Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
X-4658B -1-
Tetrahydro 2H-benzo[c]pyrroles
This mven~ion in one a~ect, provides substituted dl-
4,5,6,7-tetrahydro-2H-benzo[c]pyrroles of the general
formula
/6\ ~m
1~7 5~
~1 ~3a
R~ 2 - 3ll
wherein
R1 is H or R ;
Am is N(R )2; and
each R2 is independently allyl, methyl,
15 ethyl, or n-propyl; and `-
the pharmaceutically-acceptable acid addition
salts thereof.
The compounds of formula I ar~ prepared
by reacting a dl-5-amino-4,5,6,7-tetrahydro-2H-
benzo[c]pyrrole compound of the formula
I-NH2
I ~ v
H - ~
with an aldehyde and then reducing with a metal hydride;
or with an alkyl halide, then an acyl halide followed
by reducing with a metal hydride; to provide the
compounds of formula I wherein Rl is ~, and Am is
N(R ~2;
:.
~7~355
._ --2--
followed by reacting with an alkyl halide
and base t~ provide the compounds of formula I wherein
Rl is R2, and Am is.N(R~)2; and where desired, forming
a pharmaceutically acceptable acid addition salt of
said compound of formula I.
The above oompounds of formula I and the process for their
preparation, are disclosed and claimed in Canadian Patent Applicatlon
No. 330,566, filed June 26, 1979, of which the present application is a
divisional.
The compounds of for~ula I are useful ~s
dopamine agonis~s i w luding ~heir use in ~rea~ing
Parkinson' 5 Syndrome and as prolactin inhibitors.
Additionally, the following compound~ are
useful as novel intermediates and have the general
formula
R'l ~0
wherein o
1 3
R is H or R C;
Am is NH2 or NH-C-R3;
R is methyl, ethyl or n-propyl;
except that Rl i~ not R3-C when Am is NH2: and
the acid addition ~al~s ~hereof when Am is
NH2 .
The pharmaceutically-acceptable acid addition .
salts of the compounds of formulae I and IA include
salts derived from non~oxic inorganic acids ~uch as:
hydrochloric acid, nitric acid, pho~phoric acid, .
sul~uric acid, hydrobromic acid, hydriodic acid,
nitrous acid, phosphorou~ acid and the like, as well
as ~alts derived ~rom non-toxic org~nic aci~ ~uch as
I
': ~ ~' `'
., ~ ~: .
. -3
aliphatic mono and dicarboxylic acids, phenyl-
substituted alkanoic acids, hydroxy alkanoic and
alkandioic acids, aromatic acids, aliphatic and aromatic
sulfonic acids, and o~hers. Such pharmaceutically~
acceptable salts thus include sulfate, pyrosulfate,
bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, meta-
phosphate, pyrophosphate, chloride, bromide, iodide,
fluoride, acetate, propionate, decanoate, caprylate, ..
acrylate, formate, isobutyrate, caprate, heptanoate,
propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, mandelate, butyne-
1,4-dioate, hexyne-1,6-dioate, benzoate, chloroben-
zoate, methylbenzoate, dinitrobenzoate, hydroxy-
benzoate, methoxybenzoa~e, phthalate, terephthalate,benzenesulfonate, toluenesulfonate, chlorobenzene-
sulfonate, xylenesulfonate, phenylacetate, phenyl
propionate, phenylbutyrate, citrate, lactate, p-
hydroxybutyrate, glycollate, malate, tartrate, me~hane-
sulfonate, propanesulfonate, naphthalene-l-sulfonate,
naphthalene-2-sulfonate and the like salts.
Acid addition salts of those int~rmediate
compounds of formula IA are not restricted to those
formed with non-toxic anions since the chief use of
such salts is for isolation and purification of the
intermediates involved.
Illustrative compounds coming within the
scope of formula I above include:
dl-5-dimethylamino-4,5,6,7-tetrahydro-2H-
benzo[c]pyrrole methane sulfonate.
dl-2-methyl-5-diethylamino-4,5,6,7-tetra-
hydro-2~-benzo~c]pyrrole maleate~
dl-5-diallylamino~4,5,6,7-te~rahydro~2H-
benzo[c]pyrrole ~ulfate.
dl 2-ethyl-5-di(n propyl3amino-4,5,6,7-
tetrahydro 2~-benzo[c]pyrrole hydrochlsride.
