CA1036596A - Oxazinoindole-and thiazinoindole derivatives - Google Patents

Abstract

ABSTRACT
Oxazinoindole derivatives characterized by having an amino(lower)alkyl radical attached to the 1 position of an 1H-1,4-oxazino[4,3-a]indole nucleus are disclosed. The amino portion of the amino(lower)alkyl radical may be further substituted with one or two lower alkyl groups or incorporated in a heterocyclic amine radical. The derivatives are substituted further at positions 1 and 10 and may be optionally substituted at positions 3, 4, 6, 7, 8 and 9.
The oxazinoindole derivatives of this invention are useful antidepressant and antiulcer agents. Methods for the preparation and use of these derivatives are also disclosed.

Description

~ 6S~ AHP'5786/5921 . ~.
Backqround of the Invention ., i 1. Field o Invention This invention relates to novel oxazinoindoie ;

and thiazinoindole derivatives, to processes for their . preparation and to intermediates used in these processes.
..
.,. . . .
For convenience, further reference in this specificatton will be made to these compounds as oxazinolndole derivatives.
More specifically, the present invention relates to oxazinoindole derivatives possessing valuable pharmacologic properties. For example, these derTvatives exhlbit useful .. . .
antldepressant properties at dosages which do not eltclt undeslrable slde effects. Furthermore the present deriva~lves exhlblt properties useful for the treatment and pr~ventlon , of ulcers. The comblnation of these pharmacologlc propertles together wlth a low order of toxicity render the oxazinoindoles of the invention therapeutically useful.

2. DescrtptAion of the Prior Art Very little attention has been given to 1,4-oxazino-[4,3~a]indole derivatives prior to this disclosure. In the -.. . , ~-.
few reports that do exist, such as the reports by J.A. Elvridge -~
and F.S. Spring, J. Chem. Soc., 29~5 (1949) and W. Ro Smith and R.Y. Moir, Can. J. Chem., 30, 411 (1952), the oxazinoindole derivatives are treated more in the manner of chemical curiosities. !n these instances, the oxazinoindoies ; 25 are distinguished readily from the compounds of this invention by havlng the pyran portion of their ring system at a htgher ` oxidation state.

. , ~ 3~59~ AHP-5786/5921 ,.
Summarv of the Invention : ~ The oxazinoindole derivatives of this invention are , : . :
:. characterized by having an amino(lower)alkyl radical attache'd ':
' ~' to a IH-1,4-oxazino[4,3-a]indole nucleus. The preferred ,.
' 5 derivatives of this invention are represented by formula 1, ~}
8~9 .
a ~

:" ......................... ..
in whlch Rl ts lower alkyl or lower cycloalkyl; R2, R3J R4 and R5 are the same or differ~nt selected from the group consisting of hydrogen or lower alkyl; R6 is hydrogen, lower . . .
.;. 15 ' alkyl, hydroxy, lowér'alkoxy, lower alkanoyloxy, nitro or '~
~' halo, R7 is lower alkyl; X is oxy or thio; and Alk-NR8R9 is . .
'- an amino(lower)alkyl radical in which Alk is an alkylene ':
'.; ' selected from the group consisting of CRIORll, CRIORllCRl2Rl3, .; CR R CR R CR R and CRIORl ICR12R13CR14R15CR16RJ7 i'n -.' 2b 10 Rl I R12 R13 R14 R15, R16 and R are hydrogen -~: ~ or lower alkyl J and Ra and R9 are either the same or different ' selected from the group consisting of hydrogen and lower alkyl, .,. f~ 9 ::, . ~ or R~ and R together with the nitrogen atom to which ';
they are joined form a heterocyclic amine radical selected ;' from the group consisting of l-pyrrolidinyl, plperidino, . morpholino, piperazino, 4-~lOwer atkyl)-l-piperazinyl and '~
; 4-[hydroxy~lower)alkyl~-1-piperazinyl.
1 Various processes whereby these derivatives are ' prepared are disclosed. ' ' 30 ' , . ' .

- 3-AHP-5786/5921 .
6S9~
Detailed Description of the Invention ~: The term "lower alkyl" as used herein contemplates :
straight chain alkyl radicals containing from one to six ; carbon atoms and branched chain alkyl rad7cal containing , up to four carbon atoms and includes methyl, ethyl, propyl, . isopropyl, butyl, Isobutyl, 2-methylpentyl and the like.
The term "lower cycloalkyl" as used herein contemplates saturated cyclic hydrocarbon radicals contaTning from three to six carbon atoms and includes cyclopropyl, cyclobutyl, ..
Io cyclopentyl and cyclohexyl. .
The term "lower alkoxy" as used hereln contemplates .
~ both stralght and branched chaln alkoxy radlcals contalnlng from ..
.~ one to four carbon atoms and Includes methoxy, ethoxy, isopropoxy, t-butoxy and the llke, : 15 . The term "lower atkanoyloxy" as used herein contemplates both stralght and branched chaln alkanoyloxy radicals containtng .~ from two to six carbon atoms and Includes acetoxy, proplonyloxy, .
i pivaloyloxy, hexanoyloxy and the like. .
; The term "halo" as used herein contemplates halogens .
and includes fluorine, chlorine, bromine and iodine. ~.
~ : The compounds of formula I ar`e capable of forming ,. :
~; acid addition salts with pharmaceutically acceptable acids. . :~
.,. .
: Such acid addition salts are included within the scope of this . invention. .
, . ~ .
The acid addtt70n salts are prepared by reacting the base torm of the oppropriate compound of formula 1 wlth elt-er _4_ ' ~

' ' . ' ,.

. ~

AHP-`5'~6/59~i . ' , .
3~5 . ~
: on~ or t~Jo equi~alents, depending on tho :umber o~ baslc nitrog~ns in th~ compoandt or-pr~ferably w~th an ~XC~8 of tho appropriflte ac~d i~ an or6all1c eolvent, ~or ~xa~ple~ ether or a~
ethunol-athcr nixtUre. The~e ~altel, when administer~d tC sua~
po~ s tho Ea~s phur~acolo~ic act~Yitie~ ~ tlt~ corr~epo~dinK ::
basea. For many purpo~ea ~t i~ preferable to adr!l~ni~t~r the salts ruther than the ba~e com~ounds. Amon~ the ~cid additlon salts suitable for thi~ purpo~o ~r~ sult~ ~uch as the sul~At~, pho~phate, laotuto, tartrato~ ~aleAte~ aitr~te~
hydrobro~ldv and hydroohlorlde. Both the b~o co~poulld~ un~
th~ ~nltB huve tho distinct udvantu~ Or po~ in~ u ~ol~tivoly .;.
.,,~ . .
low ordor ~r toxlclty.
: 15 Al~o ~clud~d in thi~ in~ention are the ~teroo- o~ .
ohe~ic~l lsomor~ of the ao~pounds of formulR I whioh result fro~ a~y~etrio centers, contained ther~in~ Tho~o i60~eric for~e ~Ay be prepared by difforent ~ethodu and ar~ purified .:
~ 20 r~adily by cry~tallizatio~ or chro~atography.
:. Individual optical iso~er~, whi¢h ~ight be ~eparated .. ,; .
by fr~ctlonal crystallization o~ th~ di~tereol60~sric salts ;~
form~d ~her~of, for instsnGe, ~th d- or l- t~rtar~c ac~d or D~ -bromocamphor s~lfonio acid, are al~o included. : :

:. .
~he useful antidepre~ant activity of ~he co~pound~ o~
~or~ula I Rnd their a¢ld ~dditlon &~lta wlth p~larmaoeutically acceptable acids may bo demonstrated in ~tandard pl~r~cologio t~ts, such as, for exfl~ple~ the t~st~ de~cribed by ~. Hafli~er - -~nd Y. Burckhart in ~Psycbophar~cologioal A~ent~"~ M. Gordont Ed., Acade~ic Press, New York and Londo~, 1964, pp~ 75 - 83.
','.

AHP-5786 ~592 1 . .: .
-, , .' ...
~3~
Moro 6p~clflcall~, aR ~io~d ini the lattar r~er~o~ th~
a~itidepressa~it propertie~ o~ a co~pou~id m~y ba demonistrated by : itei capacity to auita~onlze the depre~ant ~fect~ o~ re~rplneO
:. ;
. . Furthermore, lt iB well docu~ented that reserplni~ in ~n~cal~ ~
produoen a ~odel depre~sion which cnn be u&ed for detectin~ :
tid~pr~s~nt prop~rkien, Accordinigly9 the compounds o~ the present invention antagoniæe r~serpine effects in MiCe at doses ran~ine ~rom about 1 to 100 ~ g. Several of ths preferred .. .. .
co~pou~d6, for instanc~O
~'"' 10 1,10-dimethyl-1-C~(ethyla~nio)eth;yl]-3,4-dihydro~lH-1,4-oxa~lrio-'. C4~3-aJindole hydrobro~ide ~Example 284)~
,,. 1110-di~ethyl-l C(2-dimethYl~lno)ethyl~-3.4~dihYdro~ l,4~ :
~, ', ox~zino~4~3-a~lndol~ hydrochlorlde ~E~ample 284)~
,'"' 1-~3-amino;propyl)--l,lO-dimethyl-3,1t-dihiydro-~ -1,4-oxA~i~o- :' [4,3-a]indole hydrochloride (Example 286), . I .
1,10-dimethyl-1-~3-~methylamino)propyl~-~,4-dihydro-lH-1 t 4 -. oxa~ino~4~3-a~ndole hydrochlorido (~xamplo 285) and ltlO-di~ethyl~ 3-~di~ethylamino)propyl~-3,4-dihydro-1~-1,4- -~, ~ oxazino~4,3-aJindolo hydroc~lorlde (Example 287)9 antagonize ~ ~ -the e~fect~ o~ reserpine in mice at dose rAnses fro~ about 1 to .~ .- ..
" 10 n g/kg.
When th~ ¢ompounds o~ thi~ ~u~ention are used a~
- ~ antideprossants in wAr~-blooded ra~mal~ . rat~ a~d mic~, .~ they way be uRed alon~ or in combination with phar~colo~ically i, ~
~oc~ptable carrlers, thfl proportion o~ whioh i~ determl~Qd by th~
solubility ~nd che~lcal nature of the oompound~ chose~ routc .. .. . . .. ..... .... ....
',; ' , '~, ''' '''' ' .' ' '''''. ' ';' : _6_ :
., ... .
.. . ...

A~p_5786 /5s2l - , , , .
5~6 of administration and standard biological pr~ctice. For example~
they may be ad~ini~tered orally in solid form containing such ~- excipients as starcl~, ~ilk sugar, certain types of clay and so - farth, They may also be administered orally in the form of ~olutione or they may be injected parenterally, For parenteral ~dmini~tration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
l Ole dosage of the present therapeutic agents will ; vary with the form of administration and tho purticular compound . . . chosen. Further~ore~ it will vary with ti:c partic~lar host under troatment, Gencrally, trcntment ~s initia~ed with ~mall dosages substantially less than the optimum dose of the compoundO
Thereafter, the dosage is incrcased by small increments until the optimum effect under the circu~stancesiis reached, In general, the compounds of this invention are most desirably ~dministered at a concentration level that will generally afford - effective results without causing any harmful or deleterious side -effects and preferably at a level that is in a ran~e of from about : . ;
0.1 mg to about 50 mg per kilo per day, although as afore~entioned ~ariations will occur. ~owe~er, a dosa~e level that is in the range of ~rom about ~05 m6 to about 25 ~g per kilo per day is most desirably employed in order to achieve effective results.

, 30 . , .

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; AHP-5'~&6f5~2l .

la)3~Ssr, :, . ', ! . .
Antiulcer Activi~Y
The co~pounds of fo~la I of this ln~ent~on - pos~ee8 another ufie~ul pharmacologic property; t~at i8~they are u8~ful antiulc~r aeents. ~oro particularly, tho said compounds of this inYentio~ exhibit antiulcer acti~ity in ~tand~rd pharmacologic test6, for èx~mple, the te8t described ;
'. by D, A~ Brodio and L.S. ~alitski, Proc. Soo. Exptl. Biol. Med., 998 (1963), ba~ed on the provent~on of 6tro~-induced ulc~rs.
When th~ compounds o~ formula I are e~ployed a~
; antiulcer a~ents, they may bo formul~ted and adminiAtered ~n :., . tho ~Amo ~annçr ~8 described abovo for thoir U8~ a~
ant~d0pro~ t agent~.
. ' l5 . Prooo~ w ,~. F~r the pr~par~tion of th~ oxAzinoindole~ o~ this . , invention we pre~er to use ~B startin8 material~ the compounds , : ~ . , Or ~ormula XI~ .
.. ~ , .
~ 20 ~ II

; .

~ . 25 ~n which R6 and ~7 ~re as dc~ined in th~ ~r~t ln~tanc~. .
. .
: The starting materiAl~ of formula II aro e~ther ~oll . ~' ' ' ~iOW~ for examplo, 6~atol~.and 3-ethyli~dole~ or they may bs ... i . . .
prepar~d from indole or known indole derivatiYos~ for ~xample~
~ 30 ~ 6ee P,L. Julinn~ et al.~ Ieterooyollc Compo~md~ R.C~ Eldorf$old, :.' Ed., Vol. ~, John Wiley and Sons~ Inc.~ New York, 1952, p. 1, :1 accordin~ to the ~ethod of Ro Rob~n~on~ et al., descr~bed in .. U~SO Patent No. 2~407~4~2~ i~sued S~ptember 10, 1946.
! 35 .;. ~ .
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. . .; , .
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8_ ~ , A~ 578~/5s2l ~

:: , . '- . ' .
~036S~6 . . .- , .
The starting ~aateriAl of ~Grmula II i~ th~n co~erted .
.~ to tha ke~ i~ter~ediate of formula IIX, , . . i . .
.. : ,: .

~ 5 ~R4~5c~2R3~ -~
^ ~ .
i hich R2 R3 R4~ R5~ R6 and B7 Are a~ de~lned in th~
rlr~t inuk~nc0 and ~ ~8 hydroxy, m~rcapto, -S-S03-Na or -S-SO3-K.
This aonv~r~ion ~ty be effeotod by ~cveral methoda.
~, lO O~e g~nsr~l m~thod involve~ roacti~g tho appropriate lithitlt~t ~ , , . deriY~tiro of the ~tartin~ ~at~rial of formulct II witill ethyl~no : oxido or an uppropriate low~r ~lkyl sub~titutod othylono oxid~ i to afford the desired intermsdiat~ of for~ula IXI in which Xl :
i~ hydroxy~ ~he desired lntermediato~ ~ay Also be obt~ined :
by treuting the appropri~te stnrting material of for~ula II
:;~ with tho appropriate ~thylene oxide der~vatiYe according to i the procedure of Mo Julii~, et aL ~ Bull. So~O Chim, Fr., '"'' 2291 ~lg66~. ,.
.. .. . .
, The lover alk~l ~ubstitut~d cthylene oxldes are : 20 pr~parod by known ~ethods; ~or exa~ple, s~e V. Frnn~en and ~. E. Driesen, Chs~. Bor.~ ~ , 1881 ~1~63).
: ;.
:.~ A~ alternativo ~ethod for the preparation of . :;
inter~odi~tes of formllla III in whioh R2 and R3 nro hydro6an 'I !"
inv~l~es treating tha istartin~ mator~al of formuln II with an -haloaoetic acid lower alk~I ~ster of iormula ICR4R5C0 ~low~r alkyl) in which L is halo and R4 and R5 ar~ a~ defined ;,j , . , ~.:.
i' ! `.; '.

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AHP-5786~592 1 . . ,~.
.~ ... .

~L~3~S9~;
~ ~n the ~ir~t ~ta~ce~ in the pre~e~ce of ~ ~uitable proton .;, .. . .
- acc~ptor ~d U8~g preferably an inert solvent for the reaGtiono - The a-haloacetic acid lower alkyl esters are w~ no~m, for ex~mple see IlRodd's Ch~mis~ry o~ ~he Carbon Compound~ S. Coff~y~
S Ed~, Vol. I¢, 2nd ed., ~sevior Publi~hine Co" A~sterdam, 1965, pp. 201 - 205, ~uitable proton accoptox~ include ~ sodiu~t hydrlde,alk~ etal carbonates and triet~ylamlne.
~ Suit~ble inert sol~ent~ include tetrahydrofuran, be~zene, toluenc and dimethyliormamido. Proforred conditione for the N_alkylation include the u~0 of sodium hydride as a proton acceptor and tetr~thydro~uran as an inort ~olvent, Although the opti~um temperuture und reactloll tlme wlll vary dep~ndln~
on tho r~actant~ entployed, the reaction i~ gen~rally performed .. At the bolling point of the re~ction mixtur~ for a period of 30 mintlt~s to 48 hour8~
Tho indole~ acetic acid lower alkyl ester derivativo .. obtained by the abovc N-alkylation reaction i~ théraa~ter : . .
hydrolyzed, pre~erably with a solution of potas6ium hydroxide in methanol wat~r, to giv~ the corresponding indole-l-~cetic ~ 20 acid dorivativc6 which on reduction with lithium aluminum hy~ride affords th~ desired intermediate of formula III in :~
which R2 and ~ are hydrogen and Xl is hydroxy~
A~ain alternatively, the latter indole~ acetic acid ' derivativfl may al80 be reacted with two equivalent~ of a lower fllkyl Grignard roagent, for ex~mple, ~etbyl magnoeium bro~ide~
~ . to give, flfter hydrolysis of the ~agnesium-halogen derivative,the .

