ml.) was heated to reflux for 3 hours. The mixture was cooled, filtered, and the filtrate
8 concentrated on a rotary evaporator to dryness and the residue was dissolved in
9 chloroform. The chloroform solution was washed with SYO aqueous hydrochloric acid,
brine, and was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded
11 4.90 g. of crude carbamate which was purified by chromatography on alurnina III to giYe
12 3.70 g. of pure 6-ethoxycarbonyl-3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyr-
13 rolo[2,3-g]isoquinolin 4-one.
14
The carbamate (3.7 g., 12.2 mmol), glacial acetic acid (45 ml.) and concentrated16 hydrochloric acid (60 ml.) were heated to reflux for 24 hours, cooled, and concentrated
17 on a rotary evaporator. The residue was dissolved in water and extracted with chloro-
18 form (discarded) and the aqueous layer ~ras made alkaline with ammonium hydroxide and
19 was extracted with chloroform. The combined extracts were washed with brine and
dried over anhydrous sodium sulfate and concentrated to give 2.72 g. of crude secondary
21 amine. Treatment of the crude amine in ethanol with ethanolic hydrogen chloride gave
22 the hydrochloride salt, which was crystallized.from hot ethanol to afford 2.18 g. (47%
23 yield) of 2-methyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] iso-
24 quinolin-4-one, hydrochloride as white crystuls, mp > 250 .
Anal. Calcd. for C14II20N20.HC
26 C, 62.5G; H, 7.88; N, 10.42; Cl ,12.19
27 ~ound: C, 62.50; H, 7.90; N, 10.19; Cl ,13.33
~1 -61-
113~S53
- 1 In an analogous m~nner, 2,3-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-
2 4a,8artrans-lH-pyrrolo[2,3-g~soquinolirr4-one can be prepared from
3 2,3,6-trimethyl-4,4a,5,6,7,8,8a,~-octahydrc,lH-pyrrolo[2,3-a]iso-
quinolin- 4 one.
Example G
7 Preparation of 3,4-dihydro-lH-6,8-dimethoxy-2-methvl-isoquinoline, hydrochloride
8 A solution of N-methyl-(3,5-dimethoxyphenyl)ethylamine hydrochloride (15.0 g,
64.7 mmol) in 30 mi. of water was treated with 35 ml. of 2N sodium hydroxide and
lO extracted with dichloromethane. The combined extracts were concentrated on a rotary
11 evaporator and mixed with aqueous formaldehyde (65 ml, 37~6 solution). The mixture
12 was refluxed for 2 hours, made al}caline with 2N sodium hydroxide (15 rnl.) and extracted
13 with dichloromethane. The combined extracts were washed with brine and dried ove.
14 anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (15.5
15 g). The oil was dissolved in 100 ml. of ethanol and treated with ethanolic hydrogen
16 chloride. Ether (75 ml.) was added, and the salt crystallized to give 10.15 g. of 3,4-
19 ~ dihydro-lH-6,6-d thoxy-2-methylisDquinolire, hydroohloride (6~% yield).
221
22
23
24
26
27
l~
ii3Z553
. . . ..
Exnmplc 7
I
Prc~nretion of 1,2,3,4,4a,7-he~nhvdro-5,8-dimetllo~y-2-methvlisoqt~inoline ~nd_ OC~2-
h dr~2-meth 1isoaui:lolin-6.8 clione
Y ~i . ._ .
Ammonia (lS0 ml) ~Yas condensed in a flS~Ck cont?inin~ t-butanol ~9.1 g; 123 mmol)
ond diethyl ethcr (50 ml). To the solution W8S added 3,4-dihydro~ 6,8-dimetho.:y-2-
methylis~ui~.oli~.e hydrochlcri~e (1.0 g, 4.1 mmol). After stir.ing 2-3 minutcs, l.t}~ m
wire (0 57 g~ 82 mmol~ was added in short pieces over 30 minutes. The blue solutlon w~s
stirred ~der reflllx for 2.5 hours and solid ammonia chloride (4.5 g) w~s added until the
blue color dissipated. Ether (100 ml) w~s added and the ammonia was allowed to
eYaporate o~ernight. Ice water (100 ml) was added nnd the organic phase W8S separ~ted.