N,N,2-trimethyl-dl-5-2mino 4,5,6,7tetra-
hydro-2H-benzolc]pyrrole. `~
N-methyl-N-allyl-dl~5-amino-4,5,6,7tetra-
hydro-2H-benzo[c]pyrrole.
dl-2-allyl-5-dimethyl~mino-4,5,6,7-tetra-
hydro-2~-benzo[cJpyrrole.
N-m~thyl-N-ethyl-dl-5 amino-4,5,6,7-tetra-
hydro-2H-benzo[c]pyrrole.
~-methyl-N-n-propyl-dl-2-me~hyl-5-Amino-
4,5,6,7-tetrahydro-2H-benzo~c]pyrrole.
N allyl-N~n-propyl-dl-S-amino-4,5,6,7-
tetrahydro-2~-ben~otc]pyrrole.
While ~he compounds represented by formula
I have been n~med as 4,5,6,7-~etrahydro-2H-benzo~c]-
pyrroles, an alternative ~ame can be used; i.eO, the
compounds can be n~med as 4,5,6,7~etr~hydroisoindoles~
The pres~nce of ~ substi~uent at C-S in the
benzol~3pyrrole or iso~ndole xing introduces a center
o~ ~symmetry into tho~e molecules. Thus, compounds
... : : ~ . . , .. , .. ~. .. , ~
represented by formula I include two optical i~omers
occurring as a dl pair or racemate. Resolution of a
dl pair of formula I into its optical an~ipodes can be
accompli~hed by procedures known ~o thoYe ~killed in
S the art.
The present in~ention, m a ~ aspK~, resides in a
pnx~s for p~xrmg the ~ inten~ate o~ou~ o the ~ eral fon~a
~\ ,
I I-Arn
~ \~/ IA
R~
wherein O
Rl is H or R3-C;
Am is NH2 Gr NH-C-R3;
R3 is methyl, ethyl, or n-propyl;
except that Rl is not R3-C when Am is NH2;0 and
the acid addition ~alts thereof when Am is
NH2, which comprises reacting either
(A) I~ \~=CH--N(CH3)s~
~ III
IIIH-CO-R
'
'
7~5~
wherein R3 is defined as above,
with sodium glycinate ollowed by a ring
closure reaction in the presence of acetic anhydride
to provide the compounds of formula IA where Am is
O O
NH-C-R3 and Rl is R3-C;
followed by reacting the product with base
to provide the compounds of formula IA where Am is
NH2 and Rl is H; ox
(B) f \tN~R3
HOOC~ T/ XI
HN--~COOH
wherein R3 is defined as above,
with copper powder in the presence of
quinoline to provide the compounds of formula IA
where Am is NH-C-R3 and Rl is H; ;~
followed by basic hydrolysis to provide
the compounds of formula IA where Am is NH2 and
is H.
The compounds of formula I containing an
amino group ~Am) at C--5 in the tetrahydro-2H-ben70-
[c]pyrrole ring system can be prepared by at least two
different procedures star~ing from 4-acetamido-
cyclohexanone, formula II. The first of these is
illustrated in Reaction S~quence I below: .
. - ... . . , , ................... : . . :;: .: . .; . : : -.. .. - : .
- . . : : : . :: :. ................. .. :: , : ~
,,, ,:~ ,, . , . . :.
.. --7_
Reaction Sequenc:e I
8 R
I I - ` I' =CH-N(CHo)~
~H-Co-R3 NH-Co-R3
II III ¦ sod i um
~¦~ glycinate
\1~ (CH3CO)~O
.
NH2 ~ -
15~ ~11/ V NaOH ~ ~ IV
NaCNBH3 HCHO or ~o-R3
CH3CHO or
CH3CH2CHO or
\ / CH2=CH-CHO
\ ~ R~X
H ~ VI base R -N - VII
.~ .
,, , , -
-. ~ ~ : . : ; ;, . :, , , : ;,
,.