.
;~ ' `

.
.
-~0_ , ~rlr-` ~IL(11;~65~96 .-. desired ~nt~ ed~ate~ o~ f~r~ula III ~ er ~k~l a~d ~ ~-~ ~ hyd.r~J)9 ~0e L.F~ Fie~er ~nd ~IO Fie6~r, "Ad~anced - Or~a~ic ~hond.~try"~ Re~hold Publl~hing CorpO~ No;l York, 1961 9 p~ ~720 -~ 5 When the corresponding intermediates of ' formula 111 in which Xl is mercapto, -S-S03Na or -S~S03K, are desired, a procedure similar to ;.; that described by N.N. Suvorov and V.N. Buyanov, .

Kh~n.-Farm. Z~o~ 1~ (1967), ~Che~ Abstr. ~ , 73474~ (1967)~, for converting 3-(2-bro~oethyl)-indole to indole-3~eth~nethiol, : L~y be omployed. More p~rticulA~ly~ the above intor~ediate o~
i formulA III in which Xl i~ hydroxy i8 trcAted with pho~phoru~
tribromidc in ~n in~rt ~olvont, for examplo~ other or : IS carbon tetrachlorido, followed by troakmont o~ tho produ~t with ; ~odlu~ or potas~iu~ thio~ul~lt~ to ~f~ord tho corro~yondin~ ~odlu~ .

or pot~8a~um iB-tl~indol~ thyl thio~ulfato deri~atlv~9 rospectively, namely the desireci starting materTal of formula 111 (Xl = -S-S03Na :~ or -5-S03K). Treatment of ~he latter product wTth strollg alkali, for exa~ple, ~odium or pota88iu~ hydroxide, yielde ; ' ~, . tho corro~ponding bis-C~-(indolyl~ethyl~di~ul~ldo dorivative.
' ~ Finally red~ction of the latter compou~d with lithiu~ alu~lnu~ ;.
- hy~rido g~v8~ tho de~irod i~ter~edi~to of Yor~ula ~ vhich :
. i,~ 25 ~ $8 m~rcapto. . ...
.; . ~. ... ~ . .
;,: On ~e other hand, the preceding thiosulf3ta derivative ` is treated with acid, for example, dilute aqueous solutions of .,., hydrochloric acid, sulfuric acid or phosphoric acid, to give ~. ' ;... 30 directly the desired compound of iormula 111.
., Alt~r~atlvol~ tho atflrt~ne materiAls of formula III
in whlch B2 and B3 are hydroge~ and ~ orcapto n~y bo .. . .. .. .. . . .. . . . .. .. .... .. _ .. .. .
: prepar0d by oxidi~,ing the ¢orre~pondln~ intermedi~to of formu.la . . :
i 35 III in whlch Xl i~ hydroxy~ doscribed aboYe, wlth .:' N~N-dicyclohexylcarbod~i~id~ fl~d dimethyl sulfoxido in tha ... .
, pro~oe o~ a suitable acid, ror oxa~ple, trifluoroacetic ~cid~ffee :, - I l -' ; .' ~ ~-57~592l ., .
,; .
,. .
~Q36S96 Ko E~ Pfitzner and J0 G. ~offat, J. Amer. Chcm. Soc., ~ , 5570 (1965), to givo the corrospondlrlg aldehyde d~rlvative. Thc sa~ aldohyde der~ative may also be obtained by N~alkylation of the appropriate st~rtin~ materi~l of ~ormula II with an ~ppropriato a-halo-acetaldchydo derivative (6ee '`Rodd's Chomistry of tho Carbon Co~pounds~, cited ~bove, Vol., lc, pp~ 2~ - 26) according to tho conditio~s de6cribed above for N-alkylation with a-haloacetlc acid lower ~lkyl e6tors, :; ~he latter ~ldehyde derivatiYe ~ co~verted to itB
correspond~ng ~ dithiol derivativo with hydrogcn 6ulfido~
. ~ . .
which ~8 roduced with lithium alu~inum hydrid~ accordlng ~. to tho ~othod o~ T,L, Cairns, et al., J. Amor. ahom. Soo.
. , .
. ~ ~ 3982 (1952)~ to yi~ld th~ desir~d ~t~rtin8 matoriul of : . formNla III.
.1 15 It should be not~d that thc precedins proccssos may ,............... .
.1 not be entirely pract7cal for the preparation of the compounds of . . .
~m - formula 111 in which Xl is hydroxy, mercapto, -S-S03Na or -S-S03K, and R6 ~B hydroxy or lower alkanoyloxy, For th~ rea~on, - - tho preforred startln~ materi~16 of formula II for the o ultimate preparation of the co~pou~d~ of for~ulA I in which ~ R6 $~ ~ydroxy or lower al~anoyloxy ar~ the corresponding ,, ~ cOmpouna8 of ~or~ula II in ~Ihich R6 i8 benzyloxy~ i.e. a ,, ~ . .
~ hydroxyl wit~ a protectin~ benzyl ~roup or othor ~uitabl~ ;
.,,. . . ;
. . protocting group (see J. F. W~ McOmie,!'AdvanCes in Organia Cho~i~try~'~ Vol. 3~ R~ A. Rnpha~l~ et al " Ed., Intorsci~nao :. . Publishers, New York, 1963, pp~ 191 - 294). After tho . . ~
. appropriate tran6for~atio~6 de~cribed below, thc benzyloxy ' ~

. , , ~, ~\

.. . . ~ ..
.

' ``~L'~ - - , , ... . ..
. ~ , . . .

~ P-57~6/592l ~03659~ ~

; ~ group i8 remov~d b~ hydrog~natiQn3 in the pre~eneo of ~ ~
:. e~taly~t, for ~x~plo~ lO~ ~alladi~ on carbon~ ~UBt prior ..
.- to affo~ding the d~sired corre~pond~ng co~pot~d of for~ula X
in whieh R6 i~ hydroxy. The lattor ~ay bo convertod lf de~irad to tho eorre~pondin~ eo~pound of ~or~ula I in whleh R6 i~ :
lowor ~lkanoyloxy by eonvontional ~an~, or exa~plo, by : tr~atm~nt with tho approprlato lo~0r alkanoie anhydride pr~ferably in tho pr~8ence of pyridin~
'ho abovo do~crlb~d intorm~di~to of ~or~ul~ n l~ whieh R2, ~ ~ ~4, R5t ~6, n7 ~nd Xl ~ro ~ d~fin~d in th~

iirat in~taneo nro now ~ub~oetod to a k~y roaetion eomprl~ln~
tho tro~t~nt of 6ald ~tartin~ mntori~la wlth ~ aempound of formul~ Rl - 8 z (~v) ~ whleh R~ la u~ Ao~in~d in tho flr~t in~tuneo and Z 1~ ~ol~etGd irom th~ group consletin~ o~: ;
~ ) COOR18 d Al.~C1 C~L8 :La~ wh~ch ~8 1B hydro~n or .,, ' !' ;''~ low~r alkyl and Alk 1~ ~n alkylono ~Qloctod from tho ~roup ~ consi~ti~g o~ CRlORll, CRlORllC *2R13 and CRlQ~llcRl2Rl3cRl4~l5 ; h~r~i~ Rl ~ l Rl2 * 3~ * 4 and Rl5 are hydroge~ or lower alkyl, (b) CONR8R9 ~d Alkl-C~N~8R9 i~ wbich Alkl, R8 and R9 are f ~i d~fined abovo, (¢) C~20C0~ 9 and Alkl-C~20C0~9 ~ which ~9 1~ hydro~en :, ,.. :
;' or low~r al~yl and Alkl ia as dofined abovo9 (d) hlk2-L in which Alk2 i~ an alkyl~no ~olqctod fro~ th~
group con~istlng of C ~Rllc~l2~ C~lopllcRl2~l3a~Rl4 CRlo* lc ~2~l3Cnl4Rl5C~rRl6 whorc~n Rl~ * l, ~12, R13, R14~ ~15 and * 6are n~ d~finod abovo a~d L ~ halo~
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,. ; , .. , ., ,, ", .. ...

AHP'5786/5921 ,, . -.; ', .
` 20 ~036s96 (e) AlkNR8COR in which Alk and R8 are as defined in the first instance and R is hydrogen or lower alkyl containing .
from one to five carbon atoms, . .
(f) Alk-N02 in which Alk is as defined in the first instance, and (9) Alk-NR8R9 in which Alk, R8 and R9 are as defined in the first instance, in the presence of an acid catalyst to yleld the compounds .
of formula V in which R , R2, R3, R , R5, R , X and Z are as deflned above.
.
: ., r~
:lo -. f~;;~f7 ~ z ~ `

. III ~R4~25C~R~ IV
,' . ' ~
`15 ~

. 20 Thereafter thè appropriate compound of formula V is :~ conver.~ed to the desired oxazinoindole o~ formula I according -~ to the processes described hereinafter or is actually the .~ desired. compound of ~ormula I in the case where Z is Alk-NR R
as described above-.: 25 In practising the condensation ~111 + Vl ~ V) a solvent is used generally as a reaction ~ medium~ Any solvent inert to the reaction conditions may :.- be used. Suitable solvents include aromatic hydrocarbons, for example, benzene or toluene, ethers and cyclic ethers, for.
example, dlethyl ether, dioxan or tetrahydrofuran, halogentated hydrocarbons, for examp!e methylene dichloride or carbon tetrachloride and Ihe like. Benzene and toluene are especially ~ ~ AHP-5787/5921 ~365~6 convenient and prac-~ical for th;s use. A variefy of suitable acid catalysts may be used for this condensation, for example, the type of catalyst used in a Friedel-Crafts Reaction, i.e.
p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, ` 5 boron trifluoride, zinc chloride, hydrochloric acid, perchloric acTd, tr7lfluoroacet7c acid, sul~uric acid and the like.
p-Toluenesulfonic acid, aluminum chloride, boron trifluoride and phosphorus pentoxide are included among the preferred acid catalysts. The amount of acid catalyst used Ts not especially crttical and may range from 0.01 molar equivalents to 100 molar equtvalents; hower, a range of from 0.1 to 10 molar equivalents 7s generally preferred; howev~r, not~ that th~ amoun~ of acld catalyst should be in excess of one molar equlvalent wlth respect to the compound of formula Rl - C - Z when Z is AIk-NR8R9. The time of the reaction may range from one-half to 24 hours. The temperature of the reaction may range from -20C. to the bo71ing point of the reaction mixture. 1, Preferred temperature ranges include 20 to 120C.
A more detailed description of the preparation o~
~ 20 the above intermediafe compounds of formula V and a description :. ' ` of their subsequen* conversion to the oxazinoindole derivatives of formula I are disclosed below. For convenience these descriptions are catagorized into sectlons according to the group selected for Z for the intermediate.
. ~ .
ta) Preparation and Conversion of Intermediates of Formula V tZ = COOR18 and Alkl-COORI ) .
Intermediates of formula V (Z = COOR18 and Alkl -COOR18 in which R18 is hydrogen or lower alkyl and Alk~ is as , . . . .
'' ' , ~,':' .
AH~-5786/592l ~:0~659~ ~

defined i~ the ~irst instance and Rl7 R29 R~9 R4~ ~ R6, R7 ~nd X are as defined in the first a~stance~ are readily obt~ined : by the condensation (III ~ IV--~ Y) by using ketoacid or :. ketoesters of for~ula R~ 7. in ~hlch ~1 iR a~ deflned :; 5 in the first in~tance and Z is CoO~8 or Alkl - coo~l~ as defined abov0 together with the ir.ttermediate of formula III.
Gen~rally comparable yield~ of product ~re obtained .:~ in thi~ process when either the ketoacid or the corre~ponding " ,,.:
~etoe~ter i~ used, ~owever, in the ca~e where it i~ desired ; 10 to pr~pare an acid compound of formula V in which ~ iB
.. Alk~COOR wherein Alk~' i8 CRlOR11 and ~ i~ hydro~en (io~ n ." ~, ~; acid intermodiate of f~rmul~ V), it in prePer~bla to .. ~ir~t conden~ the Appropr~a~e ~ k~toostor o~ ~o~uln IV
rather than the corresponding ~-keto~c~d and thcn hydrolyY,e the re~ulting ester product to glve the de~ired acid co~poundO
''' Moreover, in the g~neral practice o~ thi~ ~nvention it i8 often more convenient to prepare the acid compound~
of formula V by u~lng the ketoester instead of ths ketoacid in this proce~ and then hydrolyze the resulti~g e~ter product to the desired acid, the reason baing ~imply that the ketoe~ters : ~re generally more readily ~ailabl~ either co~ercial y or :~ by ~ynthesi~
; Co~pound~ of formula V in which X i~ C00~`l8 or AlklCOOR
~ wherein Alkl i8 as deflned in the first instanca and ~ is ., , . - .low~r alkyl, l.e. e~ter inter~lodlato~ of for~ula V~ are bydrolyzed readily to thelr corr~ponding acld~ Or formula Y
.~ by treatm~nt with a suitable ~lkali, for example, potao~iu~
.:" ' , ~. . ~ , .
... .
: . , . ' ~ .

-16_ Al-~-5786/592l ,........................................................................ ~.
'' ' . . ', i ~3~i596 ~: hydrox~de or ~odium carbonate9 in aqueous methanol or aqueou~
.
ethanol or by treat~ent w~th lithium iodide ln a ~uitable : organic ~ol~ent, for exal~pl3~ collid~n.e, Bee L~Fo Fieser and : M. Fieser, ~Rea~ents for Organ~c Synthesis~ John Wiley and So~
~ . 5 Inc., Ncw York, 1967, ppO 615 ~ 6170 The ~ r- and ~-ketoacid~ and ~etoe6ter& of formul~ IV are either known, for example~ ethyl pyruvate, i: levuli~ic acid, ethyl ~,a-di~ethylflcotoacstAte and ~,~-dimethyl-... . . .
levulic Acid or thoy may be prepared by ~nown me~hods described in generul organ~c chomistry toxtbook~. Eor exn~ple~ ~ oomprehen6ivo .~ review on th~ propertie~ and prepurat~on Or ~uoh a-~ Y-, and ~ ~ctoacid~ and -k~too~ter~ m~y be ~ound in ~'Rodd~ :
.j.; ahemist~y of tho Carbon Compound~ aited ubovo~ Vol, Id~
pp. 226 - 274.
~ 15 Thereaftor these intermediute acid~ and ester6 of : ~ormulfl V are convert~d to compound~ of formula I in which Rl, ~ , R3~ R4~ ~ , R6~ R7 and X are as defined in the first :~ ~nstance and -Alk-NR8R9 i8 an amino(lower)alkyl in which Alk C~2 or Alkl-C~2 wherein Alkl ~ a~ defined in the first in~tance and R8 and R9 are RB deflned in the first instance.
:~ In tho CA5e where the acid intermediat~ of formula V ~
.. i~ employed, 6aid acid ~8 Gub~ected to amidation by treatment ~ .
with a lower aIkyl chloroformate, preferably ethyl ohlorofor~ate~
`.: in the presence of trlethylamlne, affording the corre~pondin~
; 25 ~ixed anhydride, which i8 converted by treatMent wlth the : appropriate amine Or formula ~R8R9 ~n which R8 and R9 are as .;
; defined in the fir~t instance~ for example, am~onia, methyla~ine '~''` ' ~`' ' .~ ' .
~, , .
~7 .~i . 5 hHP-578~592l . ,~ .
..' 3659~;
or di~ethylar~ine, to gield the corre~pond~ng a~de of ~ormula V
in which Z i6 CoNB8~9 or AlklCONR~R9 wh~re~ Alkl, R8 and R9 are a8 deæcribed in th~ fir~t inætance.
, ... .
Alternatively, the latter a~ides are al~o obtained by tre~ti~g the e~ter intermediate~ of for~1la V, de~cri~ed ; ~bove, w~th the appropriat0 a~i~e ~cor~ing to known amidation method~, for example, see A.L.~. Be¢kwith in "The Che~istry of A~idee~l~ J. Zalicky~ Ed.~ Inter~cience Publi~her6, New York, 1970~ pp. 96 - }05.
Thereafter~ the amides 80 obtained arc reduced with a ~uitable complox metal hydride to yleld the desir~d oxnzinoindolc~. Examplo~ of suitabl~ compl~x motal hyflrid~
are ~ithium aluminum hydride~ l~thium aluminum hydride-aluminum chloride, alum~um hydride-aluminum chloride, diborane and ~5 sodium borohydride-aluminum chloride. Lithium aluminum hydride i8 preferred.
Two a6pects of thi~ latter reduction of the amides "` are worth notin~. The first aspect relates to the reductio~
of the above amide~ offo~Mula V in which Z is CONR8R9 or - 20 Alkl-CONR~R9 wherei~ Alkl ~8 as defined in the fir~t instance, ; R8 i~ hydrogen and R9 is lower al~yl, i.e. secondary amide6, - to their corresponding oxazinoindoles of formula I, i.e.
secondary amine~. In thls case a Nodification of the abo~e process in the followin~ man~er i8 among the preferred procedures, j 25 ~he aforementioned acid or ester intermedia~e of forn~llfl V is reacted with an amine of for~ula ~NR8R9 in which R8 i~ benzyl and ~ i8 lower alkyl corresponding to the B9 of the desired ', ' .