The aqueous layer wP~ extracted with ethyl acetate and chloroform. The combined
extracts were ~ sshed with brine and dried over anhydrous magnesium sulfate and con-
centrated to give 1,2,3,4,4a,~-hex~hydro-6,8-dimetllo:~y-2-methylisoquinoline (0.58 g,
68~ ~ield) ss a yello~ oil.
The crude product (l.OS g) in 20 rnl. of 7096 queous acetic acid wss refluY~ed for
5 hours and thc acetic acid was remov~d on a rotary evaporntor. The residue was
dissolved in water and washed with chloroform. The aqueous phase W85 concentrated to
a 10 ml. Yolume and chromatographed cn l)owex AG SOWX 8 eluting wsth 2 molar
a~ueous wridine to a~ford 0.11 g. of octal?ydro-2-methylisoquinolin-6,8-dione (ll.G~
ld) ~s a light yellow solid. Treatment ~ h hydrochloric acid in methanol aîforded
the hydrochloride, mp 1~3-19G.
* Trad~k
' ~ ~,J
l ~ ~
~13ZSS3
. ' , ' ' .
- Exnmple 8
2 ¦ Pr~paration o~ 3-cthvl-2.6-dimcthyl-~,4n.5.G,7.8.8n.9-octnh~dro-1l~-pyrrolo[',3-~ 1 is~
3 I.i. ,;in-~ne via oct~hvdro-"-mcth~lisoquinolin-6 8-dione
q ~
.._..
4 1,2,3,4,4n,7-He:cahydro-6,8-dimethoxy-2-methylisoquinoline (0.56 g, 2.6~ mmol)
S was hcated to 9û-100 in 70'~ aqueous acetic acid (I0 ml) to hydrolyze the bis(enolether)
6 to the octahydro-2-methylisoqllinolin-6,8-dione. To the hot solution ~Yas added zinc dust
7 ¦ (0.6 g, 9.25 mmol) and 2-isonitroso-3-pentanone (0.7 g, 6.1 mmol). The mixture ~as
8 reflu~ced for 3 hours, cooled and filtered to remove zinc and zinc acet&te. The filtrate
was concentrated to dryness on ~ rotary evapor&to,- and tl e residue was dis olves in
1 dichloromethane. To the solution was added ammonium llydroxide and the layers ~-,ere
11 separated. The organic layer ~s washed ~ith brine and dried over anhydrous sodium
12 sulfate ~d concentrated to Dive the crude product. Cllromatography of the crude
13 product on Alumina IJI afforded 3-ethyl-2,G~imethyl-~,~a,5,5,7,8,8a,9-octahydro~
14 pyrrolo[2,3 g~ isoquinol:n-4-one as a white solid (û.l9 g, 29~6 ~ield).
16 . .
17
18 _ . - .
19 : . ' ' ,- ' '_
21 . . _
23
2G
2~ .
. ,..,.' ,.
.....
` - 64 -
113;~:553
11 ~
2 1 Preparation of 2 6~imethyl-3-iso~opyl-~.4a,5,6,7,8.8a.9~ctahydro-4a,8a-trans-lH~
3 rolo[2,3 ] isoquinolin-4-one
4 A solution of crude octahydr~2-methyl-isoquinolin-6,8~ione (approximPtely 12.5
S mmol) and 2.4 g. (18 mmol) of 2-isonitroso-4-methyl-3-pentanone in 40 ml. of 7096
6 aqueous acetic acid was treated with 2.6 g. (40 mmol) of zinc dust and slowly heated to
7 reflux. After 1 hour the mixture was cooled slightly and an additional 0.4 g. of iso-
8 nitrosoketone and 1.0 g. of zinc were added and the mixture stirred for 1.5 hours at
9 reflux. The mixture was then cooled and filtered, and the filtrate concentrated at
50/20 mmHg to give a yellow oil which was diluted with 50 ml. of water and made
11 aL'caline (pH 8-9) with ammonium hydroxide. The mixture was extracted with chloro-
12 form and the extracts were washed with brine and dried over sodium sulfate and
13 concentrated to give 2.6 g. of crude product. The material was chromatographed (dry
14 column) on 100 g. of silica gel eluting with the organic phase of a mixture prepared by
equilibrating (by volume) 90 parts chloroform, 30 parts methanol, 10 parts water, and 6
16 parts acetic acid. The eluate fractions containing the product were evaporated, diluted
17 with water, made alkaline (pH 8-9) with ammonium hydroxide, and extracted with
18 chloroform. The extracts were dried over sodium sulfate and evaporated to give 1.0 g.