.:: . ~ . . .
According to Reaction Scheme I, 4-acetamido-
cyclohexanone, prepared by the procedure of Fraser and
Swingle, Can. J. Chem., 48, 2065 (1570) is reacted
with the dimethylacetal of dimethylformamide to yield
2-dimethylaminomethylene-4-acetamidocyclohexanone
(III). Reacting this compound with sodium glycinate
followed by a ring closure reaction in the presence of
acetic anhydride yields, when R3 is methyl, dl-2-
acetyl-5-aceta~ido-4,5,6,7-tetrahydro-2H-benzo~c]-
pyrrole (IV). Treatment of this latter compound withbase gives dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]-
pyrrole (V). This latter compound can be prefer-
entially alkylated on the amino group at C-5 using a
reductive alkylation procedure; i.e~, reaction with an
aldehyde (formaldehyde, acetaldehyde, acrolein, or
propionaldehyde) in the presence of a metal hydride
reducing agent, such as sodium cyanoborohydride. The
dialkylated compound, for instance, dl-5-di(n-
propyl)amino-4,5,6,7-tetrahydro-2H-benzo[c~pyrrole
(VI) can also be alkylated on the pyrrole ring nitrogen
under basic conditions using an alkyl halide R2X
(methyl iodide, allyl chloride, ethyl bromide, or the
like) to yield a dl~2-(Cl-C3 alkyl or allyl)-5-
disubstituted-amino-4,5,6,7-tetrahydro-2~-~enzo[c~-
pyrrole of formula VII.
Other methods of alkylation of the aminegroups at C-5 can be employed in addition to the
reductive alkylation procedure illustrated above for :;~
converting V to VI. For example, direct alkylation
with an alkyl halide, particularly an iodide, followed
. . ; .......................... .. . .... . . .
', ~ ` : ' ' . '_ . ,
7~5~i
by a reaction of the thus-formed secondary amine with
a suitable acyl halide; i.e., acetyl chloride or
crotyl chloride followed by reduction again with a
metal hydride reducing agent, such as lithium
aluminum hydride or diborane, yields a 5-dialkylamino
compound. This latter procedure particularly lends
itself to the preparation of unsymmetrically ub-
stituted amine groups at C-5.
A second synthetic procedure is available
for preparing the compounds of formula I as illustrated
in Reaction Sequence II below:
; . ~ , . ~ . ~ . . . . .
L~7~5~ ;
--10--
Reaction Sequence Il
R fC2H5
I' 't CH(OC2Hs)3
\ / / \ /
T aeid catalyst
NH-Co-R3 N~Co-R3
II VIII
~OOCH3
~OOCH3
1S I rNH-Co-R3 I' \rNH-Co-R3
~ ~ HOAc CH30CO\ ~
HN - _COOCH3 N / COOCH3 :
I X IX
¦ base
" I \~N~Co-R3
I I-NH-CO-R / H
H o-COOH quinoline XII
XI ¦ base
\ /
I' \!NH~i -
~ \~/
HI_~ V
. ~... .. . . ~, .. . ., . , . . ; .
., . . ~ . ~ , i ., , ~ . . .
.. . , . . ~, . . , , . ,, .. , . ,, . ,, . , . . . . . ~, . .
~.~7~
According to Reaction Sequence II, the same
starting material~4-acylamidocyclohexanone, is em-
ployed as in Reaction Sequenice I. The reaction of
this starting material with ethyl or~hoformate in the
presence of an acid catalyst such as p-toluene sul-
fonic acid produces an enol ether,i i.e., 4-acetamido-
l ethoxycyclohexene (VIII). Reaction of this deriv-
ative with 1,2,4,5-tetrazine dicarboxylic acid,
dimethyl ester [prepared by the procedure of Sauer, et
al. Chem. BerO, 98, 1435 (1965)] yields a pyridazine
_. _
diest~r (IX). Reduction of this diester with zinc in
acetic acid or other suitable metal-a¢id reducing
system causes a ring oontraction to yield dl-1,3-
dicarbomethoxy 5-acetamido-4,5,6,7-tetrahydro-2H-
benzo[c]pyrrole (X). Selective hydrolysis of thediester with base yields the corresponding dicar-
boxylic acid (XI) which, on decarboxylation with
copper powder in the presence of quinoline, gives
dl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole
(XIII). Hydrolysis under b sic conditions of the acyl
group then yields the free amine, dl-5-amino-4,5,6,7-
tetrahydro-2H~benzo[c] pyrrole (identical to compound
V from Reaction Sequence I). Other acyl protecting
groups can be used in the 4-acylamido cyclohexanone
starting material besides acetyl including propionyl,
butyryl and isobutyryl as well as benzoyl, dinitro-
benzoyl, phenylacetyl and the like.