.' ', .
-18_ . `

AHP~578~/592l :

1031~596 :: amine. ~hi~ ~tep i8 perfor~ed according to the a~idation ~tep de~cribed above~ ~he re~ulting amide i~ then reduced w-ith ~ ~:
.;: co~plex metal hydride according to the above procedures~
Thereafter the benzyl group is removed by hydrogenolysi~ in the pre~ence of a cataly~t, preferably 10~ palladium on curbon, to afford the desired secondary amine compound~ of for~ula I.
; The ~econd aspect relates to a more general modlfication ~or the reduction of the above amides o~ fo.r~lla V
in which Z i8 CoN~8R9 or Al~tl-CONR8I~9 wheroin Alkl~ ~8, arld R9 is ns do~ined in the fir~t in~tanoe~ : .
Thls modi~ioation ~8 applioablo to the roduot~on oi th~ terti~ry~ ~econdflry und prlm~ry amide8 und i~ ~ pr~orred modification for the reduction of the latter two. In praoti~ing thie modlfication, the ~forementioned amide Or Yormul~ V is treated with triekhyloxonium fluoroborate, see R.F. Borch~
Tctrahedron Lettars~ No. 1, 61 (1968)~9 or di~ethyl sulfate, 8~e `~
~- ~0 Bredereck~ et al., Che~. Ber.~ ~ ~ 2754 (lg65)o ln ~n inert ,~ 801vent~ ior exa~ple, ~ethylene d~chloride, whereby the corresponding iminoether ~luoroborate or ~athyl ~ulfAte.salt . i~ obtained, re6pec~i~ely. Subsequent reduction oi the ~alt thus : obtaIn~d with a co~plex metal hydride accordin~ to the procedure .~ .
de~cribcd above ~or reducin~ amides yield~ the desired ox~zinoindole of formul~ I. Alternat~vely, the above fluoroborate or ~othyl sul~ate salt derived ~rom a secondary or prl~r~ amldo ~ay be dècomposed by ba~e tre~tment, ~or example, with lC~
.j .
sodium hydroxide 601ution or trlethylamine~ to give th~ correspondine .
'~
. -19- ~

.

~ Al~p-5786/592l , ~ .

~ ~3~i596 , iminoeth~r derivative which i~ then redu~ed in a like ma~er . . . - , to the desired oxazino~ldoleO
~` ~hon applying the aforementioned ~teps ~n the preparation of co~pouads of for~ula I ~n whlch R6 i8 hydroxy , or lower all~noyloxy, ~t i~ preferable to use corresponding inter~edilto~ in which R6 ln benzyloxy followed by the appropr~ate transform~tions as noted prc~iou~ly to yield the de~ired compounds of ~ormula I.
(b~ Prep~rati~n and Conversion of Intermediatcs of Formula V
: (P ~ CONR R9 ~nd Alkl~CON ~ R9).
Tho inter~ediates of formula V in which ~ i8 CONR8R9 and ~lkl-COMR8R9 wherein X8, R9 and Al~l are a~ deflned in tho flrat in~tanoe~ de~orlbed in tho proviou~ ~ootion~ aro al~o obt~in~d diraatly by utill~ln~ th~ approprl1to Atartin~
... .
terials of ~ormula III and a~ , Y-~ or ~-keto3~ide~
o~ formula ~ -C-Z in which * is a~ def~ned above and Z i8 zo CoNR8R9 or Al~l-CONR8R9 in which Alkl, R~ and R9 aro as : derined above. ~h~ ketoamides required for this conden6ation are either knownO for example9 pyruvamide or a~a-dimethylaceto-acetnmide~ or they may be prepared by known method~ for lnstance~ see "Rodd's Chemi~try o~ the Carbon Compounds"~
cited above~ Yol~ ldt pp. 226 - 2~40 -~
~ Thereafter thes4 amide6 o~ formula V ar~ converted : ~ by the reduction processO describ0d above~ to the compound~ of formula I in whioh Rl~ R2~ ~ , R4~ R5~ R6~ R7 and X are a~
' defined in the fir~t instance nnd ~Alk-NR8R9 iB amlnotlower)alkyl :' in which Alk i8 CB2 or Alkl~Ch2 wher~i~ Alkl i8 a~ de~ined ln `~ the f~rst inatance and R8 and R9 are a~ defined in the first lnstAnce~
.,~ ..
,~ .

, ~ ~," .
,':
-20~

~ 57~6 /~921 .~; i ."
',':`:'" ` ` ' ' :'"
,; ". ~ ,: ' Q365~ ~
Px~parat~on and Conversion o~Intermediates of . : ~ormula Y (Z - C~i20COR19 and Alkl-CH20COR19j :'. , I~t~r~ediate~ of ~ormula V in which Z i8 CH20Co~9 '` a~d Al~l-CH20COR 9 in which AlXl and ~ 9 are ~ d~fined i~
.. 5 tho ~r~t inst~noe~ are obt~ed when a starting ~aterial of rMula III i~ conden~ed with a Xotoalcohol lower al~oic acid e~tor o~ for~ula ~COC ~OCOR 9 or RlCO-Alkl-C~OCO~9 in which :. *~ Alkl a~d ~9 are as defined in the fir~t instance in the , ; . - , :
presence of a su~tablc acid cataly~t accordi~ to the conditio~
la described aboro for.the conden~tio~ ~XII ~ IV -~ V), Tho ~etoalcohol loweralkanoic acid eslers are eirhcr known, ~or example, ceto~yl acotat~ or 5-ac~toxy-p0ntan-2-ono~ or ~ b~ prepared by lu-own r~othod~, for ~n6t~nce~ ~ec ~'Rodd's Chcmi6try of tho . Carbo~ Compounds~l~ cited above~ Vol. Id~ pp. 49 - 54.
Theso intermediates of for~lla V may then be utl1ized for the preparatlon o~ compounda of for~Nla I of :;; thi~ ~n~ent~on in the following ~anner. The intsrmediate i~
hydrolyzed w~th an a~ueou~ alcohol~c 601utio~ of A ~uitablo ~ lkAll, cr ~xample, 60dium hydroxide in aqueous msthanol ;. 20 . . to a~ford the correspo~din~ prima~y Alcohol9 It shou~d : .b~ noted that the latter pri~ary alcohols ~ay also be obtained ;. . .
:.~ by the direct reduction of the intermediate acid6 and ester~
.; .... ~ .
-. of ~or~ula Y~ de6cribed herei~ in 6ection (a)~ u~in~ a ~uitablo :: oomplex motal hydrid~ a~ described therei~, The primary ~5 `
. aloohol i6 then oxidized to the corre~ponding aldehyde. Although - . a Yar~ety o~ method6 are known ~or the oxidation of n primary ` Alcohol to lt~ corrc6ponding ald~hyde~ 6ee ~or exa~ple~
.. . .
. . , - . ' ~ \ ~ .
.;
.~,~ .
. ~' ` ' ` " .
~` .. , !
; ~ AHP-5786J592i ; ..................... ~ .

"Rodd's Chemistry of the Carbon Compounds", cited above, Vol. Ic, pp. 4 - 10, we have found that the method of K.E. Pfitzner and J.G. Moffat, J. Am. Chem. Soc., 87, 5670 (1965), usTng N,N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the présence of a suitable acid, for example, trifluoroacetic ac1d, is both efficacious and conven7ent.
Thereafter tne aldehyde is reacted with an amine of formula HNR R in which R and R9 are as defined in the first instance according to the method of K.N. Campbell, et al., J. Amer. Chem.
Soc., 70, 3868 ~1948) in the case when the amine used is ,, , ammonla or a primary amTne, or according to the method of N.J. Leonard and J~V. Paukstelis, J. Org. Chem., 28, 1397 ~1963) when the amine Is a secondary am7ne, to glve the corres-pond7ng SchTff base or Immonium salt, respectively. The product so obtained Ts reduced with sodium borohydride, see E. Schenker, Angew, Chem., 73, 81 (1961), to yield compounds of formula I in which Rl, R , R3, R , R , R , R and X are as defined in the ~i first instance -Alk-NR R9 is an amino(lower)alkyi in which Alk i5 CHz or Alkl-CH2 wherein Alk is as defined in the first instance and R and R are as defined in the first instance.
- Alternativeiy, the latter compounds of formula I
may be obtained by converting the above corresponding aicohol i!
1, ` to a reactive intermed7ate such as the corresponding halide, . l mesylate or tosylate, which may then be reacted-witu two or more molar equivalents of an amine of formula HNR R in whlch R and R
are as defined Tn the first 7nstance. Preferably this reaction is performed in a suitable inert solvent, for example, tetrahydrofuran, at 40 to 100C. or at the botling point of the ~ reactton mixture for a period of eight to 24 hours. In " 30 connection with alkylations of amines of formula HNR R in which R8 is hy~rogen and R9 is lower alkyl as disclosed herein, it is .
,, .
.
_ ? ? _ Al~-5786/5921 , , 103~59~
g~nerally ~ro adYanta~ous with re~pect to yield~ to perfor~
the alkylation with the correspondine N-benzyl derivativ~
. - of ~aid amine, i.e., a~ am~ne of formula ~NR8R9 in which R~ is benzyl and ~9 i~ lower alkyl. ~hereaftorl when all i 5 appropriate lransformations have been performed, the N-beh group may be rem~ved by hydrogenolysi~ with a catalyst, prof~rably 10~ palladium on carbon, to gi~e the de6ired co~pounds of for~ula I, Alternatively, the abovo uldehyde i~ oxidized with : ~ a Duitable oxidizing a~ent to yield the corre~pondl~g acid intormedi~tes of formula V de60ribed ~n ~ection (~)~ Althou~
A varioty o~ ~uitable ox~dizlng n~ant~ may be u~ed Por thia purpo~o, for exnmple, 6ilver oxido~ nlknline permanganate, hydro~en p~roxide~ the use of ~ilver oxide uccordin~ to the ~ethod of ... . M.D~l~pine and P. Bcnn¢t, Compt. rend., ~ ,39 ~1909) i6 preferred~
Again alternAtively, the above aldehyde is converted to ~ts oxime which on reduction with a co~plex ~etal hydride yields the correspouding pri~ary amine of for~ula I ~n ~hich ~ , ~2~
~ , R4, R5, R6, R7 and X are a6 defined in the first instance .` a~d ~lk-NR8R9 i~ an am~no(lower~alkyl i~ which Alk i8 C~2 or . 25 Alk~ 2 wherein Alkl i8 a~ defined in th~ first in~tance ~nd R
and B9 are hydrogen.
. . . .
; In turn th~se latter compound~ of ~or~ula I uay be further N-all~l~ted on the nitrogen of tho pri~ary amine with the appropriate lower all~yl halide to the corresponding compound6 Or formula I in which Y i8 -Alk_NR8R9 wherein Alk i8 C~ or . Alkl-C~2 wherein Alkl i~ aB de~ined in the first instanco und .
`; ` ' -23-AliP-5786/592l . ' ;-~03~59~
R~ $8 hydrogen or lower alkyl and R9 i~ lower alkyl ~lOe.
: ~econd~ry or t~rtiary a~in~s). Xn thi~ casa dep~ndin~ on the particular derivatlve desired the N_alkylat:ion ~ay be ffected with one or two molos o~ the alkyl halide to giv~
re~poctiv01y the ~eco~dary or tertiary amineO 0~ the oth~r hand th~ N-alkylution ~ay b~ effected in two BtepB introducing . u different alXyl ~roup each time to afford the correspondlng tortlary amine in which R8 and R9 ~re d~ferent lower alkyls~

;, 10 ~Ihan it 18 de~ired to preparc the abovo tcrtiary ~, amino compound~ in wh~ah R8 or R9 Aro ~ither or both methyl, an ~lternati~e alkylRtion method compriu~u reaatlng ~h~
appropriate correoponding primary or secondary amine wlth a~
a~uoou~ mixture o~ a substantial exoess of for~aldehyde and `., 15 formic acid accordine to the condition~ of the E6chweiler~Clarke .~ reactio~, ~ee MoL~ Msore, Organio Reaction~ 301 (l94g)a `. wheroby N-methylatio~ i8 effectedO
Another N-alkylation method which ~ay be ~pplied to the AbOVe primary ~nd seco~dary a~ine~ involv~6 acylation .. 20 with a lower alkanoic anhydride or acid halide and s~b~equent reduction of the resultin~ amide. ~ ~.
. Furthermore, the above primary amines may bc used : to prepare correspondin~ compounds of formula I in which ~;
,~ R8 ~nd R9 together with the nitrogen atom to whlch they ~re ~:
' , 25 ~oined Porm a het~rocyclic amlne radical a~ defined in the .. 1 first lnstance. When u~ed in this mànner the pri~ary amines ,~' Rre 6ubjected to known N-alkylation methods, for oxample, .. ..

",:
.. . . .

-2l~ :

:
, ~
' '':

see ~ thod J described by R. B", M~ffet, J. Org,,, Chem.~, 14~ 852 (1949~1, with the appropriate ~ dibro,,~ide~s, for example, tetramethylene dibro~ide, p~o~ntamethylene dibro~ide, biP.(2-chloxoethyl)ether~ bi~(2-chloroethyl)b~a,nzyla~ine followed :
by hydrogenation Jln the presenc,,s of 10~ p~lladiu,~ on c,arbon to re,~ove the prot~ectin,~ benzyl group, a bi~(2-ohloroethyl) lower all~,~lam~ine or A bi_(2-chloroethyl)-N-[hydroxy(lower)al~yl,,,-a~ine~ to give the correspondin,g de,~ired compound of formula I
in wh~ch ~8 and ~9 together with the nitrogen ato~.~,to which they are ~o~r.~,ed ~or,~,~,a het~a~rocyolic amine radical, i,e. a pyrrolidino~ piporidino~ morpholino~ pipe~rr~,Z,,ino, 4-(lowor)ullwl,,, l-pip~e~rflz,~nyl or l,~-',rh,ydroxy~low,e~r)~lkyL,,~l-pipc,~,ru~nyl~
reapect~ely.

(d) Prc~parRtion ,~nd Conversion of Inter,mediAt~6 o~
~'''ormula V (Z c Alk2-L,).
Intermediat~es of forTula V in which X i~ Alk2_1,, wh,,~,rein Al~' nnd L are as defined in the fir6t in,~tance, are . } ~.
., obtained when a starting ~aterial o~ ~ormula III 1~ condensed `~

,1 with A ~ r or ~-haloketone o~ formula RlCO-Alk2-L in which Rl, Alk ~nd L are a~ defined in the first in6tance in the . prese~ce of a suitable acid cataly~t according to the condition6 c, d,e~s~cribed ,~bove for the co~densation ~ IV--t V)O ''r'~e , . i .. halo~etones are ec~ither known~ for exa~,ple~ 4_0hlOrobutfa~f-2-o~e~ ;
or they ,~,ay be prepared by known methodA, for instance, ~ee ~'Rodd"s Che,,~,istry of Carbon Compound~ oited above~

.'', . ; ' :.
', . ' ~ ~ , ;,, . ' ':
' ' ~ ' -2~

P-5786t592 1 ~ 1036S96 ~
- Vol~, lc. s pp~ 70 - 71 and ~IMethod~ der Or~a2lischeIl 5hemi~9 IIouben-W0yl~ B. lguller~ Ed.o Vol V/3~ Georg Thie~e Verlag~
Stuttgart 1962, pp. 511 - 10763 ~herea~ter the~e intermediates of formula V are : 5 treated with a two molar exce~8 of Mn amine of formula NR8R9 in which R8 ~nd R9 Rre as defined in the f~rst instance to yleld the co~pound~ o~ formula I in ~hich Rl, R2, R3, R4 ~ , R6, R7 and X are as described in ;the flrst in~tance, ; and _Alk_NR8R9 i8 an amino(lower)alkyl in which Alk iB Alk ; 10 ae defined in tho fir~t instance and R8 and R9 ar~ a~ do~^~nod nbove. Preferably thi~ r~action 1~ porformed ~n a ~uita~)le ~; inert ~olvent, for example, totrahydro~urun u~. kho boilin~
.. , .. ~ .
:: poi~t of the renatlon mi~turo for u porlod of a ko 24 hour~, (e) Preparation a~d Cor~r~ of Intermediatoc of For~ula V (æ - AlkNR~CORCu) l 15 ;. Inter~ediates of formula V in which Z i~ AlkNR~CO
~ whereitl Alk, R an~ R are as defined in the fir~t inat~nco :.: are readily obtAined by the condon~ation (III ~ IV -~ V) by . u~lng ketoamide~ o~ formula * - C - Alk - NR8COl~ in which ~`

~ , Alk, R8 and R are a~ defined in the fir~t ~nstance ".2 together with the appropriate ~tarting material o~ form~la III. ~ :
The ketoa~ides used here~n are either knOW119 ~or ;:
exampla, ~or~amidoacetone ~Ao Treib~i and W. Sutter, Chem~
.. . .
Bor " 84, 96 (1951)~ sea ~1BO ~.~. Wiley and O.H. Boru~ :
J. Amer. Chem, Soc.~ ~, 2005 (1948~ or may be prepared by known procedure~, for examplo, 800 "Methoden dor Organi~chen Chomio", cited abovc, Vol. XI/l, 1957, e6pecially pp. 58 - 62, . ' ' , : ~ "'.' ' ''1, : ~: ::
.

. ~ .

-26_ ~: :
~ P- 57~6 /592 1 : ' :
.. . . .
~036S96 ::
. i :, i 285 - 289 and 508 - 509, and F. Fo Blicke, Organ~c Reactions, -`
~ 1, 303 (1942), .:
: Thereaft~r, reduction with a co~plex ~etal hydride ... .
: converts the instant intermedlateFi of formNla V to oxazinoindolc~ of ~rmul~ I in whlch Rl~ R2, R3, R4~ ~ , R6, R7~nd X Are ~B descr~bed in the first instance, and -Alk.~NR8R9 i . 8 an amino(lower)alkyl in which Alk and R ~re a~ defined ln the ; firBt instance and X9 i~ lower alkylr 1"'' ~ ..
: ~f) Prepar~tion and Conver6ion of Intermediatcs of Formula V ~Z = Alk - NO ) . lO 2 Intermediates of for~ll~ V in whiah Z i8 Alk-N02 i ~ ~
;j whoroin Alk ie as d~fined in t~le f$r~t l~stance, ~ro obtained by the oondon~ation (XII ~ IV ~ V) ~he~ the ~t~1rtlnK m~t~ri~lu . i : o~ formul~ III a~d appropriate a~ Y-~ and ~n~troketones of formula R - C - Alk - NO2 in which Rl and Alk are a~ :
~ 15 de~ined in tho r~rst instance are employed thsreln in the ,~ prosence of a eultable acid catalyst. Xn thls case trifluoroac~tic.
acid is the preferred acid catalyst ''j The nitroketQnes used hereln ~re either ~nown, ~or ex~mplo, l-nitro-2-propanone, No Levy a~d C. ~. Scaife, J. C:he~, .. Soc., llOO, ~1946) and 5~nitro 2~hexan~ne, H. Shechter, et alO~ :~
. ~, , ~ . .
J. A~er. Chem. Soc. ~ ~ 3664 (1952) or they msy be prepared by .~,r,,~ known methods1 for example, ~e0 Le~y and Scaife, cited above, ~, ~ ,S : , ~ Shechter, et al. ci~ed above, ~'Rodd'~ Chemistry of Carbon ~ ~
,~", , l j , Compound~O cited above~ Vol. lc~ p~. 71 - 72 and ~Mothod~
d~r Organl~chQn Ch~io"~ c$ted above~ Vol, XJl, 1971~ p. 203, ;"
. ~
` I
.. . .

