CA1117955A - Tetrahydro-2h-benzo [c] pyrroles - Google Patents

Abstract

Abstract of the Disclosure Novel tetrahydro-2H-benzo[c]pyrroles, useful as dopamine agonists, particularly as inhibitors of prolactin secretion and in treatment of Parkinson's syndrome, are described herein. These compounds are prepared by reacting a dl-5-amino-4,5,6,7-tetahydro-2H-benzo[c]pyrrole with an aldehyde and then a reducing agent or with an alkyl halide, then an acyl halide followed by a reducing agent; and optionally with an alkyl halide and base. Also described are novel intermediates having the general formula IA
wherein R1 is H or ;

Am is NH2 or ;

R3 is methyl, ethyl or n-propyl;

except that R1 is not

Description

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 ~ 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 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

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~ ;

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.

:. . ~ , .

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~

..

,. ", 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 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~

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 . ~ . , ., : ~
, ; , :

., .: : :: , . .~: , .
: ,. :.. .:, : :, 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 "

. ~
. : , ;.. ::
: , , . . .: , . ,. . :
, : :: : : ., :. ~ :
- , .: , . ~: :

. ~ :: : : ., . :
, . ,:

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.

~ .~

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 o U7 o , ~C s E~

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æ ~ s `, :.. ' ` , ` , : : . ,. ~ . '' ':,, . ," '': i` ' ', ' 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. ~

, , ~ ,......... . .

Claims (2)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing an intermediate compound of the general formula 1A

wherein R1 is H or ;

Am is NH2 or ;

R3 is methyl, ethyl, or n-propyl;

except that R1 is not when Am is NH2; and the acid addition salts thereof when Am is NH2, which comprises reacting either (A) III

wherein R3 is defined as above, with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride to provide the compounds of formula 1A where Am is and R1 is ;
followed by reacting the product with base to provide the compounds of formula 1A where Am is NH2 and R1 is H; or (B) XI

wherein R3 is defined as above, with copper powder in the presence of quinoline to provide the compounds of formula 1A

where Am is and R1 is H;
followed by basic hydrolysis to provide the compounds of formula IA where Am is NH2 and R1 is H.

2. As an intermediate a compound of the general formula IA
wherein R1 is H or ;
Am is NH2 or ;
R3 is methyl, ethyl, or n-propyl;

except that R1 is not when Am is NH2; and the acid addition salts thereof when Am is NH2, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.