19 of solid product whlch was recrystallized twice from ethyl acetate to give 470 mg. of I
pure 2,6-dimethyl-3-isopropyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-
22 g] isooui olin-4 one ss s crystslline solid, mp 244-24~,
24
26
27
.. ~. ,.~ .
1~ 1132S53-
IExample 10
2 1!eDaration of_3.6-dimethvl-2-(2-proDenyl)-4,4a.5,6,7,8,8a,9-octahydro-4a.8a-trans-lH-
i
pyrrolo~2.3~] isoauinolin-4-one
4 In a similar manner to that described in Example 9, 3-isonitroso-5-hexen-2-one
and 2-methyl-octahydroisoquinolin-6,8-dione afforded 3,6~imethyl-2~2-propenyl)-
4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, mp 221-
7 223,
~ . . .
9 Example 11
Preparation of 3-cyclo~ropyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-
il pyrrolo[2,3~] isoquinolin-4~ne
12 In a similar manner to that described in Exampie 9, cyclopropyl-2-isonitroso-1-
13 propanone and 2-methyl-octahydroisoquinolin-6,8-dione afforded 3-cyclopropyl-~,6-
14 dimethyl-4.4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, mp
lS 258-259 (dec.).
16
17 Example 12
18 Preparation of 2-benzvl-3,6-dimethyl-4?4a,5,6,7?8,8a,9-octahydro-4a,8a-trans-lH-~yr-
19 rolo~2,3~] isoauinolin-4~ne
2Q In a similar mamler to that described in Example 9, 3-isonitros~4-phenyl-2- 1
21 butanone and 2-methyl-octahydroisoquinolin 6,8-dione afforded 2-benzyl-3,6-dimethyl- ¦
22 4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3~] isoquinolin-4-one, mp 234-
24 235.
26
.'
- 66-
1i3~553
. '- I
. ',-, I
! ~¦ Example 13
2 j~ Pre~aration of 6-methvl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pvrrolo[2 3~2] iso-
3 quinolin-4-one
4 Ill fl similar manner to that described in Example 9, except that no zinc was used,
5 aminoacetaldehyde dimethyl acetal and 2-methyl-octahydroisoquinolin-6,8-dione afford-
6 ed 6-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3~] isoquinolin-4-one,
~ m ~ 208-210
J , . ''
24 -.
~6
. . ~,"' ' .
~ .....
1132553
11 ' ' '' . ''
' ' :
2 eparation of 3-ethyl-1,2,G-trimethyl-4,4a.5,6,7,8,8a.9-octahydro-4a,8a-trans-1 H-?vr-
3 rolo[2,3-g3 isoquin~lin-4-one
4 Liquid ammonia (80 ml) was condensed into a flask containing a suspension of
2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-gl isoquinolin-4-one
6 (0.984 g, 4.0 mmol~ in etller (24 ml). Sodium metal (0.138 g, 6.0 mmol) was ad~ed and
7 the solution stirred until all the sodium had dissolved. A solution of methyl iodide (1.28
8 g, 9.0 mmol) in ether (16 ml) was added and the mixture W2S stirred at room j
temperature until the ammonia evaporated. Water and chloroform were added and the
aqueous layer was separated and extracted with chloroform. The combined extracts
11 were washed with brine and dried over anhydrous sodium sulfate and concentr~ted to
12 give 1.14 g. of crude product ~^~hich was chromatographed on Alumina III to give 0.572 g.
13 of white solid product. The chromatographed free base was conYerted to the
14 hydrochloride salt with~ethereal hydrogen chloride and crystallized from ethyl 2cetate-
ethanol and ethanol to give pure 3-ethyl-1,2,6-trimethyl-4,4a,5,6,7,8,8a99-oct~hyd.
16 4a,8a-trans-lH-pyrrolo[2,3-g] isoguinolin-4-one, hydrochloride (0.33 g, 28% yield) as
17 white crystals, mp 241-243.