, ..

: , .
: .
. . ` ~

..

- ~ AHP'5786/5921 .

~365~6 - Thereafter, these intermediates of formula V are reduced with a complex metal hydride, preferably lithium aluminum hydride, fo afford the oxazinoindo-les of formula I
in which Rl, R2, R3, R4, R5, R6, R7 and X are as defined in the first instance, and -Alk-NR8R9 is an amino(lower)alkyl in which Alk is defined in the first instance and R and R
are hydrogen.
If desired the latter compounds may be N-alkylated . . .
according to the methods described in section (c) to give the compounds of formula I in which Rl, R2, R3, R4, R5, R , . R and X are as defined In the first Instance and Alk-NR8R9 is an amino(lower)alkyl Tn whcih Alk, R8 and R9 are as defined In the flrst Tnstance.
~g) Preparation of Come~u_ds of Formu!a V ~Z = A!k-NR8R9) _ IS Compounds of Formula I
The above described starting materTals of formula 111 in which R , R3, R , R5, R , R and Xl are as deftned in the first instance are condensed in the presence of an acid catalyst with an aminoketone of formula RICG-Alk-NR8R9 in which Rl, Alk, R8 and R9 are as defined in the first instance to give directly *he oxazinoindole derivatives-of formula I
of this invention.
The requisite aminoketones for this reaction are either known, for example, I-dimethylamino-3-butanone, 1-methylamino-3-pentanone~ see F.F. Blicke, cited abov~, or they may be prepared by known procedures, for`example, see "Methoden der Organischen Chemie", cited above, Vol. Xl/l, pp. 58-62, 285-289 and 508-509.

. .
'',''' ' ~

. ' , , ~ - AHP'5786/5921 ~03659~
In practising this present condensatiron it is generaily advantageous to utilize substantially equimolar amounts of the starting material of formula lll and the aminoketone in the presence of an acid catalyst. In this particular condensation the amount of the aforementioned acid catalyst to employ ranges generally ;
from about 1.01 to lOO molar equivalents with respect to the amount of aminoketone reactant, a range of from 1.05 to lO molar equivatents being preferred. Optionally, one may employ the acid addition salts of the aforementioned aminoketones, for example the hydrochlorlde or the sulfate salt. In this case the amount of acid catalyst may range from O.OI to lOO molar equivalents, preferably . , .
0.1 to 10 molar equlvalents. Boron trifluorTd~ is a preferred ac1d ca~alyst for the present condensation~ The reactlon may be performed conveniently and advantageously without a solvent, although a high boiling solvent, for example, toluene, o-xylene or Isobutyl ether, may be used. Reaction time and temperature depends on th~ particular reactants employed and may be varied.
The most convenient reaction time is from one-half to 48 hours, ~ preferably one-half to four hours, and reaction temperatures i!'j: 20 from 20 to 200C, preferably 60 to 140C. The reaction in each individual case is performed preferably at the lowest temperature at which the reaction proceeds smoothiy and expeditiously with a minimum of decomposition.
In the case where the starting material is one of formula 111 in which X is -S-S03Na or -S-S03K, it is preferable to have at least one equlvalent of water present in the reaction mixture. This water may be added directly to the reaction or it may be included as part of the acid catalyst. Examples of the iatter instance would be when p-toluenesulfonic acid containing ..
water of crystallization or concentrated hydrochloric acid are employed as the acid catalyst.

The following Examples illustrate further this in~ention.

, AHp-5786/592 1 ~ ~36S9~
~,7' EX~fPLE 1 `~

, ``'' :`.`
.- 5 Procedure A:
- , Commercial ~-butyl llthium in hexane (3.05 mole) i~
diluted with 1000 ml o* dry tetrahydro~uran (THF). ~o this cooled (-10 to 0C) solu~ion the 6tarting material of ;. ~ormul~ katole (393 g, 3.0 mole) in 1000 ml of dry T~P~, `
: 10 i8 add~d dro~wise. 'rhe reaction is stirred at ~he sdme low .... :
`. temperature ~or 1 hour and then 300 ml o~ ethylene oxi~e in ~00 ml of dry ~ ~ i8 added to the mixture. The temperature o~ the reaction iB allcwed to rl~e to roam temper~ture and ,, at thi~ temperature the reaction i6 stirred overn~ ht.
", ~ .
~ ~ i~ ~vaporated and the re~idu~ id di.~olved in i methylene chloride and wa~hed with concentr~ted HCl. The ,~ methylene chloride solution i6 then wa6hed ~ith 10~ ~odiu~ -.

. bicarbonate, w~ter and dried (MgS04). The solvent i8 ; evaporated and the product di~tilled at reduced pres~ure to ~.

.. 20 gl~e the title compound, b.p. 124C/0.25 mm.

''~ Procedure B:

:~. The ~tarting material o~ iormula II, skatole ' : (35 g, 0.276 mole) in 300 ml of dimethylformamide (D~F) i8 ` ~ :

,: .
~: adaed dropwi6e to stlrred mixture o~ 60dium hydride (14.0 g, 55 - 25 oil dispen~ion) i~ 325 ~1 Or DMF. ~he mixture i6 heated at ~i 40C ior two hours. A~ter cooling 1~ an ice-water b~th ethyl ;~
.:
~:, bromo~cetate tll6.5 g. 0.7 mole) is added dropwise keeping :,' , the temperature belcw 20C. After the addltion, stirr1n~ i8 i; ~ .
'' ~' '`

': ,, : '' ': , ., :.
_30-- .

A~IP~~786/592l ~ 1036sg~
. : ,.
~- continued for fi~e minute~, and then ~ater added cautiou~ly to destro~ ~ny excess hydride. ~he reaction mixture i~
partitioned between water and ether. ~e ether layer washed ~lth wQter, dried (MgS04) and evaporated under reduced pres~ure.
The residue, 3-methyl-indole-l-acetic acid ethyl , " eBter, iB di~solved in 900 ml o~ methanol, potassiu~ hydroxide t90 g) in 400 ml of l:l methanol-~ 0 is then added. The mixture i8 stirred at room temperature for 1 1/2 hours. ~;~
;!, ,:
- The methanol i~ evaporated under reduced pre~u~e. The ' 10 re6idue iB dlluted with ~ater (800 ml) and extracted (3x) with ether. Acidi~ication with 6NHCl of the aqueouB ph~e yields ~-methyl-indole-l-acetic acid, m.p. 174-176C.
; The l~tter compound ~1~7 5 e, 0.25 mola) in 1000 ml o~ ether 18 ~lowly added to a stirred mixture of ,'~,;, i .
~ 15 lithium Qluminum hydrlde (l~.5 g) (0.~2 mole~) ln 700 ml . . .
o~ ether. The reactlon i~ keptbelow 15C u~ing an ice-watel bath. The reaction i6 stlrred for fiftecn mi~ute6 after the addition, the exces~ hydride destroyed ~i~h water, and the precipitate collected. The ether ~iltrate i~ waæhed wlth ; 20 water, drled o~er sodlum Eul~ate and evaporated under reduced pres6ure to ~ord an oil. ~Chrcmatography on ~illca gel uBing 15~ ethylacetate in benzene as eluant gives the ; title cQmpound, identical with the product of procedure A.
.. . . .
By ~ollowing the procedure A of ~xample l other 1 25 indole-l-ethanol intermediDte~ o~ formula III for exDmple i thoDe li6ted i~ Exal~ples6to 55, may be prepQIed by the -. , ~
. . . .
,: ' ~ -31-.;~ , . . . . .

:

'.',' - ~036596 , appropriate choice o~ the 6tarting material of formula II and ~;-ethylen~ oxlde derivative. For example, by replacing ~katole and ethylene oxide with equivalent ~mount6 o~ 3,7-d$methyl-indole, R. Robin~on et al., cited above, and 3,3-dimethyl-: 5 1,2-epoxybutane, V. Franzen and H,E. Driesen, cited above, ~,~
respectively~ a mixture o~ ~-isoprQpyl-~,3,7-trimethyl-indole-l-ethanoL and a-isopropyl-~3,7-trimethyl~i~dole-1-e~hanol~
are obtained. Such mixtures o~ po8ition~1 isomer6 may be separated by fractional distlllation, fract$onal recrystalli~a-, ~ 10 tion or chron~tography. Likewi~e, the replace~ent of skatolewith 3-l~opropylindole, R. Robinson et ~1. cited abo~e, in ;;
prooedure A o~ Exam~le 1 yields 3-i~opropylindole-1-ethflnol.
By followin~ procedl~ B o~ Exnmple 1 other indole-l-et)~nol intermedlates of ~ormula IXI ln which R2 and R3 ~ 15 are hydrogen may be prepared by the a~propriate choice o~
; the starting material of formula II and a-haloacetic acid ; lower alkyl e6ter o~ fo~mula LCR4R5C00-(lower alkyl) in which ~ L iæ halo and R4 and R5 are hydrogen or lc~er alkyl. For ;1 example, by replacing skatole and ethyl bromoacetate with equivalent amount~ o~ 3-ethylindole, R. Robinson et al., cited above, and 2,3-epoxybutane, F.G. ~ordwell and P.S. Landi6, J. A~erO Chem. Soc., 79, 1593 ~1957), respectivelyJ ~,~-dimethyl-, 3-ethyl-indole~l-ethanol-is obtained. Likewise the replacement o~ skatole with 3~butylindole, R. Robinson et al , cited above, ln the procedure B o~ Example 1 yleld~ 3-butylindole-1-eth~nol.
.. . .

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., -32- . :
, '. :

; AHp_~786 /592l )36596 - ~;XhMP~E 2 _~ .

R - C~ snd X

Procedure A-M,N-dicyclohexylcarbodlimide (9.0 g) i~ ~dded to a cool.ed~ stirred solution o~ 3-methylindole-1-ethanol (3.0 g~
in 30 ml of dimethyl ~ulfoxidebenzene (~:1) cont~ining trifluoroacetic acid (o.6 ml) and pyrldine (1.12 ml). ~he reaction i~ stirred at room temperature under nitrogen for 5 hour6. ~he reaction mixture is now diluted with 300 n~
.;. ..................................................................... . .
,~ o~ ether~ followed by the dropwise addltlon o~ a 601ution .... .
o~ oxalic acid (3.78 g) in 11 mL o~ m~thanol. After thirty minute~, water (300 ml) i~ QdAed and tha insoluble material 1~ collected. Ihe org~nic pha~e i~ wa~hed with w~ter (2X), 5~ aqUeoUB sodi~n bicarbonate (2X) a~d water (2X). A~ter drylng (M~S04) the oreanic phase iB evaporated to yield 3-methyLindole-l-acetaldehyde. The latter compound i6 therl ; converted to lt& corresponding gem-dithiol wlth hydrogen 6ul~ide ~nd reduced with lithium ~ inium hydrlde according to the method o~ T.L. Cairn~ et ~1. , J. Amer. Chem. Soc., 74, -~
3982 (1952), to yield the title compound,~ Cm~C13 2570 cm~l.
~ Procedure B:
.: ' To a stirred æolutlon o~ 7 2 g Or 3-methylindole-l-ethanol, described in Ex~mple 1, in 500 ml. o~ dry ether (lce bath) i8 610wly added 1.2 ml of phosphorus tribromide ln 100 ml o~ dry ether. A dark red olly complex ~cparake~.

The reaction ~ixture iL stirred 36-48 hours at room temperature~
then decomposed with ice and water. 'rhe separated ether-layer ...

, .
' :
~ : .

~ ~IP-57~6 /5921 ;~' , :'~ ~ ' ` ~ ~036S936 `~ -~ quickly ~rashed~,Tith a 10~ ~olu~ion o~ s~dlum blcarbonate .; and with water again, drled over calci~ chloride for 2 mi.n., .
decan~ed, and dried over magne~iu~ fiulfate for 30 min.
The ~lltrate i~ evaporated yieldine 1~(2-bromoethyl)-3-me~hyl-: 5 lndolo.
A eolution o~ 10.4 e. o ~odium th~o6ulfate in 60 ml~
o~ wat~r and 100 ~1. of ethanol i8 poured onto 806 g. ~f :
1-(2-bromoethyl)-3-methylindoleO The reaction mixturo i~ 6tirred ; . . und heated at reflux for 3.5 hr., nllowed to cool~ and evaporated to dryne~s~, The solid residue i~s dissolved in boilin~ i~opropanol~
driod w~.th a hydrate~ alkali--alu~inum ~;ilic~to (~Moleoular Si~vos~
and filtcred~ Chlllin~ of ths filtrate cau~ie~ 6 ~ of the aodiu~indolylelhyl thlo~ulf~te derivative to proo~pltat~. ~hl~
oateri~ collect~d by filtration ~d washed with ethor. Th~
isolatod intermediaeo io heatcd at reflux with a solution of .sod~u~
hydroxide (9 g. of NaOH, 60 ml. of water~ 140 ml, of ethanol) for ~:. 3 hr. Ethanol i8 removed under reduced pres6ure~ the aqueous rnsiduo dilutea with wator and extrac~d with thr~e port~on~ o~
~ther. Combined ether cxtr~cts ~re wa~ed ~th wator, ~aturatod brino ~olutio~, and dri~d o~&r magne~iu~ ~ulfate. The filtrate io ovaporated; to yield bia-~2-(3-methylindolo-1-yl)ethyl~disulf~do.
. Tha latter product (1.4 8.~ in 100 ~1. of dry ether `` i8 dropp~d into a ~tirred 6uspensio~I of 600 ~g. l.iAl~4 in 80 ~1. :
;` of drg other. ~hc reactio~ ~ixture i~ heated to reflux for 3 hr.
and tben ko~t forl5 hr. at roor~ temp~rnturo. Docor~po~ition with 2.8 ml. of water ie carriod out in ~ ~tr~arD Or nitrogen. After ., 60 ~in~ of ~tirring~ a white prooipit~to i~ filtered off with ~uction, t~o cako W~B w~h~d wlth ether~ ~nd tho flltrate driod ,'' . :

.: .
: ' '.
.: ' ' ' , - AHP'5786/5921 .. ''', ~ . .
`.;. .
." , :
~ 1~36S9~- ;
over magnesium sulfate. The clear ether solution is evaporated to give the title compound.
Alternatively, the collected sodium indolylethyl thiosulfate derivative ~6.4 9) is suspended in 100 ml of 50%
phosphoric ac7d and 35 ml. of ether. The mixture is stirred at room temperature for 18 hr. The ether layer is separated and tne aqueous layer stirred with 35 ml. of fresh ether at 40C. for 18 hr.
Thereafter, the combined ether layers are dried (MgS04), filtered and evaporated to give the tTtte compound.
By followlng procedure A or B of Example 2 other tndole-l-ethanethlol intermedlates of formula 111, for examijle those descrTbed in Examples 57 io 106 may be prepared by the approprtate chotce of Indole-l-ethanol intermediates of formula 111. For example, by replacing 3-methylindole~
ethanol w7th an equivalent amount of ~-isopropyl-~-3,7-trimethyl-indole-l-ethanol, ~-isopropyl-~,3,7-trimethyl-indole-1-ethanethiol is obtained. Likewise, by replacing 3-methylindole-1-ethanol with an equivalent amount of 3-isopropylindole-1-ethanoi, 3-isopropylindole-1-ethanethiol is obtained.

..
~ 20 .:....................................................................... .
., ' ' ''':
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, ~I , ~35-.

.

! - " AHP-5786/592l 3659~ ~ ~
... , . :
.-. ~ ....
. ................................... , ~
i -- ' .,",,, ~
. i~dole-l-acetic acid (V, Rl and R7 ~ CH ~
COOH ) .