:. . ~ , .
12
This invention i~ fuxther illustra~ed by the
following prepara~ive examples:
Example A
PREPARATION OF DL-5-AMINO-4,5,6,7 TETRAHYDRO 2H-BENZO[c]-
PYRROLE
~ reac~ion mixture was prepared from 15.5 g~
of 4-acetamidocyclohexanone [prepared by the pro~edure
of Fraser and Swingle, C~n. J. Chem., 48, 2065 (1970)],
RO g of the dimethylacetal of dLmethylformamide, 1.5
ml. of triethylamine and 500 ml. of benzene. The
benzene was distilled therefrom over a 1.5 hour period
until the volume was reduced to about 1/2 of the
original volume. An additional 250 ml. of b~nz2ne
were sdded. The reaetion mixture was heated just
below the boiling point of ~enzene for about 2 hours
and was then distilled again until the volume was
about one-half of that originally present (250 ml.)
The above process was repeated once more except that
the volume was reduced to one-third of the original
volume (167 ml.l. The reaction mixture wa~ then
cooled and filtered. The filter cake consisted of
dl-4-acetamido-2-dimethylaminomethylcnecyclohexanone
formed in the above reaction; weight ~ 6.45 g.
Evaporation of the f il~rate to dryness yielded a
residue, chromatography of a chloroorm solution of
which over 200 g. of"Florisir using chloroform con-
t~ining increa~ing amounts o~ methanol (0-5%) as an
eluan~, yielded more dl-4-ac~amido-2-dLmethylamino- :
methylenecyclohexanone; M.P. - 132-133C. (from
~enzene~; yield ~ 5.55 g.; total yield ~ 12 g.
~nalysis C~lc.: C, 62.83; ~, 8,63; N~ 13.32
Found: C, 63.07; ~, 8.38; N, 13.12
*Trademark ~or a highly Qelective adsorbent o~ white, hard
granular or powdered ~agnesia-silica gel.
~.
.
. . . .. . .
.;, ' ' , :: ' ' . , .
'; ' ' ' ' ' ~ ' . ' ' ': . '
. . - . : :~.,' ' . . :".!
.
.: : : ,. . .
' . ~ I
: ,~ : :
: . , ~
7~
-13- ~
~ '
Potassium glycinate was prepared by reacting
9 g. o~ glycine and 6.7 g. of potassium hydroxide in
400 ml. of anhydrous ethanol. 22.6 g. of dl-4-
acetamido-2-dimethylaminomethylenecyclohexanone were
added thereto and the resulting mixture heat~d to
refluxing temperature under a nitroyen atmosphere for
1.75 hours. The reaction mixture was cooled, diluted
with ether, and filtered. The filter cake, which
weighed 2R.7 g., was add~d to 400 ml. of acetic
anhydride and ~he resul ing mixture heated to reflux
temperature under a nitrogen atmo~phere for one hour.
The reaction mixture was cooled and the volatile
- constituents removed by evaporation in vacuo. The
resulting residue was suspended in chloroform and
filtered. The filtrate was chromatographed over 350
g. of"Florisil', u~ing chloroform containing increasing
amounts (0-2~) of methanol as the eluant. Fractions
shown by TLC to ~ontain dl-2-acetyl-5-acetamido-4,5,6,7-
tetrahydro-2H-benzo[c]pyrrole ~ormed in the abov~
reaction were combined and ~he ~olvent evaporated
therefrom. Crystallization of the residue from ather
yielded purified dl 2-acetyl-5-acet2mido-4,5,6,7-
tetrahydro-2~-~enzo[c]pyrrole melting at 151-153C.;
yield ~ 17.7 g.