18 Anal. Calcd. for C16H2~L~20.HCl:
19 C, 64.74; Hg 8.49; N, 9.4~; Cl ,11.94
21 ¦ Found C, 6-.~!2; H, 8.63; Il, 9 29; C;, 12.03
23
26
27
~132~5;~ I
6~ample ls
Preparation of l-ben%oyl-2,6-dimethyl-3-ethyl-4-.a,5,6,7,S,8a,9-octahydro-4rl,8a-tr~ns-
3 lH-pyrrolo[2,3-g~ isoquinolin-4-one
To a suspension of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo-
[2,3-g~ isoquinolin-4-one (492.7 mg, 2.0 mmol) in dry tetrahydrofuran (10 ml) at -30 was
6 added butyllithium (1.6 ml, i.4 mmol, 1.5 M solution in hexane) over 2-3 minutes via
7 ¦ syringe. The solution was stirred st -30 for 1 hour and benzoyl chloride (336 mg, 2.4
8 mmol) was added over 2-3 minutes. The resulting solution was stirred for 1 hour at -25
9 to-35 and for O.S hours at room temperature. The solution was poured into ice water
(30 ml) and extracted with chloroform. The combined extracts ~ere washed with brine
11 and dried over anhydrous sodium sulfate. Evaporation of the solYent afforded the crude
12 product (0.9 g), which was chromatographed (dry column, silica gel, eluting ~ith a
13 chloroform-aqueous methanol-acetic acid solution). Column ractions were treated
14 with ammonium hydroxide and extracted with chloroform and washed with ~Jater and
dried over anhydrous sodium sulfate. Evaporation of the sol~ent gave l-benzoyl-2,6-
16 dimethyl-3-ethyl-4,4a,5,6,7,8,8a,g-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]-isoqu-nolin-4-
17 -one as a solid which was recrystallized from cyclohexane to give the pure product, mp
18 1~4-146.
lg Anal. Calcd. for C22H26M2O2:
C, 75.4~; H, 7.48; ~, 7:99
22 I?oun C, 75.63 H, 7.79; N, 8.01
24
26
27
- 69 -
1132553
Utilizing the procedure of E~cample 15, the following compounds were prepared.
2The isolated compounds are the 4a,8a-trans isomers.
4Erom 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g3 isoquin-
S¦ olin-4-one and benzyl chloride, there was obtained 1-benzyl-2,6-dimethyl-3-ethyl-
6 1 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one.
8 From 2,6-d.metllyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[ ,3-g]-
9 isoquinolin-4-one and l-trimethylacetyl ch!oride, there was obtained 2,6-dimethyl-3- 1
ethyl-1-(2,2-dimethyl-1-oxopropyl~-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo~2,3-g3 isoquinolin-
11 - 4-one, mp 110 -112 .
12
13 From 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo-
14 ~2,3~] isoquinolin-4-one and methyl iodide, there was obtained 3-ethyl-1,2-dimethyl-6-
(~-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3~ isoquinolin-4-
,¦ one, mp 180-18
223 . .
26
70_
~1325S3
Example lG
2 Preparation of 3-ethvl-2-methyl-6-(2-propcnyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-tralls-
3 lH-pyrrolo[2,3-g] isoquinolin-4-one
4 A mixture of 3-ethyl-2-metllyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]iso-
S quinolin-4-one (0.470g, 2.û3 mmol), allyl bromide (0.5 g, 4.13 mmol) and potassium
6 carbonate (0.85 g, 6.16 mmol) in acetone (35 ml) vas stirred. at room temperature for 2
7 hours and was filtered. The filtrate was concentrated and the residue (0.53 g~ chroma-
8 tographed on Alumina III to give the product (0.40 g). This product was treated with
9 ; ethereal hydrogen chloride to form the hydrochloride salt, which was recrystallized
from ethanol-ethyl acetate to give 3-ethyl-2-methyl-6-(2-propenyl)-4,4a,5,6,7,8,8a,9-
11 octahydro-4a,8a-trans-lH-pyrrolo[2,3-g~ isoquinolin-4-one hydrochloride as a white solid,
12 ;mp 214-217.
13 Anal- Calcd- for C17H24N2 HCl- 0 SH2O
14 C, 64.24; H, 8.25; N, 8.81; Cl ,11.15
lS Found:C, 64.50; H, 8.48; N, 8.96; Cl ,11.37
1 6
17 Examples 16a-dd
18 Following the procedure of Example 16, the compounds listed in Table II were
19 prepared from the indicated 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]-isoquino-
lin-4-one and the indicated halide. Each compound displayed spectral characteristics
21 consistent with the described structure. I`,Ielting points are for the free base or
22 hydrochloride salt (.HCl) as indicated. Compounds isolated are the 4a,8a-trans isomers.