. .
; A Dlxture o~ the intermediate o~ formula III, . 3-methylindole-1-ethanol(26.5 ~ 0.15 mole), de6cribed ~n Ækn~ple 1, ln tolue~e (600 ml.~, ethyl acetoacetate (36 g., ... . .... .
0020 ~olo) and ~-toluenesul~onic acid (2.0 B.) ~ heated at .
ro~lux ~or 6 hr. U8~ng ~ water separator. The toluen~
. :
~ ' 801ut~on ~8 washQd ~ith w~ter, 5% bicarbonate ~olution, und :1 again wlth waterO The solution i8 then dried o~er sodlum ; . nulfate and the ~olvent eYaporated under reduced pressure ko Bive an o~ he oil was ~ub~ected to chromntoerAp~ on 1l 15 ` ~il$ca gel. Elutlon with 10~ ethyl ncet~te in ben~ene and ,., . . concentration o~ the eluate ~fords the ester, 3,4~dihydro-l;10-dimethyl-1~-1,4-oxa~ino~4,3-a]indole-1-acetic acid .~ ethyl ester~ as ~n oil~ ~ fllm 1725 c~
, I - . .
roly8iB o~ thiB ~ster to th~ titla co~pound i8 :; ~ 20 offected ~8 ~ollows: The ester (39.9 g.~ i~ dis~ol~ed in ¦ 800 mL of methanol contai~ing 22.5 g. o~ K0~ in 20 ~1. o~ .
uater~ A~ter stirrin~ for 5 hr. at 50C~ and for 12 hr~ at .- .
. ~ room temperature, the solvent is e~porated under reduc~d . pressure. The residue i8 t~ken into ~ater and washed twice .~ 25 ~th ether, acidifled with 6N HCl and extracted with ether. ;`
.:. . ,i .
. . The other ~olution i8 waRhed once ~ith vater, dried (Na2S04) !;~' - ~' and ~porated under reduced pre6sure to afford a ~olid. The . ~olid i8 recrystRllized from petroleu~ ether to afford the t~tle co~pou~d~ ~pO 138 - 139C., n~r (CDC13) ~1.75 ts, 3~), 30 2006 ~nd 3~18 (d, J ~ 14.5 cp~, 2~I), 4.07 tm, 4H). :~
. ,' . ', .
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~ ~HP-5786 /5921 . ~ .
', . ' . ~.
1~365916 An equivalent amount of methyl Rcetoacetat~ may --replace ethyl acetoacetate in the procedure of this ~xa~ple.
In this case, 3,4-dihydro-l~lO-dimethyl-1~1 194 oxazinoL4~ a~-indole-l-acetic acid methyl e6ter is obtained as th~ efitor.
~n equi~alent amount of propyl acetcacetatc ~ay replace ekhyl ac~toacetuke in the procedure of thi~ Ex~m~le.
In this case~ 3~4-d~hydro-l,lO-dimethyl-lH-l~4-oxRzinoC4~3-a~
indole-l-acetic acid propyl ester i~ obtained a6 the e6tcr.
,.
:,'. ;' . i "
'.': "

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

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

.. .... ..

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~ ...... . .

AHP-5786/59~l ~

.:, ':

,~''' ~ ' ' ', A mixture of the intermedi~te of formula III, 3-mothylindole-1-etha~o} (29.7 e.. 0.17 mole), de6cribed in Example 1, ethyl leYulinate t26.96 g.~ 0.187 mole) and E~toluenesulfonic acid (2.25 g.) in dry benzene (650 ~

- i6 refluxed with ~tirri~g for 12 hr. with hydrated alkal i-~luminum ~ilicate (~olecular Sieves ~ 4), The benzene ~olution i8 wa6hed with 5~ aqueous Na~lC03~ followed by ~ator. Concentrations of the ~olution g~vo a rosiduo~ ~hich .. ,.. , _ . , , ,,,",, ~8 pa~sed through u ~ilic~ gel oolumn using 15~ athyl acetate in benzene to afford the e6ter, 3,4-dihydro-1,10-dimethyl-~ 1,4-ox~inor4,3-a]indole-1-propionic acid ethyl e6ter, -~

; a~ ~noil, ~ m~lC13 1730 cm~l.
: I . . ....
Thi~ e6ter (41.9 ~ dissolYed in 650 ml. of methanol co~taining 23 g, of K0~ in 50 ~1. of water and heated i _ at 50C. fer 1 hr. The solvent i6 eYaporated and the residue talcen into water. The aqueou~ ~ixture is wa~hed with ether twi¢e~ acidified with 6N HCl and extracted three time6 with ether. The ether ~olutio~ i6 wa~hed once with water, dried 25 - ~ orer HgS04 and eYaporated, under reduced pre~6ure to yield solid. The 601id i6 recry6tallized from ethyl acetate-.. , ~, . .
petroleu~ ether to ~i~e the title compound~ m.~. 115 - 116C.
nmr (CDC13) ~1.62 (B~ 3H), 2.30 (m, 7~), 4.04 (4~), 7.21 - 7.52 , 4~), 10.~3 (1~).

.
.~

' ; ~ .:
:
. .

- ~ ~ 38 AHP-5786 /592l ~, ' .

~36596 A m~xture of the ~ntermediAte of for~ula III, 3rmathylindole-l-ethanol (500 mg.), levulinic acid (580 mg.)~
75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diato~aceou~ earth (Celite) i6 Btirred magnet~caïly at roo~ temperature for 15 min. and then at 70C. for 1 l/2 hr.
The reaction mixtura i6 filtered. The filtrate ~ wa~hed three times with 5N NaOH; the co~bined aqueous pha~e i8 washed t~ice . . .
- with ether and then rendered acidic with coId 5q% ~ICl. ~he ~queous pha6e i~ extractcd with ohloroform. The chloroform oxtraat is dried (Nn2S04) and e~por~ted to dryncas~ Roary~talliza_ tion of r~iduo from ethyl acetato-petroleum other ~ford~ tho title oompound, identical to the nroduct of nrocedur~ A of this Example~
The procedure of Examples3 and 4 (Procedure A) may "; .
be followed to prepare other intermedlate6 of formula V in ~hich ~l, R2, R3, R4~ R5~ R6, R7, X are as defined in the first i~stan~e and Z ts COOR10 or Alkl-COOR~O where~n * a~d Alk ~; - Are A~ defined in the first i~tance. Ex~mple~ of such compou~ds are listed in Tables I and IIo In each of these ~n6tances ~ntermediate of formula III and ketoe~ter listed . .
therein are u~ed in an equivalent amount to the intermediate~
~ of formula III and ketoester6 listed in Examples 3 and 4 ;~ (Procedure A). Note that in each of the6e i~stance~ ~n ~ OBter i6 obtained pr~or to hydrolysi6. Thi~ ester is th~
corresponding intarmediate of formula V in which Z iB
~, :' ' , ' .' " ' ~.
-~Ce I i te I s a trademark "''~ ''~ , ...
.. . , . ~
~.:, I .
:
' ' ' " '`' .

~ 39-~IP 57S6 /592 1 r ~.
. ~ .
~365~6 : CCO~ or Al~l-COO~ wherein ~ i8 lower al~yl ~nd Al~- iu defined in the fir~t instance, the alkyl p~rtion of said ;' i e~ter being derived from the R portion of the ketoe~ter '!~
of Pormula IV employed thereinr ~lkewiee, the procedure of Æxample 4 ~Procedure B) may be used to prepare the product~ listed in Tables I and II `
.: except that in thi.B case an equivalent amount o~ the correspondin~
ketoaoid of formula IV i8 u~ed in~tead of the k~toe~ter list~d in the table. `; `

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A~-5786 /5921 ~ 6S~
, ,, ,,~ i-, .

- FORMULA IV PRODUCT: (PREFIX LIST~. -.IN~ERMEDIATÆ OF . . ~ 4_0XAZINO~4~3-a~ DOLF
. eXAMe~ FORMULA III IN ~IICH ~ IS 0~ Rl_c_Alkl_CO O ~ l-(SUFTIX LISTED BEIO
,''.. ' . ,.. , ., . _ , . ,, . _ ........... _ . ............... _~
. I . .. . R2 R3 ~4 R5 R6 R7 Rl ~ -C R10 . ~REFIX//SUFFIX .
:: 5 ~ H ~ H H C~ CH3 CO C ~ 5 l,10-diQethyl// ~ .
.. 10 . carboxylic acid -: 6 c~3 H H ~ ~ C~3 C2H5 CO C2~5 1-cthyl-3,10-dimethyl/, ':.-" ; . . . carboxylic ~cid ::
;:I 7 I-C ~ H ~1 - ~ 5_C ~ C ~ i ~ CO c~3 1,3-dii~opropyl-8,10~ .
; . . . l . . ; . ~ hyl~,/carboxy~ic 8 CH3 CH3 H H 5-OH 3 CH3 CO c~3 totra~thYl~/
~5 15 . . carbox~llc ac~d 9 H H H H 7-C2R5 C2~15 n ~ ~ CO ~ 6~10-diethyl-1-propy~
. . I . c~rhoxylic acid . io ~ H i-a3~ H ~ ... L- ~ D co ~ l-cyalopPropy -~,10-: _ : . : ~: - .................. carboxylic acid : 20 . C ~ CH3 C2~5 C2~5 C2H5 ~ CO CH3 1-cyclopentyl-4,4,10-~: carboxylic acid . . 12 ~ ~ C ~ H ~ - C~3 CH3 ~H2C~ C2H5 ~ 4,10-tr ethyl~/

13 ~ ~ ~ ~ ~- - C~3 C2~5 ~C~2c 2~5 l-ethyl-10-methyl~
14 X ~ ~ H H C ~ ~ ~ CH2C ~2~5 AC~tiC acid, m.p~
- ~ ~ ~ 1 ~ L
,,.,, .~
'., ., .: " _~ . .
~ L~3 6 S 9 6 TABLE I
,., ~ ' - . ' ~-: ? - -- - . ... ... . ~ -., ' . :-:
.. : . 5 }Ea~t)ESTER OF PRODUCTo (PRE;FIX LISTED ;
": ~ . INTERME;DIATE OF FOR~A IV, B~)W) _3 ,4-DIi~YDRO_l}I~,~ . .
; ~ . E~E FO; 2M~L ~ III I~ WHI( II Xl IS O~l R~ CO .OR10 l-(SIJ~l?IX LISTI~;D B~;LOW) :

: ~2 R3 R4 R5 R6 R7 R L Allcl_co R10 PREFIX//SITFFIX
. _ . _ _ ._ . I 15 H R ~ ~ H C~3 ~C3E7 C~2C C2H5 ~ opropyl-10-methy~!
: :~ . . . acet~c acid ~
16CH3 ~ ~ ~ H C~3 ~ c3~ C~2C~ C2~5 3,10-dimethyl-1-propyl~/ .. : .
~ceti¢ acid t, ? 17CR3 H C2~5 c~3 H C~3 C2~5 aH2C C2H 1 ~4-diethyl-3 ~10- : .
.; . 5 d~methyl//acetic acld ¦ ~ .18 H ~ H ~ H ~ C ~ ~ ~ C2H5 ~,l,10-tri~ethyl// .
. . . . acet~o Acld .
19 ll ~ H ~1 H ~2H5~ ~ ~ C2~lS ~;~-dimethyl//acetic . ~cid :; 20H H H ~ ~ C ~ -C ~ CX2C C2H5 l-t-butyl-10-methyl//
; . . acetic acid ' _. 21~ H . H H C~3 -c4~ CH2C C2H5 l-butyl-10-~ethyl// ~:

. ZO 22H: H H H 7-C ~ C2~5 -C3H~ ~2G C2~5 propyl~/acetio a~d - 23H H H H 5_Br C2~5 C2~5 ~2C C2~5 8-brom~-1,10-d~ ethy~ f /

24 ~ ~ H ~ 5-~C~ ~R~ c~3 CH2C C ~ 10-butyl-8-methoxy-1- .:~
. . ~ethyl//acetic aci~
¦ 25 H ~ X H 5- t- ~ CR3 C ~ CO C2H 8-acetoxy-10-t-butyl-i 25 OCOC~ 5 l-methylt/acetic acid '. ...
: . 268 H ~ H 5b~ 1 ~ ~ c~3 C~2C C2H 8-benzylo.~y-10-. . ~ . oxy 5 i~opropyl-l-methyl//
. . _ _ _ _ . ~ . _ . acot1c ac1d ,''' ,_ ." ~.
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A~-5786 /5921 , .
)36Sg6 ,..... : .
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. `. KEI~OES~E2 OF PROD~CT: (PRI:FIX LISI~:D .
~ERME;DIA5~E 0~ FOR~A IV~ 23ELOW) ,.3,4~DIHYDRO-lH-l, -, . O 4-OXAZIN0~4~3-a]INDOI~:_ :,. E~ F~ ~RM L4 III IN ~HIC~I X IS OH R~ ~c~ o 0*O l-(SU~FIX LISq'3 Bi~OIl) ." R2R3 ~4 R5 86 - R7 R~ ~Q R~ PREFIX~/S~TX
27 H El ~ H 4-CR3 C,~3 n~C3H7CH2C ~2~5 9~lO-dimeth 28 H H H ~I 6-CH3 C~3 n~C3~l7CH2C ~2H5 acetic ~cid :~
Z9 ~ H H H 5.. N02 ~C~17 ~-C3117 CH2C C2H5 ~

~0 E~ ~ CH3 c~3 H C~3 ~-C~H7 C1~2C ~2H5 propyl//ncetic aoid . ~ ~L CH3 '~3 ~ ~ 5-OC2~5 C2~5 D CH(C~ C2}~5 l-cyclopropyl-~,lO-. triethyl-3,3-di~ethyl-~-. ethoxy//acetic acid 32 CH3 3 C2~5 a2H5 6-C2~5 n-C4H9 O C(C~3)2C C2H5 ~a~l3_tetra~ethyl-4~4~7 .
: . . trlethyl//acetic aci~
33 C~3 H IC~ nC ~ 4-n-C ~ Ca3 ~2~5 CH(CH3)C ~H5 4,4,9-tripropyl/~acetiYc ac~d ~l 20 34 H ~ ~ H ~ C2H5 3 ~ C(c~3)~c C2~5 a,a_di//thyl-lO-ethyl-l-C2H5 ~ C2~5 C?~5 4-C2H5 C2~5 t-C4~9 C~_C ~ ~ ~2H5 li' opropyl-3;3,4,4~9 t 10-I . . ~ . e3aethyl//acetic acid .1 35 ~ ~ ~ ~ 4-~ C ~ 7 CH CH CO H O-m~thyl-9-$odo-l- , I . 3 2 Z 2 5 60propyl//propionic aoid 2~ 37 C~3 J~3 C~3 C~3 7~ ~C ~ ¦ 2~5 C2H5 C ~ H~ ~ C2Hc 5~ cetlox4-l,lO-dieth /-;1 . propio~ic acid . 30 ~ b b ~ 6-Ob 3 ~-C3~ C~C ~ C C ~ tbyl-l proipy~ _ ... . .

. I
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.. ; ; l~OESTi:R OFPRODUCT: (PREFIX LISTED :
. FO~UI.A IV~ BE.OW) _3 ,4-DI~ o-~
: 5 INTERMEDIhT~; O~ 1 ' 1 10 4-OXAZINO~4,3-a~ OLE-,, l~X. FOR :ULA III IN W~ ~CH Xl IS OH ~ _d_Allc -CO-OR l-(SUlTIX LISTED B~:TO',~)~ ;
=~ R2 E~3 ~4 B6 R7 Rl A ~ co * PPEFIX//S~IX :, 39 C~3 H H ~I 7-NO2 C~3 ~2 C2~5 L-cyclobuty -3 ,10- , . propyl//propior~ic acid. . .
40 ~I H 3 H 5_CH3 C~3 ~ ~)2 ¢~Z C2~5 -cyclopropyl~ ,4~_ , I . ?rop~onic aoid ., . ! ! .
41 c~3 ~ ~ H ~ 3 C ~ ~ ( ~ 2C ~2H5di~ropyl//proplonlc . . uoid 42 3 ~ C2H5 C2~5 ~ CH3 C2H5 ~H(C ~ 0 0~3 a ~,3,10-p ntamethyl- :
~. propionic acid ~ 43 ~ H CH3 CH3 H C?H5 C2H5(Ca3)2~ C0 CH3 1,10-dlethyl-~,~,4,4- , .' . ~. tetramethyl//propionic-:, . . aoid . :
44 ~ ~ ~ H ~ ~ C2H5 CH3O ~ ~ ~ ~ C0 CH3 l-Gyclop2ntyl-10-methyl- .
. . ~-propionoxy-4-prop71- . ~ .
.~. . . . a,~,~-trlethyl// : ~ -. . . . propionic acid , 45 ~ H ~ ~ 4-ocH3 C~3 ~-C3 ~ CH2~HtC ~ c2 ~ a,10-dimethyl-1,3-~-I . d~propyl-9-methoxy/~
pro~ionic acid :.
46 Cz~, H H ~ 5-N02 C~3 CH3 ~ ~ C2~5 a,~ , 3-pentaethyl~/
;,~ . . propionic aeid 47 c2~ 2~ H H4_C2~5 CH~ n-C~ ~t~ ~ C~ ~ ~H3 ~,~-dipropyl-3,3~9,10-l25 , . tetra~thyl//propionic: . ~ . acid :
48 ~ ~ ~ H 6-OC2~5 C2H5 D ~ C2~5 1-cyclopropyl_7_;thoxy-. . propionic ~cid .1 . _ _ _ . . ~ _ - I .
.. . .

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_ A A_ 3659~i . . , i . ~
,.: . .

.,, l , _ . , _ ... . . ... _ _ ! . ~ - . -~ERMEDIATE O~ ~ IV~ ~ 3EIOW)-3,4_DIIDDRO~
Et. FO~ :IJLA III }~J W} rCR Xl . i OH Rl_C_A11cl_CQ OR10 --~SlEEI~7~,a;~IlRDoI,3 -- R2 R:3R4 ~5R6 R7 Rl Alkl_CO R10 PR~IX//SU~FIX
.. 5. 49 t~ 8 H 8 II C~3 c~3 2 2 2 C2~5 l,10-di~ethyl//butrric . 5o C~3 ~I H 1~ ~ 3C2~5 ~ 83)CH2CH2CO C2H5 l-e th~ Y~3~10-t~methy~

51 C~ c~3 ~ 8 ~ C~l-C3~7 ¦ (C~ )2C~ ~CC C2H5 Y r-diothy~ pr 10 . butyricaoid 52 ~2~5 ~ ~I -N02 ~2~r5 ~-C4~9~ CC~C~3)2J3C C;2~g n;tro-a"B,r-trimethyl/; .
. . butyric acid .
S3 ~ CH ~ ~ ~ -n-C3~, ~ n-C3~7 C~(~2Co C2~ 1 9~1o-triypr3op3~ eth;

. butyric ~cid 54 ~ E~ ~I }~ 7~H ~Hg C2H5 ~ )2Cc C2~I5 10-butyl-l_ethyl_6_ .

