Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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~C~67497
.
Following the intr~duoti~n of re erpine and ~h~pr-
pr~mazine in p~ycho~berapeutic medicine in the early 195~ ~8,
great effort ha~ been expended in the seelrch for ~ther ~ran-
~uilizing agents having improved biologi~al pro~ilesa
It has now been found that cer~ain indoles, and
more particularly A Berie8 0~ 2-sub~tituted:-5-aryl-1, 2, 3, 4-
: ~etrahydro-~-car~oline~ de~cribed in Appliaati~n Serial No.
22325~, are extremely e~fective as tranquilizin~ agents.
y-Carb~line~ are nQt new in the chemical and
10 pakent literature; antihi~tamine activity i~ claimed in
Britis~ Patent 721,171, anti~epressant activity in U.S0
patents 3,419,568, 3,6~87,960, 3,705l902 an~ 3,718,657, anti-
trypanosomal activity in German patents 2,117,286 ~nd
2,115,738, depre~ant an~ analgesic ac~ivity in U.S.~patent`
15 3,466j293 an~ tran~uilizing act~vity in U,S. patent~ 3,~87,961
and 3,755,5840 ~ :
: ~he present invantion is direoted to intermediate~
: leading to chemotherapeutia y-carbo}ines and having ths;
' formulao
9 .; :.
X~ ~ .
~1 :
~ I
where X ie fluor~, ohl~r~, bromo, methyl ~r hydrogen and Z
`
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lLg~67497
is f luoro, chloro, me thoxy or hydro~en .
The final ~-cRrbolines havin~ chemotherapeutio
properties are thos`e o~ Formula I in whic:h the N-atom a~ the
2-position i~ subatituted by a sub~tituent R which i~ alkyl o~n-
taining from 1 to 6 carbon atoms, benzyl or substitutedalkylene of the f~rmula
-A-M~\_Y
~Y
wherein A i5 ~lkylene containin~ from 1 to 5 carbon atoms,
~1 ~)Rl ~Rl
M 1~ -CH=CH, -CH2-, -~ H- or -~-(CH3)- wherein Rl i9
hydrogen or alkanoyl containing ~rom 2 t~ 5 carbon atoms
and Y i8 fluoro, chloro, methyl or hydrogen, with the
proviso that when z i8 hydrogen, X i8 fluoro, chloro,
bromo or methylO
In accordanoe with the process employed for
synthe~izing the aaexNcr~ of the present invention the
following scheme i8 illustrative:
1067497
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X~ ~3=~C02C2}~5 ~(32C2E5
HNH2 ~ E~
II J
&~ [~ ~C02C2HS
~2
Na2C3 ~
~; III
IIIKOH ~,~_~ ~H
~, l
C2H50H/H20 ~ ~ J~l~ ~J
R-Ha~
..
~i
., ~
5 wherein X and Z are as previously defined, ~al is a halogen
or ~ulfonate ester and R is hydrcgen, benzyl, alkyl having
1 tc 6 carbon ato~ns or ~ubctitute~ alkylene of the formula:
,
.
` ~`` 1~67497
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-A-M ~ ~ Y
wherein A i~ alkylene havin~ l to 5 carbon atom~, M i~
f~
-C~2- ~r -~- and Y i8 a~ previou~ly defined.-
In practice, the ~-arbo}ines of F~rmula II are
conveniently prepared from the commercially-available 1-carb-
ethoxy-4-piperidone and the requi~ite phenylhy~raæines bythe
classical ~ischer ind~le ~ynthesis which o~mprises heating
appr~ximatel~ equim~lar amounts of the appropriate phenyl-
hydrazine hydrochloride with the piperidone in a reaction-
inert solvent~such a~ abs~lute ethancl~
Arylation of II i~ e~feated through the rea~tion ofII with a suitably ~ubstituted ~-brom~benzene derLvative, em-
ployin~ a 2-3 fold molar exce~s of the bromobenzene deriva-
tive f3r optimum yielde of the product, III. In additiQn,
equimolar amounts, plu~ as much a~ A 1004 exc~s~ ouprQus
brcml~e and sodium aarbonate are employed in~this r~action,
reaction bein~ conducte~ in a reaction-inert ~Ive~
such a~ nitrobenzen~, hexamethylphosphoramide or N-me~hyl-2-
pyrrolidione ~t a temperature o~ 125-225C. wi~h a ~referred
range of 175-2~C.
Hydrolysis of c~mp~unds r~lated to III i9 effected
by heating an ethanol ~olution of the ap~ropria~e 2-carbethoxy-
5-aryl-1,2,3,4-tetrahydr~carb~line with at least tw~ m~lar
equivalents of pota~sium hydrsxide.
Thi6 ~equence of reac ions i8 preferred for the
preparation of the useful intermediate~ of the instant
:~ invention of Formula I.
The f~llowing examples are provided s~lely for
the purpo~e of illu~tration ~nd are not to be con~trued as
3~ limitations of thl~ invention, many variation~ of which are
possi~le without departing from the op1rit ~r scope thereofO
(9674~7
EXAMPLE 1
8-Fluor~-5-~-fluorophenyl)-1,2,3,4-tetrahydro-r-
oarboline (I- X - F and Z ~ F)
~ ~~
A. 8-Fluoro-2-carbethoxy-1,2,3,4-tetrahydro-r-carboline
aarbsline (II: X - F~
_ _ _
A mixture of 15.9 gO~(0.093 moLe) of N-carbethoxy-
4-piperidone and 15.1 g. (aO093 mole) of ~-fluor~phenylhydra-
zine hy~rochlorlde in 150 ml. of ethanol i~ heated to reflux
f~r 2 hrs The reddi~h reaction mixture iæ cooled and filter-
ed, and the collec~ed solias washed wlth a ~mall amount ofc~ld 95~ ethanol, 2103 gO (88% yield) ~ m.pO 169-170Co~ The
analytical sample is reary~tallized from ethano~-water,
mOpO 169-170C.