Analysis Calc.: C, 65.43; H, 7.32; N, 12.72;
~ound: C, 65.72; H, 7.34; N, 12~45a
* Trademark for a hard, p~rous, granular magnesium ilicate
or magnesia-silica gel, used in chrsmatography~
..
,. ",
--14
A hydrolysis mixture was prepared from
5.1 g. of dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-
2H-benzo[c]pyrrole, 50 g. of sodium hydroxide, 50 ml.
of water, and 200 ml. of ethanol. The mixture was
heated to refluxing temperature under a nitrogen
atmosphere for about 16 hours and was then cooled.
The cooled mixture was diluted with water. The
alkaline aqueous mixture was extracted several times
with methylene dichloride, the methylene dichloride
extracts were combined and thP combined extracts
washed with saturated aqueous sodium chloride and
dried. Evaporation of the solvent therefrom yielded a
residue comprising dl-5-amino-4,5,6,7-tetrahydro-2H-
benzo[c]pyrrol formed in the above reaction. A
chloroform solution of the residue was filtered
through 105 g. of alumina (grade II). Concentration
of the resulting filtrate yielded 2.52 g. of a yellow
solid comprising dl-5-amino-4,5,6,7-tetrahydro-
2H-benzo[c]pyrrole.
Exam~le B
PREPARATION OF dl-5-ACETAMIDO-4,5 t 6,7-TETRAHYDRO-2H-
BENZOtc]PYRROLE
~o a solution of 6.7 g. of 4-acetamido-
cyclohexanone [prepared by the method of Fraser and
Swingle, Can. J. Chem., 48, 2065 (1970)], in 150 ml.
of anhydrous ethanol were added 25 ml. of ethyl
orthoformate containing a few crystals of p-toluene-
sulfonic acid monohydrate. ~he reaction mixture was
stirred at ambient temperature for about 16 hours,
3 a~ter which ~ime ~he volatile constituents were
,
. . - . .
, . . ........................ . . i
- . ; ~. , ., i :
5~i
-15
removed by evaporation in vacuo. The residue com-
prising the diethylketal was dissolved in 200 ml. of
toluene and the toluene was removed by distillation
under a nitrogen atmosphere, until all of the diethyl-
ketal had been converted to the l-ethoxycyclohexene
derivative. The solution was cooled, washed with
aqueous sodium bicarbonate and dried. Evaporation of
the toluene yielded a residue comprising 4-acetamido-
l-ethoxycyclohexene melting at 100-102~C. after
recrystallization from an e~her-hexane solvent mixture;
yield = 6O2 g.
A solution of 3 g. of 4-ace~amido-1-ethoxy-
cyclohexene in 40 ml. of dioxane was added slowly to a
solution of 3.2 g. of 1,2,4,5-tetrazine dicarboxylic
ester [prepared by ~he method of Sauer, et al.,
Chem. Ber., 98, 143S (1965)] in 100 ml. of dioxane.
The reaction mixture was stirred at ambient temperature
for about 3 days after which time ~LC indicated one
major spot with several minor spots present. The
reaction mixture was evaporated in vacuo, the resulting
residue dissolved in chloroform, and the chloroform
solution chromatographed over 200 g. of Florisil using
chloro~orm containing increasing amounts ~2-5%) of
methanol as the eluant. Fractions shown to contain a
single major spot material by TLC were combined and
the solvent removed from the combined fractions in
vacuo. The residue was crystallized by triturating
with ether; mp = 137-139C: yield = 3.21 g.
Recrystallization of the residue from the ether-
methanol solvent mixture yielded purified dl-6-
.:: . , ~, ''- :
.
~, '` ':; `~' : ,'
. ~ ` .
...
, . ., :
~5'~
-~6-
acetamido-1,4-di(carbomethoxy)-5,6,7,8-tetrahydro-
benzo[d]pyridazine meilting at 143-144C.
Analysis Calc.: C, 54.72; H, 5.58; N, 13.67;
Found: C, 54.75; H, 5.64; N, 13.49.