23
24
26
27
-- 71 --
1525
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- 74-
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113;~553
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Example 17
2 Preparation of 3-ethyl-2-methyl-6-(?-hydrox~/-2-ph~nyleth~1)-4,4a ~,6,7,8.~a.~octa-
hydro-4a,8a-trans-lH-pyrrolo[2,3-g3 isoquinolin-4-one
4 A mixture of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,~-octahydro-lH-pyrrolo~?,3 g] is~
quinolin-4-one (0.83 g, 3.58 m mol) and styrene oxide (O.Sl g, 4.22 mmol) in meth~nol (2;,
6 ml) was refluxed for 2.5 hours, coolcd, and filtPred. The filtrate was concent,at~d an~
the residue chromatographed on Alumina III to give 0.69 g. of crude product. Re-
8 , ¦ crystallization from ethyl acetate-ethanol afforded O.l9S g. of 3-ethyl-2-meth~;1-6-(~-
9 'hydroxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g].soquinolin-
- 4-one as a white solid, mp 218.5-22û . -
11 Anal- CalCd- or C22~2hN22
12 C, 74-97; H, 8.01; N, 7.95 .
13 Found: C, 74.87; H, 7.92; N, 7.95
14
15Examples 17a-17f
16Following the procedure of Example 17,: the compounds listed in Table I~I weFe1~prepared from 3-ethyl-2-methyl-4,4a,5,6,7,8,8n,3-octahydro-lH-pyrrolQ~2,~-~ iscquin~
18lin-4-one and the indicated epoxide. Each compound displayed spectral characteristics
19consistent v,~ith the described s.ructure. Melting poi!lts are for the free b2se o~
2Q hydrochloride salt (.HCl) as indicated. ~he compounds isolated are the 42,8-trans
21 isomers.
22
24
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Example 18
2 P~^~ution of racemic 3-ethyl 2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-
3 lH-pyrrolo[2,3-~] isoquinolin-4-one
'I The racemic free base (prepared as in Example 4) (1.20 g.) was dissolved in
S methanol and a solution of d-(+~tartaric acid (0.74 g.) in methQnol was added. The
6 ' solution was concentrated and recrystallized twice from methanol. The crystalline d-
7 (+)-tartrate salt was treated with ammonium hydroxide to liberate the free base, and
8 the free base was treated with anhydrous ethereal hydrogen chloride to give the
g hydrochloride salt. After two recrystallizations from ethanol and drying at 80/0.005
mm, there was obtained 0.15 g. of the (-)-enantiomer as a white crystalline solid, mp
11 1i 24û-245.
12 ~ rotation: [ ] 25 -120.78 (c 0.8196, water)
i3 Anal. Calcd. for C15H22N2O.HCl. 0.25H2O
14 ~ C, 62.70; H, 8.24; N, 9.75
Found: C, 62.44; H, 8.33; N, 9.6i
16 ~,
17 I The mother liquors from the crystaLlization of the d-(+~tartrate sal. were
18 treated with ammonium hydroxide to liberate the free base which was treated with a
19 I solution of l-(-)-tartaric acid (0.46 g.) in methanol. The solution was concentrated and
recrystallized twice from methanol, converted to the free base and hydrochloride salt
21 ~j as described abo-/e to give 0.10 g. of the (+)-enantiomer as a white crystalline solid, mp
22 ,240-244.
23 ,rotation: [ ] 25 + 121.38 (c 0.44~6, water)
24 ,Anal. Calcd. for C15H22N20.HClØ25~I20
; C, 62.70; H, 8.24; N, 9.75
26 , - Found: C, 63.02; H, 8.20; N, 9.88
27
-- 84
.
~, . .
11325S;3
Example 19
3 Prepara~ion of N- [ 2- ( 3-ethyl-4, 4a, 5, 6, 7, 8 , 8a, 9-octahydro 2-methyl-4-c~
4 4a,8a-trans-lH~7rrolo[2,3-g]iscquir~l:in-6-yl)ethyl]-4-fluorob~nzanide
N-l2-(3-ethyl-4,~a,5,6,7,8,8a,9-octahydro-2-methyl-4-oxo-4a,8a-trans-lH-
6 pyrrolo[2,3~ isoquinolin-6-yl)ethyll-4-fluorobenzamide was prepared by heating 3-
7 ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]isoquinolin-4-one and 1-(4-
fluorobenzoyl)-aziridine in a mixture of benzene and methanol for 2 hours. The crude
9 product crystallizecl from ethanol as a white solid, mp 252-253. The starting
aziridine was prepared from ~ziridine and p-fluorobenzoyl chloride and sodium
11 bicarbonate in water.