~, tetra~ethyl//butyric ., 3 ~ CH~5 H -C2R5 ~9 C2H5 ~ 2~3 C2~5 10-t-buty~l-9-ethoxy-1- :
~ 20 . .= 'octamethyl//butyric acid :~ 55a H H H H H 2H5 CH3 CH~CH2C0 C2H5 10-e~hyl l-methyl// ~:
. ~ propionic acid , Z5 . m.p. 119 - 121C.
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AHP-5786 ~592 1 - - ~ 36S~6 ~ -TABIE II `~

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. . PR~)DUCT: (PREFIX .
' !i ' . . . ~OESTE~2 0~ IISTED ~W)_3,4_. ~;)R~SULA IV, . . DIHYDRO_l~I_l o4-THIl~ .:. . INT~EDIATE ~F ~ . . ~4,3_a~INDOI~
EXA~IPD~; . FOR11tlLA III IN W~ICH Xl I~; S~ ~l-C~ kl_CO OR10 ~SU~X LISTE~D BEI.O'~) '. . _ ~ _ _ ., . -v ., ~.
R2 R3 X4 R5 R6 R7 Rl A~kl C R10 PR~FIX//SUFTIX ._ .
. . El ~1 H El C~3 C~3 CO ' C2~5 cnrbo~lic acid :

. ~ 57 CH3 ~ ~ ~1 ~1 C~3 C2H5 CO C2H5 1 cthyl-3,10-di~et~y~i/, 10 ~ i-C~ H ~1 ~ 5_CH3 C~3 i ~ CO c~3 l ~3-d~ i80propyl-8~10-. . . . L~thyl~/carbox~rlic , .
: . . aoid . 59 C~3 C~3 H H 5~~ C~3 C~3 CO C~13 8-h~droxy~ 3~10-:: . . . earboxylie acid :
, 15 60 ~H H ~ ~ -C2~5 C2~5 nJC~ 7 C0 C ~ 6~10-diethyl-1-propy~//
. , . . e~rboxylie scid 61 ~ ~ i-C3 ~ ~ ~ ~ ~ D coCH3 l-eyel oprol7/-4 ~ lo .
:'.; . earboxylie aeid ~
62 C~3 3 C2H5 C2.H5 ~ C2~5 ~ C0 CH3 1-eyelopeAtyl_4~4~10- ~:
. 20 . . . .................. triet~yl-3,3-dimeth~
. . . . ~arboxylic aeid `
63 X ~ H 3 3 .CH2c C2 ~ L,10-dim thyl//

64 ~ ~ ~ ~ ~ ~ C ~ C2Hg C~2C ~2~5 l-ethyl-10-mathyl// ..
i- 25 . ~ ~eetie aeid ..
65 ~ ~ ~ ~ H C ~ ~~ ~ C~2C0 ~2H5 10- ~thyl-l-pro yl/; ;~
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I AHP-5786/592l TABLE II
''` ''' ' ,,~, .
. , , . ,_ . . . . ~D~CT: t~XEFIX ~ .
. . XE~OESTER OF ISr~D ~EI0~ 3,4 . INTE~MæDIATE OF FO~ ~LA IV, IHYDRO-lH_1,4_Ta¢AZINO~
.: EX.: FO. ~IA III ~I WHI~ ~ ~ ~; S~ * ~ Alk.-C~ ORlO 4~3-a]INDOLE-l--~ . ~2 ~ ~4 ~ ~6 ~ R7 ~ Alkl C~ ~ PKEFIY//S~FFIX
. ~ 66 B H . H HCH3 l ~C3 ~ CR2C C2H5 l-i opropyl-10-~ethyi~./

67 C~3 ~ H ~ ~3 ~c3 ~ C~2C C2H5 3~10-dimethyl-1-propy~//
acet~c acid 7 ¦ 68 C~3 HC2H5 C~3 H C ~ C2R5 C~2C c~5 1~4-diethyl-3~10-. . dimethyl//acetlc acid : .~ . . 69 tI }l ~ H H IC~3 3 ~(~50 C2H5 a ,1,10-trim9thylt/

: 7o H ~ ~ ~ ~2~5 ( ~ C2}Ts l~oyoloh~xyl-lG-ethyl-. . o~-dimethyl//acetic .
. . ~cid . 71 ~ ~ ~ ~ ~:~ -C4H C~2C C2H5 acetlc acid :
72 H ~ H ~ H 3 -C4Hc ~H2CO C2~5 l~butyl-10-methYl/t .
. . . acetic acid 73 ~ ~ H ~ 7-C~3 C2H5 -C ~ CH2C ~2~5 10-ethyl-6-Gethyl-l-: . . propyl/~acetic ~cid 74 ~ H ~ . 5_Br C2~5 C2~5 C82C C2H5 8-bromo-1~10-dietb~l//
.:. . . acetic acid E ~ H . a 5~ . ~ CH3 C~2C C ~ 10-butyl-8-~ethoxy-1- -.
. . ~ethyl//acetic acid :~

76 ~ ~ ~ ~ 0000~ t ~ c~3 CH2CO C2~5 8_acetoxy~10-t-butyl 77 ~ ~ E . oxy l ~ ~ C~3 C~2CO C2H5 8-ber~yloxy-10- .
` . ~ acetic acid . _ . , _ ~ ~ ._ l ;`
1 ~;
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~ 47- ;
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TABI~ II
. . ",.,~ ' .
.~....................................................................... .
''. ' _ ~ . . - . _ . .. .. .. ~ . ` ,''' .~ . . . . . PROD~CT. (P2EFIX :
. XE~OESTE2 0~' LIS~D BEIO'J)-3,4-.. INTERMEDIATE 0~ FOR~NIA IV, DIHYDRn_~1_1,4_T~IAZlNO_ .
... Fl 1~ LA III IN IC~I ~ IS E~ Rl_C_Alkl_co_oR10 ~4 3_o]INDOL~
--~ ~ R4 ~ R6 ~7 ~ ~ R10 PREFIX//s~FETx 78 ~ ~ ~ n 4_C~3 CH3 n-C3 ~. C~2C ~2~5 acetic ~cid .~ ~

79 ~ H X ~ 6_C~3 C ~ n-C3 ~ C~2C ,~H5 7,10-dimethyl-1-propylJy ¦ 10 80 ~ ~ ~ 5_NOz n_C ~ n-C3H7 CH2C C2~15 8-nitro-1~10-dipropyl//
.. ~ 81, ~ ~ CH3 C~3 ~ C~3 -C3 ~ C ~ CO C2N5 4,4~10-trimethyl-1-: ' l . . . propyl~/aeotie aoid 82 CH3 ~H~ H ~ 5-OC2H5 C2~5 D CHtC~o C2H5 l~eyclopropyl-a,~,10- ...
. . triethyl-3,3-di~ethyl-8-.. ! . . ethoxy//acetie acid 83 C~3 ~H3 C2H5 C2H5 6-C2~5 n- ~ 9 ~ C(CH~2CO C2~5 10-butyl-1-cyclohexyl-~.~ . . \_/ ~ a,u,~,3-tetramsthyl-4,4,7 .~. . . . . triethyl//acetic aei~

2 84 C ~ ~ 1-C~ ~ ~ 4-n_C ~ C~3 ~2~5 C~(C ~)C ~2~5 4~4,9-trip3~pyl// nethyl_ 85 H ~ H H ~ C2~5 n_C3 ~ C(CH3)2CC C2H5 propyl//acetic scid : 86 c2~5 2E~ C2~5 C2~5 ~-C2~5 C2H5 tJCI ~ C~-C ~ ~ C2H5 dii~opropyl-3,3,4~4~9~10- :-~
. .. . . . ~ . ho~aethyl//scetie acid . 25 87 ~ ~ ~ ~ ~ 3 C~3 C ~ C~2CO c~3 l~10-di~ethyl~/ ~
~; . propionic acid , 88 ~ H ~ ~ ..CH~ -.C3H7 CH2CH2CO C~3 10- ethyl-l-propyl~/

.: 89 ~ H H ~ 6-oH CH3 _C3H7 C ~ ~ C2H5 ~,~-diethyl-7-hydroxy . 30 10-~ethyl-1-propyl//
'.' . .__ _ . _ ~. ~ ~',""

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~ 48- .
... . . . . . . . .. . .

~ 1~659~ii AHp-5786~s92 1 ~ ' TA~13 ~I

,. ,, . ~ _ ~_.

. . . . PROD~CT~ EFIX
KETOEST~R OF L~TED BF~ow)-3~4-~NTERMEDI~TE OF FOR~IA Ivr . DIHYDRO-lU-1,4-T~Ih5INO_ .EX. FOR ~IA III ~ ~CH ~ IS S~ Rl_C_Alkl_co_oR10 (S~FFIX LISTE~ BEI~J~
~ ~ R4 ~ R6 R7 R~ Alkl-CO R10 PREFIX//SUFFIX
_ _ . . . . .. __ . . ._ ~
9o c~3 ~ ~ ~ 7-N02 C ~ 0 ~ l2GO C2H5 1-cyclobutyl-3,10-. limethyl-6-nitro-a-. . .. . propyl//propionic acid;
. 91 ~ ~ ~ 5-C ~ C~3 ~ ~ ~ 2C ~ ~ C2~5 3-cyclopropyl-a, ~ ,-. . propionie aeid ¦ æ ¦Od~ d¦ ~ H ¦ d ¦ 3; ¦ C~3 ~ ~r ~ ~ ¦ ~ 5 ¦diprepyl// ,ropiorie 93 3 H a2~5 C2~5 ~ C~3 C2H5 ~C~ ~ a~3 1 1~ 4-tri~tFIyl/~
.. . . . . propionio acid . 15 94 : ~ C ~ CH~ H C2~5 C2H5 (C ~ )2C~2C0 CH3 1~10-diethyl-~,4,4- :
: . . .. 1 tetra~ethyl//propio~e-. .-~_ aeid . . 95 ~.... H ~ H ~ C2~5 CH3 ~ 2C(~ C0 CH3 1-oyeLopentyl410-mO~e)t :: . . : .: ~ ~:- ~ -triethylJ~
. ~ 7 H ~ ~ 4-OC~3C ~~-C3 ~ CH2CN(C ~ c2~5 d;propyl-9-~ thoxy// :
.. . propionie acid 97 ~2R5 ~ ~ ~ 5-~2 C ~C ~ ~ ~ C2~5 1~10-d~thyl-8-~itro-. . ~ 9 ~ 3-pel~t~ethyl// . .
. . propionie aeid :
: 98 c2~c 2~ ~ ~ 4-C2~5CH3n-C3H7 ~_C~ C~ ~ 3 ,1-d~pro~;y~-3,3,9,10-~ 99 ~ ~ H ~6- W2~5 C2~5 D ~ o C2~5 -cyclopropyl-7-ethoxy-.. 30 . ~ . ,~10-triethyl//
.. propionic acid .:
~ ' ~ _ _ _ . .. __ _ ,,, . __ . .
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,' ' AHP-5~86/592l ,~
- ~LaJ3659~
. TABLE II
'. , _ . - - .. .. -- -_ , : . . , . ,. . . '.
. . ~ RODUCT: (PXEFIX
. . .. XETCES~ER OF ISTED B~LOW)_3,4_ INTERMEDIATE OF FOR~.~ A IY9 I~Y~120-1~-104-T~IAZINO_ .
. . FOR. ~LA III ~1 ~n~ rc~l xl . s s~ Rl~C-Alk1-CO-OR10 . 4,3-a~J DO E-l_ .: ~2 ~ R ~ ~æ R7 ~ Alk~_CO R10 PREFIX//SUFFIY.:. ' .. ., ... _ ..... _ ~ ~
100 H H H H HC~3 c~3 2 2 2 c2~5 l~10-di~ethyl//butyric lOl¦CH3 H ~ ~ H~ C2~5 ~ ¢~)CH2C~CO C2~5 1- thyl-~,3,10-tri~ethy~

102 c~3 C~l~ H R HClt3 ~-C3}17 ~(C~ )2C ~ ~C{ C2~t5 Y Y-dicthyl-l~propyl~
: . . . . butyrio ~cid 3 2 5 ~ H H _NO~~2~5 n-C4~19 ~C(C ~ )2~3C C2~5 1-butyl-3,10-dlothyl-7-. ~.tro-x,~,~-trim~hyl~/
. . . b~yric ~cid . l5 104 3 C~l ~1 ~ -n-C3~, ~ n~C3~I7 C~ 32C C2H5 a~-diethyl-3,3-di~ethyl . . butyric ~cid . o5 H H ~ H 7-OH L~ ~ C2H5 ~ 2C C2~I5 10-butyl-1-ethyl-6_ . . tetr~methyl//butyric !20 06 ~ ~ 3 H 2 5 ~ 9 C2~5 [C~C ~ )2~3C C2H5 10-t-butyl-9-ethoxy-1-octame hyl//buty ic acid ¦

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h}lP-57~9'i /592 1 :` ~Q3~iS96 , E~AI~PLE 1~7 __ :,'.` -Tr1~eth~ y~ bL_~ ~Y~
~ tam~de _ ~ ~ nd Rf CN~Q~_ _ :' 5 5~
~riothylamlno (6 ~ nd thon othyl chloroformato ~5 gO) Aro add~d to ~ coolod ~o~ution (-5C.) o~ 1,10-di~ethyl-3,~-dlhydro lH-1~4-oxazinoC4,~-R]lndol~ acetic acid (10 e.).
~;; de~crib~d in ~x~mpl0 3, in 150 ~1. of tetr~hydro~uran (THF~r Ator .... .
: 10 being stirred for 2 hrO at 10Co the su~pensio~ i~ furkher ooolod :;
. ` to ou. 10a. ~nd treated with metllylan~rle (66 n~. of the 4 ,~, water ~olution) and ~tirred at el~on tenlperat~lro for an ndditlonal '~' hour, Mo~t of the THF i~ evaporatod and tho roe~due p~rtitionod betweon cthor and wator~ Tho other nolution i~ wuuhod wlth wator~ driod tMgSOl~) flnd ooncontratod to afford a solid. The .. aol~d i8 re~rystalli~od ~rom ethyl ac~tate to ~fford ths titlo -~:. compound, ~.~. 131 - 133C.
,:, ~ . .
; In the sAme ~annor but rcplacing the 40~ Aqueous ,j~t~',, 801ut~0n of methylamine with ~n equiv~lent amo1~t of thP
I 20 am~no~ of formula HNR8 ~ , ammonium hydroxide (concentrat~d~, .: dlmethylamine (30% aqueous ~olution), n-hexylamine t20~ aque~u~
~olution), di~thylamdno (30~ aqu~ous solution~ i80propyl3~ine i`~
~, ~40~ ~queou8 801ution)~ ethylamino (70~ aquoous 801ution)9 1 . pyrrolidine t50~ aqueous ~olution), piperidine, morphol~ne~
.l 5 . N-methylpip~razine, ~:
O~dim~thyl-3~4-dihydro~ 4-oxa~sino~lt~3-~l]indo~ ac~ mid~
1 ~p. 156 - 157C., nmr (CDC13) Sl.69 t3H), 2.33 t3~1), .
- .. .. ..... .. ..

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Al~-5786/592l ~0365 96 :. N9N~l~10-tetra~ethyl-3,4-dihydro-IH-194-oxszino[493 a~indole~
acata~id~, nmr (CDC13) ~ L 78 (3X)t 2~33 (3H)9 2~95 (6H)g 1,10-dimethyl-N-hexyl-3,4-dihydro-l~I-1,4-oxazinoC4,3-a]indole l-acetamide, N~N_d~e~hyl_l~lO_dimethyl~3~4_dihydro_1H_1,4-oxazino[4~3-a~-$ndolo-l-acotamid0, l,10-dimet~yl-N-i~opropyl-3,4-dihydro-lH-1,4-oxazino[493-a31ndolo_ l-acetamido, . . :
l~10-dimethyl-N-ethyl-3,4-dihydro-lH-1,4-oxaz.inoC4,3-~]indole-1-ncetamid~, m.p, lll~ - 116C., .'.l-~(l,10-dimethyl-3,4-dihydro~1,4-oxazino~,3-a~indol-1-yl~-acety l ~py rro l i ~1 l n~, l,10-dimethyl-3,4-dl}lydro~oxazinoC4,3~a]indol-1-yl)-~` ~cetyl~pipqr:ldin~ ,

4-C(1,10-dimethyl-3,4-dihydro-1~-1,4-oxAzino~4,3-a~indol-1-yl)-~cetyl]morp~oline, and ~ ethyl-4-[tl,10-dimethyl-3,4-dihydro~ 1,4-oxAzino[4,3-a3~ndol-l-yl)acetylJpipcrazine, Are obtainod re~pecti~ly.
i . _ B~ ~ollo~ng th~ procedure of Exa~ple lC7 but - 20 u~ing as ~tartlng ~at¢r~al a~ ~quivalent amount of ona o~
- th~ acid compound~ of formula V, de~cribed in Examples 14 .
to 106, instead of 3,4-dihydro-1,10-dimethyl-3,4-dihydro-IH-1,4-oxazlno~4,3-a~indolo-1-acotic acid, and u~ing Rn squ~valcnt amount of an ~ppropxiato a01no ~uch a~ ammoni~
or a pr~mary or s~condary amino doscribod in Exampl~ 107, then the correspond~n~ a~ldo compound of ~ormula ~ iB obtainod.
- . .
.
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.
, , .... .. .....

Al~ 57~6/592 1 ~ 1036S96 Exainple~ of ~uch a~de~ ar~ ted fil8 prOdUCt~ l Tabl~
IY, V and YX together with the appropri~ta starting n~teriQl ~nd a~ne used for the prep~r~tio~ of th~ ~ld~ oach ca~e the st~rtinB mate~*al i8 notod by the exAmple in ~hloh it ls ::
yr~ rod.

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AHP-578~592l 3~i:S96 .