A solution was prepared by adding 2.59 g. of
dl-6-acetamido-1,4-di(carbomethoxy)-5,6,7,8-tetra-
hydrobenzo~d]pyridazine to 100 ml. of glacial acetic
acid. 5 g. of zinc dust were added and the resulting
mixture stirred at ambient temperature for about 1
day. An additional 5 ~. of zinc dust were added after
6 hours. The reaction mixture was then filtered to
remove unreacted zinc dus~ and the resulting iltrate
poured over ice~ The filtrate was made basic with 14N
aqueous ammonium hydroxide and the alkaline mixture
extracted several times with a chloroorm-isopropanol
solvent combination. The organic extracts were
separated and combined, and the combined extracts
washed with saturated aqueous sodium chloride and then
dried. Evaporation of the solvent therefrom yielded
dl-5-acetamido-1,3-di(carbomethoxy)-4,5,6,7-tetra-
hydro-2H-benzo[c]pyrrole formed in the above reaction;
yield = 1.83 g. Recrystallization from methanol
yielded crystalline material melting at 231-232C.
Analysis Calc.: C, 57.14; H, 6.16, N, 9.52
Found: C, 57.05; ~, 5.99; N, 9.26
A reaction mixture was prepared containing
1.8 g. of dl-5-acetamido-1,3-di(carbomethoxy)-4,5,6,7-
tetrahydro-2H-benzo~c]pyrrole, 80 ml. of THF and 20
ml. of 2N aqueous sodium hydroxide. The reaction
. :: . .~ ; .. : ; ;~ - :: :
- : . . - ., ., . . , ,. i
: ` ` ~, , . , . , ~ , ' .,: .-
7~;
~17-
mix~ure was heated to xefluxing temperature under a
nitrogen atmosphere for about 3 hours af~er which time
it was cooled and the volatile con tituents evaporated
therefrom in vacuo. The residue was dissolved in 25
ml. of water and She ~queous ~olution made acidic by
the addition of lN aqueous hydrochloric acid. The
diacid, dl-5-acetamido-1,3-dicarboxy-4,5,6,7-~etra-
hydro-2H-benzo[c]pyrrole, formed in the above hydrolysis
being insoluble in the acidic layer precipitated and
was collected by ~iltrationO Recrystallization from a
benzene-methanol solvent mixt~re yielded crystal~ine
diacid melting at 233-235C. with de~mposi~ion.
Analysis Calc.: C, ~4.13; H, 5.30; N, 10.52
Found: C, 53.90; H, 5.37; N, 10.45
A reaction mixture, prepared from 850 mg. of
dl-5-acetamido-1,3-dicarboxy-4,5,6,7-tetrahydro-2H-
benzo[c]pyrrole, 50 mg. of copper powder and 25 ml. of
quinoline, was heated to 200C. under a nitrogen
atmosphere. Ga evolution was noticeable as the
temperature approached 150C. ~eating in the range
200-210C. was carried on for 15 ~inutes after which
time the reaction mixture was poured over ice. The
resulting aqueous mixture was extracted with chloro
form, and the ohloro~orm ex~ract was ~eparated, washed
with O.lN agueous hydrochloric acid, 10 percent
aqueous sodium hydroxide and finally wa~er. The
chloroform was removad ~h~refrom by evaporation in
vacuo to yield 0.26 gO of a dark oil as a residue.
Chroma~ography over 15 y. o~lFlorisilnusing chloroform
containing from 0 to 1 percent ~ethanol as the eluant
., :, .
: , , ~............................. , ~; ,,',, : ;
. :
~L7~
-18-
yielded 40 mg. of dl-5-acetamido-4,5,6,7-tetrahydro-
2H-ben~olc]pyrrole. The product was identical to the
compound prepared by deace~ylation of dl-5-acetamido-
2-acetyl-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole from
Example A.