, ~ .
Anal- Caac d for C14~152N2F C~ 64-1; H~ 5- ; N~ 10-7-
Foun~ C, 63.8; H, 5 8; N, 10.6.
B~ 8-Fluoro-5-t~-flU~rOphenyl~-2-carbethoxy~1,2,3,4-tetra-
hydro~ carboline ~ X and Z = F).
To 30 ml. of N-methyl-2-pyrrolidione i~ added
3.45 g ~00013 mole) o~ 8-fluoro-2-carbethoxy-1,2,3,4-tetra-
hydro-r-carboline, 708 g a ~0 ~ 045 mole) of ~-fluorobromobenzene,
4.14 g. (00014 mole) of cuprous bromide and 1.5 g ~0 014 mole)
of sodium carbonate, and the re~ulting mixture heated in an
~il bath at 200C ~or 6 hrs. The mixture is allowe~ to
cool t~ ro~m temper~ture overnight, and i~ ~hen decanted into
300 ml of water con~ ining 60 ml of ethylene diamine.
Benzene ~20C ml.) i8 added and the two-pha~e system is filter-
ed thr~ugh a supercel pad. ~he filtrate i~ sub~e~uently
ex~racted several times with a total of 70~ ml. of ~enzene.
m e extracts are combined, washed suacessively with water and
a saturate~ brine 801utio~ an~ dried over anhydrous s~dium
~ulfate~ Removal of the solvent provides the crude product
a~ a dark, residual oilg
The crude product in benzene i8 chromatographed
on a silica gel column ucing 10% ethyl acetate-benzene
as the eluateO Fractions 1 through 16, comprise~ of
1~ 25 mlO each, and c~ntainin~ ~-fluorobromobenzene, are
collected and di~carded. FractionQ 16 to 3~ are combined
`---"` 1067497
-6-
and concen~rated in vacuo to an oil which solidifies on
~tanding at 5Co ~vernight. T~e product, 3.5 gO (76%
yield), i~ tri~urated wi~h pentane and filtered. ~he analy~i-
cal sample i~ recry~allize~ from pentane, m.p. 118-120C.
Anal. Calc'd fvr C2~H1802N2F2: C,
Fcund: C, 67.4; H, 5.2; N, 7.8.
. C0 8-Fluoro-5~-fluorophenyl)-1,2,3,4-te~rahydro-~-
car~oline ~I: X and Z - F)
A su~pension of 3 56 g. (0.01 m~le~ of 8-fluoro-
S-~-fluorophenyl)-~-carb~thoxy-1,2,3,4-tetrahydro-~-
~carboli~e and 8 2 g. ~0.146 m~le) of potassium hydroxide
in 53 ml. o ~thanol ~ontaining 5 ml. of water i~ heated
to r~flux overnight. An additlonal 3.0 g. of potassium
hy~roxide~added and th~ heating continued f~r 23
hr~. Th~ brownish s~lution i~ ccoled, conc~ntrate~ in vacuo
to dryness and partitioned between water and diathyl ether
~he a~ueous layer i5 further extracted with ether, and the
ether layers combined, washed with a saturated brine solu-
tion and dried over magnesium sulfate. Removal of the
solvent provides the desired product aq an orange solld,
2~6 g~ mOp~ 125-127Co- ~he analytical sample i6 recry~-
tallized from pentane, m.p. 127-128C.
Anal. Calc'dO for C17H14N2F2:: ,
Found: C, 71~6; H, 5.1; N, 10,2.
T~e hydrochloride salt is prepared by bubbling
hydrogen chloride into a solution of the free base in di-
ethyl ether, mOp- 270-272C~
67~97
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EXAMPL~ 2
Starting with the appropriate phenylhydra~ine
and employing the prooedure~ of Example 1, the foll~wing
5-aryl-1,2,3,4-tetrahydro-~-carboline~ are prepared as the
free ba~e and hydrochloride salt~: 8-chl~ro-5~ luoro-
- phenyl)-1,2,3,4-tetrahydro-~-carboline hydr~chloride, m.p.
269-271C.; 8-broms-5-phenyl-1,2,3,4-tetrahydro-r-carb~line
hydrochloride, m~pO 28~-28ZCl; 8-methyl-5-phenyl-1,2,3,4-
tetrahydro-~-aarboline, m.pO 288-289C.; 8-fluoro-5~
1~ chlorophenyl)-1,2/3,4-tetrahydro-y-carbolin~ hydr~chloride,
m.pO 282-285C.; and 8-chloro-5-phenyl-1,2,3,4-tetrahydr~
carboline hydr~chloride, mOp. 276-278Co and aB the free
b~e: 8-fluoro-5-~-methoxyphenyl)-1,2,3,4-tetrahydro-~-
carboline, m.pO 119-122Co; 8-chloro-5-~ hlorophenyl)-
1,2,3,4-tetrahydro-y-carboline; 8-bromo-5-~-fluorophenyl)-
1,2,3,4-tetrahydrc-~-carb~line; 8-methyl-5-(E`chlorophenyl)-
L,2,3,4-tetrahydro-~-carboline; 5-(~-fluorophenyl)-1,2,3,4-
tetrahydro-~-carboline and 5-~-ahlorophenyI)-1,2,3,4-tetra-
hydro-~-carbolinec