,. _ . . . . ....... _ .. ;.. _ .- . ~
: . NO. OF THE EXAMPLE PXODUCT: [(PP~IX LISTED BElO~)_ .. :. IN WHICH STARrING . 3,4 DI~YDRO-lH~ ,r~b~-ZIB~r~
. ~ MA~ERIA~ IS ... ~ W)]_ _ : EXAMPL~ PREPARED .. . - ~-AMIN~ P~EFIX//SUl~IX
. _ __ . ~- l . .... _ ... _ ........ _ 4 ~ 2 N~l 10-tri~cthyl//propiona~ido~
109 ~ . ~ l,10-dimethyl//propionamid~, .
. . ; . . ~.P. 97 - 980C. ~
. ~: 1~0 4. ~ ~ ~2N~ N~N,l,10-t~tramethyl//propiona~id~, 2.88 t6H)3 ~1.64 (~H)7 2.33 (3H~ :
~!',' ; lo i11 4 C2~ ~ l,10-dimothyl-N-othyl// .
. ~ .. . .. ~ . propion~mid~, ~cp~ 104 ~ 106C.
.. ii2 4 .......... tC ~ ~ NtN_dl~thyl-l~10-dimoth71//
... .. ~ ~ propio~m~do . 113 5 ~ ~ N~l~lO_tr~mot}lyl//oarboxamlde .. l5 114 5 3 l,10-dimethyl//carboxamide .: ; 115 6 ~: (C ~ )2N~ l-ethyl_N~N~3~10-tetramethyl//
. .:~.. . carbox~mide .
:. 116 7 6 ~ 3 2 1~3-dii~opropyl-8,10-dl~othyl-N_ 1. . ~ h~xyl//carboxa~idn . :
,' ! 20 117 8 ~ 2 ~ 2 -~thy1-8-hydrox~ ,3,10- ::
.~ . . ; _ . tetr~methyl/~carboxa~ido :
l 118 9 C ~2 l ,lObdi~thyl-N_methyl-l-propyl// .
i~ . : . : I arboxamide ~: . 119 10 ~ )2NH . -cyclopropyl-N~N-dimethyl-4,10- ;
25. . ~opropyl~/carbox~mido :
. 120 Il . 3 2 ~cyclop~tyl-4,4,10-triathyl- :
. ~ : ~N,3,3~tetra~ethyl//carboxa~ide . . 12 3 ~ ,1,4,10-tetramethyl//ccetamide .. .. 122 13 N ~ ~thyl-10-methyl//acetamid~

: 30 123 13 3)2 H . -ethyl-N~N,10-trimethyl//acctamdde .
: . .. ... 124 i3 6 ~ ~ 2 -~thyl~N-hex~l-10-methyl//acot~rld~ ~.
. ~ ~ .. ...... ~. _ _.___ . ~ ._~............................. .
. ~ ~ ~ , . ~ .:
.. j . . . .
~'' . .
,, ., :.
:', :
. - .
.
.

36ss~
v ~A~LE III
.. ~ .. _ ~ , . _ _. ~

,! W~IC~ STAXTING ~4-D~lyDR0 lh_lIX~L~SrED B~LOW)~
. ~ EXAMPLE PREPARED
. , , =,,__ --¦ 125 13 ~C2~5)2NH 10-m~thyl-N,N,l-triot4yl//ac~tamid~
1 126 14 : C~ ~ N~lO_dim~thyl~l-propyl//ao-t~mid-~

¦ 127 14 N ~ lOL~thyl-l-propyl//acet~mdde ~- .
¦ 128 14 (C~3~2M~ I--propyl-N~N,10-tri~ethyl//~ ~
. ~ ~cotamido, m.p. 84 - 860C. i ~ 10 l 129 14 ~-C6 ~ 3 2 N_hexyl_10-methyl-1-propyl//
., Mcetalnidc .j 130 - 14 : ( 2 5~2N~ ~c~mid~, ~G~lcl3tlh6y8lol_P-r~pyl/~

. ~i31 ~lS ' 3M~2 Nj~O_dim~thyl~ opropyl~/ . :
. .. . . ~co ~mldo ~ ~ 132 ~ 15 2 5 Z. N~N_diethyl-l-isopro~)yl-10-methyl~
:- 15 acetamdde .
. . - 133 .16 C ~ MH2 1-propyl-N,3~10-trimethyl~
. ! . . . ..... ~cetamido .
:. . - 134 16 : ~ 3)2 ~ 1-propyl-N,N,3,10-tetramethylf~ .:
!l~ . . . ac~t~mide - . .
; ~ ^ 135 - 17 -- ~ 2 . 3,10-d~ethyl-N,N,1,4-tetraethyl// ~
. 20 . . ~cetamide :
! 136 18 C ~NH2 N~a,l,10-tetramethyl//acetamide :
137 ~ 18 NH3 ~,l,10-tri~ethyl~/acetamide ~:
138 18 -(C~3)2N~ h~N,a,l,10-penta~ethyl//àcet~id~
:: 139 19 C2~ ~ 2 ~-cyclohexyl-N,10-diethyl-a~- :
. . . dimethyl//acetamdde .:
: 25 140 20 C~3~2 l-t-butyl-N,lO~l~thylf/ac~tamldo . 141 ` . -- . C~ ~ l-butyl-N,10-di~thylf/acetamide ;. : 142 22 . C?~ H2 N,lO_diethyl-6-methyl-1-propyl//
. ~ ...... acetAmide ~ -:,' . ' _ . ,.,_ ~
, ,,~ . .
:' ' ` ' ': '' ,.,, . , .
' : ', , ' ~,:

~ -55~

~ J~ IJU/ _~ 7~ I

)36S91~
TABLE III
__ ~ .. .. ~

IN WHICH STARTI~iG . ~,4_DI~YDRo 1~l 1X4LIST~D
EXAMæLE ~FA~I.D _ _ _ _ _ ~ SUFYIX LIS~D B~LOI~

~43 2~ 2 5)2 8-bromo-N~N,ltlO-tetraethyl// .;
. . . aoetamido : 144Z4~ ~ 1~-butyl-8-methoxy~ ethyl//
. . . ac~tamido 14~25 t 4HgN ~ 8_acetoxyON,10-d~-t-~utyl-1-met~y~f~

. 14626 ~ 8-benzyloxy-10-~opropyl-1-mcthyl//
. ac~tamid~ .
: 1~727 (C~3)2N~ l-pro~yl~N,N,9,10-tetramothyl//. . ucetamide ;
14828 (C2~5)2N~ N~ d~ethyl_7~10_dlmethyl-1-prop~

149 29 6 ~ 3NH2 1,10-dipropyl- N_hexyl_8_~itro//
~L5 . acota~ide . .
~50 CH~ ~2 1-propyl-N,4,4,10-tetramothyl//
. . acetamido . 151 31 3 1-cyclopropyl-a,,10-triethyl-3,3-. . d~ethyl-8-ethoxy//aceta~ide . 152 32 C2H~ ~2 10-butyl-1-cyclohexyl-fx,3,3_ .: tetramethyl-N,4,4,7-tetraethyl~
. . acotamide .
153 33 3 2 1-ethyl-N,,3,10-tetramothyl-4~4,9- .
. . tripropyl//acetamido . .
154 34 3)2 ~1 lO-ethyl-l-propyl_N,N~~~
. . t~tramethyl//aoetamid~
: 155 35 (C2~5~2~H . I-t-butyl-a,a-diisopropyl-N,N,;,3,-:~ . . 4,4,9,l0-octaethyl//acetamlde !5 15~ ~ 36 CH3N~2 ~10-dimet~ 9-iodo-1-isopropyl//
. . ?r~?iO~a~ido 157 38 CB~ H2 ~-diethyl-N,10-dimethyl_7-hydrox~
.. . . . _ , ._ ... _ L-propyl//propionamido . ' ' , .
~.

'; J t :
A~P-5786/592l L~3~iS96 .``'., , ' ~ , ~: ;- ' _ _ . . _ : ~. . . . . _ _, APIME

. . 158 39 . ~ 1-cyclobutyl-3,10-dimethyl-6_ 1 ~: 5 . . . r~tro-a-propyl//propionamide l .
. 159 43; C2~ ~ 2 ~94l4-tetramethyl-N~l~10-~ . . triethyl//propiona~ido :4 ~.
.; . 16D 45 3 ~ 2 a~10-dimethyl_9-methoxy_N,~,3_ : :
: . . tripropyl//propionamid~

161 48 2 5N~2 tet raethy I //p rop i onam 1 de 1~2 49 ~ N~1~19-6triml6h~c//but~ramido~ :
163 49 3 2 . ~,N~l,lO_tetramethyl/~ utyrfl~id~ .
. 164 52 -n~ ~ H9hH2 Nll_d~butyl~3,10_di~thyl_7~nit~p-l :
15 . ... . . a~r-tril~ethyl//butyra~ido,umax 3 .
165 53 3 ~ 2 a~-diet~yl-3,3-dimethyl- :
", , ~ . . ~ .. , N~N~1~9tlO_peIltapropyl//butyra~ido 166 54 n C4H~N~2 N~lO_dibutyl-l-~thyl-6-hydroxy-. . . ~ ~Y~Y-totra~ethyl//butyramido 167 55 . 9-ethoxy-1-ethyl-a,~ ,r,r~3,4-. . _ . . -octamethyl_N~N~10-tri-t-butyl//
. . ~utyramido . ' . 1 67a ; 553 ~-~SNH2 N, I -d i methy l - I O-ethy l //
. . _ . :~. . prop ionami ~e, m.p . 138 - 139C. :-.. ,. . . . . ~ . . . - ., . .~
~ 25 167b l4 C2H5NH2 ~ ~cetamide,~ i3 i680 cm i.
'.' . ... . . ' .

:'~' ' . ''' ' ~ . ....... . . ' ,1, . , . . ' . .. . ' " "
:., .. ,,, ~ _ ,. . ., . ' .. , . . ,.
~ ., . . . _ _ ,_ . : , ' i . , , , .:.

:' . '' ' . :.

:, ~ . 1, . . . .
.~ , . . ..
~1r~ '' ' ~:

AHP 5786'592 1 - ~65~
E IV
.~. . ' ' ----``, . , , _ ---- _ . . , ~
- NO. OF T~: Ea~A~LE PRODUCT: r(P~ X LISTED R~OW)_ .
IN WHICH STARMN~ :. 3~4_DIHYDRO~ ,4-OX~ ;O~,3~-~ , MATE~ S . INDO~ SU~IX LISTED BE~O~.I ) ]
: . . EXAMP1E PREPARED AMI~; . ~ _ _ ~ = ~
,, . ~ .. _ -.~ - _ _ : -- -- .
. 168 4 . , p~rrolld~no l-~(l,10-d$~thyl//propionyl]- , .
. . pyrrolidino .
169 4 plporidlno l-C(l,10-dimethyl/~propio~yl~_ . . piporidin~ :
.~ 170 ~ ~orphol$ne 4-[Sl~10-di~ethyl//propionyl]- , . :
: ~ . . . . ~orpholine, m~p~ 160 - 162C. ~

171 4 plp~r~zine l-C(l,10-dimethyl//propionyl]_ !r . RiPor~zl~O
.. 1.72 4 N-~othyl- l-meth~1-4~(1,1Q~dimeth~l//
.. _.............. . pl~eraz~ne propio~ylJplpor~zln~ ~
. 17~ 4 N_piperAzin~- 1-(2-hydroxyothyl) -4-C(l,10-. . ~ ~ ~thunol dimoth~l//propionyl~pipera~in~
. l5 174 5 pyrrolidino l-~(l,10-di~thyl//carbonyl]_ . l pyrrolidino 175 5 ~orphollne 4-~(1,10-dimQthyl//carbonyl~_ .. morpholln~ .
. . 176 6 N_~thyl- . l-etbyl-4~ othyl-3,10-dimethyl~ . .
-20 . . p~perazino carbonyl]piperazine . ~ . 177 i2 . p~p~ridin~ 1-r(1,4,10-tri~ethyl//Acatyl~-: - ~lp~ridin~
. . 178 13 ~orph~line 4~ thyl-10-~othyl~acetyl]- :
; l . ... . morpholine . 25 179 13 N_piperaz~ns- 1-(3-hydroxypropyl)-4~(1-ethyl-. . propanol 10-mcthyl//~cetyl~piperazine .
: ~80 14 ~yrrolidina l-[~10-mothyl-l~prop~l//acetyl~-:1 . . . . pyrrolidine ~ . 181 14 morphOl;~0 4-~(10-mathyl-1-propyl//acetyl~-: . ~ . . _ ~orpholino . 30 182 15 pipcridine l-r(l-i~opropyl-lO_m~thyl~/
. acetyl]piperidino . . . . 183 16 plpera~i~a 1-t~3,10-dimethyl-1-propyl//~cety~3 .~.
. . ~ _ __ pl~orazlne _ ~ ¦
, : ' ~ -58-A~IP-5786/592l , ~a36s~al6 ~ IV
, . .. ..... ~ :
.,.~ ., __ . , , ,j ., . _ ~ _ : '~
. . ~ NO. OF THE EXAI~PLE . PROD~CT- C~PR~FIX LISTÆD B~IO.~) :
- , ~ IN WHICH SrA~T~G . 3,4 DI~XDRO-l~ Y~Y ~lOL~,~3-al-.. . MA~IAL IS . IMDOLE-l-(SUFFIX LISTED ~E ~W)~ ::
.. 'I E~E PI~EPAR~ ..... ~, PRi~IX~X-- , . ~_ ~ ~ - ._ . _. _....... , 184 18 N_ethrl~ l-ethyl-4-r(a~l~10-tri~ethyl// ;
... . . pipcr~zine acetyl]piporazina .. 1 . 185 26 p~rrolldine 1-r(8-benzyloxy-10-isopropyl-1--. ~othgl//acetyl~py~rolidin~ - ~:
. . 186 27 plper~din6 1-~t9,~0-dim~thy1-1-propyl// ~ :~
" ac0tyl]piperidine ~ .. , :'.
: 187 31 morp~oline 4-C(l-cyclopropyl-a,a,lo-triethyl-. 3~3~d~mcthyl-8-ethoxy//aoctylJ- .
: ~ . . . m6rpholino . 188 37 pip~raz~ne l-C~-acetoxy_l,lO_dlethyl x,3,3,-4,4-pontam~thyl//prop~a~gl]-.. . plperaz~n~
~l l5 189 40 N_plpsr~ih~- 1-~2-hydro~yothyl)-4-~ cyclo-. othnnol propyl-x,~ 4,8,10-heptamethy~y' .
propionyl]piperazine :, lgO 41 pyrrol~din~ l~ ,10-tri~ethyl-,~-dipropy~ .
. . propionyl~pyrrolidine i.............. 191 43 ~orpholine 4-C(1~10-diethyl~ ,4,4_ .~ 20 ~ tetramethyl//propionylJmorphol~no : .~ 192 48 N_propyl_ l-propyl-4-~1-cyclopropyl-7- :~
. . piperazin~ ethoxy-x,~,10-triethylJ/propi~yl~ .
. pipcrazane . ~:
:~ 193 49 p~rrolidin~ l-~(l,10-dimethyl~utyryl~-.1 . pyrrolidl~e .:
194 49 N_piper~3~ne- ~1-(hydro~ymethyl3-4-~1,10- . . .
. ~othunol di~ethylJ/butyxyl]piporazi~o . :
-: . 195 51 piperidlne 1-CY,Y-diethyl-l-propyl-3,3,10- : n ,.;. . . trimcthyl/~butyryl]piperidino . ,.
;'" . ` . . ,:, : . ,'~:' ~, . . .__ I - ' I ~ ~........ ' '".. " , : ,1 .
,1 :.'. ' .
.~ " ,-', .
i . '. ~ .

:1 ^59~ , ,: , A~ b /~Y2l Q3~596 `. !eAB~E V
.: .. -, . ~_ . . . ~ ` . = = `-~ - -- _ IN W~IICH SThRTING PRODUCT:
. . E3iUMPL~ MA ERIAL IS AMINE W
.. ' ,_ __ ~ ~ _ ~ ~_ .
.: . 5 lg6 87 C ~ 2 N,l,10-trimethyl//propiona~ido 197 . 3 i,10-dimethyl//propionam~de . 198 ~7 ~ )2 N,N,l,10-totra~othyl//~roplonamide 199 87 C2~ ~2 l,10-dim~thyl-N-othyl//prop~ona~id200 87 (~5~2M~ N,N_diethyl_l~10-di~othyl// .
io . prop~ona~ide 201 56 C~3N ~ N,l,lO_tr~m~thyl//c~rboxamide 2oe ~ NH l,10-dimothyl//cnrboxamid~
. . 20~., 5Z ~S)2N~ l.~t~yl-N,N13,10-t~tram~th~
. . .. _ ~ c~rboxa~ido 204 58 ~ 2 1,~dii~oprop~1-8,10-di~ethyl-l~-hoxyl//~arboxa~l~e .;. 205 59 C2~ ~ N_othyl_8_hydroxy-1~3,3,~.0-:, . . tetr~thyl//carboxa~ide .. 206.:~ 60 C ~ J~z 6~10-d~ethyl-N-Lsthyl-l-propyl~/
.. . - . .:. carboxa~id~
207 61 (C ~ ~2M8 l-cyclopropyl-N,N-dimethy}_4910_di . . i~opropyl//carboxamidc , :
.!0 - ~- 62 3 2 1-~yclopentyl-4,4,10-tricthyl- ~
. ~ N~N,3,3-tetra~cthyl//carboxa~id~ .
209 63 ~ 2 ~. N~l~10-tri~ethyl//flceta~id~ .
i 210 64 3 l-ethyl-10-methyl~/acetamddo ~-., 211 64 (C~3)2N~ l-eth~l-N,N,10-trimethyl~/acetami~ .
.. 2i2 64 6 ~ ~ 2 l-e thyl-N_hoxyl-lO_methyl/face~mi~
,;, . . 213 ~ 64 2 5 2 10-methyl-NlN~l-triethyl~/~oetamide .
.~ 214 65 C~3N~ N~10 dimothyl_l-propyl//acet2~idc 215 1 65 N~3 = ~ ~ V ~ .