FINAL PRODUCTS
Example_l
PREPARATION OF dl-5-DIETHYLAMINO-4,5,6,7-TETRAHYDRO-
10 2H-BENZO[c]PYRROLE
A solùtion was prepared by adding 2.52 g. of
dl-5-amino-4,5,6,7-tetrahydro-2~-benzo[c]pyrrole, pre-
pared in Example A, to 100 ml. of ~ethanol. 1.2 g. of
sodium cyanoborohydride were added followed by 6 ml.
of acetaldehyde. The reaction mixture was stirred at
ambient temperature under nitrogen atmosphere for
about 16 hours, and was then diluted with aqueous
sodium bicarbonate. ~he aqueous layer was extracted
with chloroform, and the chloroform extract separated
and washed with saturated aqueous sodium chloride.
The chloroform solution was then dried and the solvent
removed therefrom by evaporation. The resulting
residue was redissolved in chloroform and the chloro-
form solution chromatographed over 35 g. of Florisil
using chloroform containing increasing amounts (2-4~)
methanol as the eluant. By combining fractions shown
by TLC to contain a material different than starting
material, 1.84 g. of solid were obtained which was
rechromatographed over Florisil. Combining fractions
shown to contain dl-5-diethylamino-4,5,6,7-tetrahydro-2H-
benzo[c]pyrrole by TLC followed by evaporation of the
~. ~
.
i . ~ . , ., : ~
, ; , :
., .: : :: ,
. .~: , .
: ,. :.. .:, : :,
--19--
solvent from the combined fractions in vacuo yielded a
residue weighing 0.66 g. The residue was dissolved in
ether and treated with an excess of an etheral solution
of maleic acid. dl-5-diethylamino-4,5y6,7-tetrahydro-
S 2H-benzo[c]pyrrole maleate thus prepared was recrystal-
lized from a methanol-ether solvent mix~ure to yield
purified compound m~lting at 81-83C.; yield = 385 mg.
Analysis Calc.: C, 62032; H, 7.84; N, 9.08
Found: C, 62.37; H, 7.57; N, 8.94
Example 2
PREPARATION OF dl-5-DI-n-PROPYLAMINO-4,5,6,7-TETRA-
HYDRO--2H--BENZO [c] PYRROLE
Following the procedure of Example 1 but
substituting propionaldehyde for ~cetaldehyde, dl-
5-di-n-propylamino-4,5,6,7-~etrahydro-2H-benzo[c]-
pyrrole maleate was prepared, melting at 134-136C.
after recrystallization from an isopropanol-ether
solvent mixture.
Analysis Calc: C, 64.26; H, 8.39; N, 8.33
Found: C, 64.32; H, 8.68; N, 8.17
Example 3
PREPARATION OF dl-2-METHYL-5-DI-n-PROPYLAMINO-
4,5,6,7-TETRAHYDRO-2H-BENZO[c]PYRROLE
2 millimoles (680 mg~ of dl-5-di(n-propyl)-
amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole were
dissolved in 75 ml. of dimethylacetamide (DMA). 10
millimoles (l.lg) potassium ~ertiary-butoxide were
added and the resulting mixture stirred for 20 minutes
under ni~rogen. Next, a solution of 2.1 millimoles of
"
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-20-
me~hyl iodide (0.13 ml) in 5 ml. of DMA was added in
dropwise fashion. The resul~ing reaction mixture was
stirred at ambient temperature for 5 hours a~ which
time an additional 0.13 ml of methyl iodide was added
and the subsequent mixture stirred for an additional
3.5 hours. The reaction mixture was then diluted with
water and the aqueous layer extracted with ethyl
acetate. The ethyl acetate layer was separated and
washed with water followed by saturated aqueous sodium
chloride. The ethyl acetate layer was then dried and
the ethyl acetate removed therefrom by evaporation.
An ether solution of the resulting residue was chro-
matographed over 35 g. of Florisil using ether as the
eluant. Fractions shown by TLC to contain dl-
2-methyl-5-di-n-propylamino-4,5,6,7-tetrahydro-2H~
benzo[c]pyrrole wexe combined and the solvent removed
therefrom in vacuo. NMR of the residue thus obtained
indica~ed that the dl-2-methyl-5-di-n-propylamino-
4,5,6,7-tetrahydro-2H-benzo[c]pyrrole had been pre-
pared.