12
Example 20
14 Preparation of 3-ethyl-2,6-dimethyl-4,4a,5,6,~,8,8a,9-octahydro-4a,8a-trans-!H-Dyr-
rolor2,3-g] isoquinolin-4-thione
16 A mixture of 2.48 g. (0.01 mol) of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octa-
17 hydro-lH-pvrrolo~2,3-g] isoquinolin-4-one and 2.44 g. (0.008 mol) of P4Slo in 100 ml. of
18 dioxane was stirred and refluxed ~or 17 hours. The dioxane was evaporated at reduced
19 pressure and 150 ~1. of water and enough ammonium hydroxide were added to bring the
pH to 8-9. The mixture was extracted with chloroform and the extracts were washed
21 with water and dried over sodium sulfate. Evaporation of the solvent gave the crude
22 thione (3.3 g.) as a gummy material. Dry column chromatography gave 1.2 ~. solid
23 thione which was recrystallized twice from acetonitrile to give pure 3-ethyl-2,6-
24 dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-thione,
l mp 194-196 (dec. ) .
26
27
1 113Z553
1 Example 21
2 PreDarat-~n of 3~ethvl-2-methvl-4.4a.5,6,7,8,8a.9-octah~dr~lH-pyrrolo[2~3~,~-iso-
3 quinolin-4-thione
4 A mixture of 1.45 g. (6 mmol) of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-
lH-pyrrolo[2,3~] isoquinolin-4-one and 1.77 g. (4 mmol) of phosphorus pentasulfide in 6~
- - 6 ml. of dioxane was stirred and refluxed for 10 hours. The mixture was cooled and the
7 dioxane solution was decanted from a dark residue which was dissolved in 75 ml. of
water. The solution was made alkaline (pH 8-9) with ammonium hydroxide and the
- 9 aqueous mixture was extracted with chloroform. The extracts were washed with water
and dried over sodium sulfate. Evaporation of the solvent gave 420 mg. of crude thione
11 which was chromatographed (dry column, silica gel) together with 100 mg. of additional
12 crude product obtained by hot water treatment of the residues from the initial isolation
13 followed by the same chloroform extraction procedure. Elution of the dry column with
- 14 the organic phRse of a mixture prepared by equilibrating (by volume) 90 parts
chloroform, 30 parts methanol, 10 parts water, and 6 parts acetic acid gave purified
16 thione after ev~poration, dissolut~on in water, neutralization to pH 8-9 with ammonium
17 hydroxide, and extraction with chloroform. After washing with water, and drying over
` 18 sodium sulfate, evaporation of the chloroform afforded 250 mg. of 3-ethyl-2-methyl-
19 4,4a,5,6,7,8,8a,9~ctahydro-lH-pyrrolo[2,3~] isoquinolin-4-thione as a yellow solid, mp
190-194. Recrystallization from acetonitrile gave the pure 4a,aa-trans isomer, mp 203-
21 205.
22
23 v
24 . .
Z6 - ; ~ -
27
~25S3
1 Example 22
2 Preparation of 3-eth~1-2-methvl-6-(2-phenvlethyl)-4,~a,5 6,7,8,8a,9-octahvdr~4a 8a-
3 trans-lH-pyrrolo[2,3~a] isoauinolin-4-thione
4 A mixture of 248 mg. ~1 mmol) of 3-ethyl-2-methyl-4,4a,5,6,~,8,8a,9-octahydro-
lH-pyrrolo[2,3~] isoquinolin-4-thione, 276 mg. of potassium carbonate, and 222 mg. of
6 2-bromoethylbenzene in 15 ml. of 3-pentanone was stirred and refluxed for 3 hours. The
7 solvent was removed on a rotary evaporator, 25 ml. of water was added, and the j
8 mixture was extracted with chloroform. Purification by dry column chromato~aphy as
detailea in Example 21 gave 100 mg. of purified product, which gave 50 mg. of 3~thyl-2-
methyl-6-(2-phenylethyl)-4,4a,5,6,~,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3~D~ isoquinoli
-4-thio~, m~ ~ ~6 ~ ion o - a.e~ t-i e.
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26 .
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