As evidence of the utility of the compounds
of formula I in the treatment of ParXinson's Syndrome,
it has been found that they affect turning behavior in
a test procedure utili~ing 6-hydroxydopamine-lesioned
rats. In thi~ test, nigro-neostriatal-lesioned rats
are employed prepared by the procedure of Ungerstedt
and Arbuthnott, Br _ n Res, 24, 485 (1970)o A compound
having dopamine agonist activity upon injection causes
the rats to turn in circles contralateral to the side
of the lesion. After a l~tency period, which varies
.,
; -21-
from compound to compound, the number of turns is
counted over a 15-minute period. The compounds are
dissolved in water and the aqueous solution injected
into the rat by the intraperitoneal route at a dose
level of 1 mg/kg. dl-5-Di(n-propyl)amino-4,5,6,7-
tetrahydro-2H-benzo~c]pyrrole maleate gave an average
of 34 turns per rat with 1/3 of the rats exhibiting
turning behavior in the above test.
The compounds of formula I are also useful
as prolactin inhibitors and as such can be employed in
the treatment of inappropriate lactation, such as
postpartum lactation, and of galactorrhea. As evidence
of their utility in the treatment of diseases in which
it is desirable to reduce the mammalian prolactin
level, the compounds of formula I have been shown to
inhibit prolactin according to the following procedure.
~ dult male rats of the Sprague-Dawley strain
weighing about 200 g. were housed in an air-conditioned
room with controlled lighting ~lights on 6 a.m. - 8
p.m.) and fed lab chow and water ad libitum. Each rat
received an intraperitoneal injection of 2.0 mg. of
reserpine in aqueous suspension 18 hours bafore
administration of the isoindole. The purpose of the
reserpine was to keep prolactin levels uniformly
elevated. The compounds under test were dissolved in
water and were injected intraperitoneally at doses
ranging from 5 mg/kg down to 50 mcg/kg. Each compound
was administered at each dose level to a group of 10
rats, and a control group of 10 intact males received
an equivalent amount of solvent. One hour after
treatment all rats were killed by decapitation, and
150 ~1 aliquots of serum were assayed or prolactin.
~ .~
22-
The difference between the prolactin level
of the treated rats and pxolactin level of the control
rats divided by the prolactin level of the control
rats gives the percent inhibition of prolactin secretion
S attributable to the compounds of formula I. These
inhibition percentages are given in Table 1 below.
In the table, column 1 gives the name of the compound;
and columns 2-4 the percent prolactin inhibition at
the given dose level.
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o
o
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-24-
In using the compoun~s of formula I to
inhibit prolactin secretion or ko treat Parkinson's
syndrsme or for other pharmacologic action, a pharma-
ceutically active compound of formula I above, or a
salt thereof with a pharmaceutically-accep~able acid,
is administered to a subject suffering from Parkinsonism
or in need of having their prolactin level reduced in
an amoun~ effective to alleviate some of the symptoms
of Parkinsonism or to reduce an elevated prolactin
level. Oral administration is preferred. If parenteral
administration is used, the injection is preferably by
the subcutaneous route using an appropriate pharmaceu-
tical formulation. Other modes of parenteral adminis-
tration such as intraperitoneal, intramuscular, or
intravenous routes are equally effective. In particular,
with intravenous or intramuscular administration, a
water soluble pharmaceutically-acceptable salt is
employed. For oral administration, a pharmaceutically
active compound of formula I either- as the free base
or in the form of a salt thereof can also be mixed
with standard pharmaceutical excipients and loaded
into empty telescoping gelatin capsules or pressed
into tablet~. The oral dosage range is from about
0.01 to 10 mg/kg of mammalian weight and the paren-
teral dose range from a~out 0~0025 to 2.5 mg/kg of
mammalian weight. Intraperitoneal dosages of 10-30
mg/kg of dl-5-di(n-propyl)amino-4,5,6,7-tetrahydro-
benzo~2HJpyrrole maleate in the mouse resulted in no
deaths but dosages of 100-300 mg/kg were fatal. Some
30 toxic side ef~ec~s wera observed at the 30 mg~kg dose ,-
level. ~
, , ~ ,......... . .