"r~
::, .. " ,. . c~

AHP-57~6 ~592l .....
~S9~

`, " ~ , ~ ....... _ . r~ RIAL ~ 3R40DUICHyD~(PlH~ rLIsTED BEL40~)_ . _ P~ . _ - _ ~ =~ r=---. ~

216 . 65 - (C ~ )2~ l-propyl-N,N,10-tri~ethyl// .
: 5 . . . acet~mide 2~7 n C6 ~ 3N~z N_hexyl_lO_methyl_l_propyl// .
. acetam~de 218 65 . (C2H5)2N~ NON_dieth~l-10-m~thyl_l-propyl . acet~mide .
. 10 219 66 ~ 2 N,lO_di~ethyl~ opropyl// :
. . acet~ide , 220 66 ;~ 5 2 N~N_diethyl_l_~sopropyl-10-~ethy~0 ! noetnmido 22~ 67 . CH3NH2 1-propyl-N,3,10-tr~methyl// .
. ~oetu~lde 67 . 1-propyl-N,N,3,10-tetramethyl// :
; i ac~tumi de ' 223 68 ~ 2 5)2NH 3,10-dim~thyl-N,N,1,4-tetr~etl~
., ,,~. . . . . a~atamide .20 2224 6 C ~ ~2 N~l,lO_tetramethyl//acctamide .: . 9 ~ . a,l,10-tri~ethrl,~/acets~ide ::

I ~ 226 69 (C ~ )2NH N~N~~l~lO_pentamethyl~/aceta$ide .
.. . 227 70 C2~ ~ 2 l~cyolo~x~l-N~10-diethyl_x~a-: diEethyl//aceta~ide ; :
~; -25 228 71 C~ ~ l-t-butyl-N,10-di~ethyl~J/acet3mide . 229 72 ~ 2 l-butyl_N,10-dim~thyl//aceta~ide ; 230 73 C2H ~ 2 N~lO_diethyl_6_methyl-1-prop~l~/

; 231 74 .~ 2 5 2 8_bro~o-N~N~l~10-tetraethyl~/
. ; 30 ~ . aceta~ide ~` 232 ?$ - 3 10-butyl-8-methoxy-1-methyl/~ .
. . . ~etamide . . _ _ . , .... _ ... ~ ._ . . ~' ~
.~ . . ' ' ,. '~.

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

~L~36~9~
. . --. ~ :
. " ~ . .
;,; l . . . ~ . . ..... ..
. IN WHICH STARTL`IG ... ~ PR4DUCT. r(PR~FIX LIST~D B~IOW)_ EXA~n~LS ERIAL IS ~ AMIt~E INDoLE-l-p~rl//5ù~ B ~o./~]

. 233 76 t-C4~9N~2 8-acetoxy-N~10-di-t-butgl-1-methyl//aceta~ide .;
234 77. ~ ~-benzylo~y-10-isopropyl-1-. . n~st~yl//acQta~ide . 235 7~ 3 2 ~._pr~pyl-N,N,9,10-tetramethyl//. ..
: acetamide ~ -236 - 79 2 5 2 N~N_diethyl-?~10-di~ethyl-1-. . . pro~yl//acetamide : 237 80 6 ~ 3NH2 1,lO^dlpropyl-N-hexyl-8-nitro//
. acetamide ~ 238 81 C~3N~2 1-propyl-N,4,4,10-tetra~othyl//
. I . _ . ~c~taLide I l5 ~39 82 NH~ l~cyolopropyl-a,a,10-triothyl-.I . 3,3-dimethyl-8-cthoxy/facetamide : I 240 83 2 5 2 10-butyI-l-cyclohexyl-x~a~3,3-.. . tetramcthyl-N14,4,7-tetraethyl//
. l . . aoetamlde , 20 241 84 . CH ~ 2 1-ethyl-tl,,3,10-tetramethyl~
.. :, 4~4,9-tripropyl//acetamide .
: . 242 85 3 2 10-ethyl-1-propyl_N,N,a~_ :
. . . tetramethyl//acet~mide . 2~3 86 l-t-butyl_~a-diicoprop~l_-. ~ ~N~3~3,4~4~9~10-octaethyl// .
.. 25 . ... . acetamide .
: . 244 88 ~ 2 N~lO_dimethyl-l-propylj/ .
.~. propio~amide .. 245 88 (CH~)2N~ l-propyl-N,N,10-trimethyl//
:j . . propionamide 246 ~ 9 NH3 1-cyclobutyl-j~lO_di~cthyl-6_ . . . nitro-a-propyl//propionamide 24? 94 C2~5N~2 . ~ 4~4_tetra~ethyl-N~l~10-triethyl//propionamide . ~ ~ ._.. _ _ . . . _ . _ ~
".", ' ~ .
.' ~ ' , ' .
: j!
, ~ -62-' ` A~--7 7~ Y~: I
: `~ 365i96 T ~ V
. ~
:- . .- ._ _ ,, .. _ J NO. OF T~E EXAMPLE ~ODUCT: [(PPE~IX LISTE~ BE~O'.J)_ IN WHIC~ STABTING . 3,4_DIHYDRO ~ N~ ~,3-aJ-H~TE~IAL ~S . IMDOLE_l_~SUF~IX LXSTED ~LOW~
EUU~ PREPAR~ A~NE
,. ~ = ., .. . .. _ ...... __ . .
- ¦ 248 96 n~ ~ ~ 2 1 ~10-dimethyl-9-methoxy-N~1~3- .

5 ` . . tripropyl~/prop$onam$de . 249 gg Cz~ ~ l-cyclopropyl-7-ethoxy-N,,~,10-. . tetraethy I //prop ionami de .
250 100 . CH~ ~2 1 ~l~10-trimethyl//~utyramide J
. 2~1 lC~ 3)2 N,N,l,lO_tetra~ethyl//butyr~mide . 10 252 103 n~C4HgN~2 N~l-dibutyl-~10-diethyl-7-nitro- :
. ~ -trimethyl//butyramlde .
253 104 ~n~ ~ ~ )2N~ ~-d~ethyl-3,3-di~ethyl-N~N~l~9,lC
. .. . . pent~propyl//~utyram~de ~ 254 105 ~-C4~9NH2 Y~10-d~butyl-1-cthyl-6-hydroxy- .
: l~5 .~ . ... . ~~Y~Y totr~athyl~ utyr~mido . 55 106 ~ C4~9)~NH ~-athoxy-l-ethyl-~a~ Y~Y73,4~ .
. . . .-. ~otamethyl_N~N~lO_tri.-t~butyl~/ .
:~:. . ~ .~ . ......... ~utJram~de .. , . .-~ , .. ,............. - ~ ;~
',, , l . .. ~ .. , . . :'':.
.. 20 .: :-~ . ~ .

1 . ~ - - . -., ,,,, .,,~~
.

~ . .. ,..... .. . ' : . . ~... , :
. ... ., ~.,".. , ' . . ~, , . ~ . :
. . . .. _.. ~ =
. , ' _ ,. .. .. ~

. . . :
. :

~ ";., .

1 ~ AHP-5786 ~592l t! ~0 .3. 6.S9~i . . .
. ~ ~ ^ . . .
. .... . .. _ ....... ~. .
-i . NO. OF THE EXAMPLE PRO~UCT: ~(PP~IX LISTE~ BEIOW)_ , . IN WHICl~ STABTING . 3,4-D~HYDRO-lH-1~4-~HIAZIhO[4,3-~ _ .
. ~! MA~ERIAL IS . INDOIE-l-(SUFFIX LISTED B~LOW)~
: EXAMPLE PREPAR~D ~ ._.
. ; ... . . .... ..
256 87 pyrrolid~ne l-C(l~10-di~ethyl//propionyl]-~: 5 . . pyrrolid~ne , 257 87 piperidine l-C(l,10-dimethyl~/propionyl~_ : piperldine :: . 258 87 ~orpholine 4-~(l,iO-dimethrl//propionyl~- ~
:~ . ~orphol~ne .
. I 259 87 pipernz~ne l-C(l,10-dimcthyl~/propionyl~-:1 10 . . . _~... .. pipera~ine S 260 87 ~-~èt~ 1-methgl-4-Ctl,10-dimethyl//. . . p~per~ino propIonyl~piperszine ;, Z61 87 ~-piper~na~ i-(2-h~droxyethyl)-4~C(l~10-. . othanol d~ethyl//propionyl]piper~z~ne . I 262 5G pyrrolidine l-C(l,10-di~ethyl//carbonyl~_ : .pyrrolid~ne . .263 .56 n~rpholine 4-~(1,10-dimethyl//c~rbonyl~_ .
. . . ~orpholine : 20 264 :.57 N_~thyl- l-ethyl-4-[(1-ethyl-3~10-di~ethy~
.. .~ pipera~i~e carbo~ylJpiperazine ~
' 265 63 plp~rid~ ~_t(l ~10-dimethyl//acetyl]-~:~ . -. :. piperidine . 266 64 ~orpholi~e 4-[(l_ethyl-10-~ethyl~acetyl]_ ; . . : ~ ~orphollne -. 25 267 64 N piperazine- 1-(3-h~droxypropyl)-4-t(1-ethyl-. propanol 10-methyl/f~cetylJpiper~zine : 268 65 pyrrol~dine l~C(10-methyl~l-propyl//acetyl~-;: . . pyrrolidine . æ~ ~ 65 ......... ~orpholine 4-~(10-~ath~l-1-propylf/~catyl~- .
. ~orphollne :: 270 65 piperidi~e l-~(l-isopropyl-10-~ethyl//
. . acetyl~piperidine ~ ~ - .. - - -. - - ~ -~ - -.~.1 _ , ."__ , ,,,, ,,, ,, ,,,,, ,, _ .~ ' .
'' ~ . , ~ -64-A~--~ ~Ot~ / ~ Y;~ I
3659~i '' ~ ~A~E YI

.: . _ . . . , . .. . . . _ . :
~ NO. OF ~H~ EX~PL~ PRODUCT: ~(P~FIX LISTED ~F.T~II)_ ~1 . IN W7lICH STARTING ~ . 3,4 DIHYDRO~ l,4-T1iIAZ~10~4,3-a~
MATE~IAL IS . INDOLE-l-(SUFFIX LIST~D BELOW)~
EXAMPLE PREPARÆD ~ - AMINE ~ ~ /SUFFIX
. _ --- .. _ . . ~
271 67 ......... pipcruzlne l-~(3,lO-dimethyl-l-propyl/~ .;
., 5 . . . ~cetyl]piper~zlne .. , 272 . 9 . ..... -ethgl l-etbyl~4-[(x,l,lO-trimethylj/
. . . . piperaz~ne ~cetyl]piperazlne 7 . . 273 . . 77 pJrrolidine 1-[ (8-benzyloxyl-lO-i80propyl-... : . l-~eth~ cetyl]pyrrolid~e .: 274 78 pip0ridine 1-~9,lO-dimothyl-l-propyl~/
;: 1 . acetyl]pip~r~dino :
275 ~ ~orpholine : 4-[(l-cyclopropyl~x,a,lO tr~ethyl_ . . . . 303-di~oth~1 8-ethox~//acetylJ- ..
~ 1 . ,. . ~ . rl~ ,, morpholine .; 276 88 piperu~in~ l-~tlO~m~thyl-l-propyl// ..
. l5 .: ... . . propionyl]piporidine .. . 277 9l N_piperazlne- l-~2-hydroxyethyl)-4-r(l-cyclo-. ... -~ e~thanol . . propyl-a~a~ 4,8,lO-heptameth~/
, . . l propionyl~piperazlne .
~ ~ ~ ... ...... ,, . , . .
:;1 . 278 ~ g2 _ . pyrrolldi~o l-ttl~3,lO-trimethyl-x~a-diprop~i/, !;
; ... . .... .-.. . ..... .-.......... propiony}]pyrrolidine -. 20 279 . ~4 ~ ~orphol~ne 4-C~l,lO-diethyl_~,4,4_ . ~ . ~ - - -~ totramethyl//propionyl~morpholine l 280 . ... 99 - . N~propyl- l-prop~l-4-t(l-cyclopropyl-7--~ . . . _ .......... pi~erazi~e eth~xy-~lO-triethyl// .
~ . . . ~ . . - propionyl]pipera~ne : :

28l .. . p~rrolidine l-C(l,lO-dimethyl/~butyrylJ-. pyrrolidl~e :
. 282 ;lOO - -piperazine- l-(hydroxy~ethyl)-4-t(l,lO-: ~ . . ~ethanol dim~thyl//butyryl]piperazine .. . 283 lQ2 piperidin~ l-t~,Y-diethyl-l-propyl-3,3,10- :~
~ . . . tri~ethyl/hlltyrylJpiperidine ~,~ ...... . . ' : ' . .

: . . , . _ _~ . ,. ._ _. ......... ,., l ~:
., ~ , ;~;.
., , . . .

,: . .
. ,, , . . . ' ' ? , .

AHP-s~86 /592l ;~ ~6596 _.. ~. ~ r :-~' ~ ~ HCH
. . . .
Tho amid~, Nll,iO_tri~ethyl_3,4-d~hydro_lH_1,4-oxazino-C4~3-a]i~dole-i-~cetAmide ~11.0 6.)~ deGcribed in EXumple 107, . . in 200 ml. o~ T~F ~R ~dded dropwise.to a stirred mixture of 7 l~th~u~ Mluminum hydride t6.3 g.) ln 20Q ml. of T~F. Th~
. . .,, ,, ~
roaction iB reSluxed ~or 2 hrO and cooled. ~he excess hydride deatroyad with w~tnr. The m~xture i~ filtered a~d the filtrate ; ov~por~t0d. The re~idua i~ taken i~to ether, washod ~ith wat0r .. j and th~ 4clut~0n i8 o~apor~ted to afford tho tltle aompo~1ndt :. nmr (¢DC13) ~1.6~ ~, 3~1j, 2.34 ts~ 3~), ,.
The ¢orreaponding hydrobromlc acid addition c~ltt 1~10-dimethyl~ 2-(methylamino)ethyl]_~,4_d~hydro~1H_1,4_ !
...................... ox~zlaot4,~-a]lndole hydrobro~ide, hu~ m.~. 249 - 251C., : a~ter recrystalliæation ~ro~ isopropanol.
. In the same munner but replaci~g lithlum aluminu~
., ~ .h~drido wlth ~n equiralent amount of lithiu~ alu~anum hydrids-;! 20 alu~lnu~ chlorida~ alu~inu~ hydrid~-aluoi~u~ chloride, diborano a a~d eodiu~ borohydride-~lu~lnu~ chloride, the titlo ~ompound i8 ~1BO obtained.
' In ths sa~e m~nner but replacing N,l,lO_trimeth~l_ 3~4-dibydrG-I~ 4-oxazinoC4~3-aJindole-l-acetamide with an equiva-lent amount of the following amides descrlbed in Example 107, ., ~ ~`' " , , ~ .
. . ' ~.
.`

.: , . . ' ' .~ -66-t~ . .. .

A~-5786 /592l ~03~;59~
~ - . l,10 di~ethyl-394-dihydro-lH-1~4-oxazino~4,3-a~indol~-l-acetamide~
; : N~N~l~lO-tetramethyl-3~4-dihydrorlI~-1,4-oxazino~4,3-a]indole~
.: , aceta~de, l~10-dimethyl-N hexyl-3~4-dihydro-lH-1~4-oxazino~4,3-aJindole-l-aceta~de .. . .
N~N-diethyl-l~10-dimethyl-3t4-dihydro-lH-lt4-oxa~ino~4~-3-a]indole 1- .
acetamidc~
:~ 1,10-dimethyl-N-i~opropyl-3,4-dihydro-1~-1,4-oxazino~4,3-aJindole-l-acetamido 9 1~10-dimothyl-~J-othyl~,4-dlhydro-~-1,4 oxazinoC4t3~ dole-1-:, ~ Acetamidu ,, .
l-t~l,10-dimethyl-3,4-dihydro-lH-1,4-oxflzino~4,3-a]indol-1-yl)- ,'.
acetyl~pyrrolidine~
' ~ I t(l~lo-dimcthyl-3~4-dihydro-~ 4-oxazino~ 3-a]ind :. 5 acetyl]plpcrid~ne 9 . 4-~1,10-dimethyl-3j4-dihydro-IH-1,4-ox~z~no~4,3 a~indol-1-yl)-acetyl]morpholine, and . . i-methyl-4-~(1,10-dimethyl-3,4-dihydro-1~-1,4-oxazino~4,3-a~indol- .~.
1 yl)acetyl~pipera~ine~ then there are obtai~ed, . '0 1-(2-a~inoethyl)-1~10-di~ethyl-3,4~dihydro-1~ -oxazino[4,3-a]-indole~ nmr (CD513) ~1.62 (3~)0 2.~ (3~), .
1,lO~dimethyl~ (2-dimethyla~ino)ethyl]-3,4-dihydro-lH-1,4-.~ oxazino~4,3-a~indole, nmr (CDC133 ~1~60 (3H), 2.30 (3H)~
corresponding hydrochloric acid add~tion ~alt (hydrochlorido~
. . .
`5 haa m.p, 237 - 239C., after recry~tallization from methanol-ether~ .

:~ , ' '~i\ ' ., .
`
,.; ~ ,~ , A~' 778~ /5921 :;
~.(1 36596 .: l,lO~dimethyl-1 L2-~hexylamino)eth~ 3,4-dihydro-lH-1,4-oxazino-. ~4,3-a~indole"
1-[2-(diethylamirlo)ethyl]-1,10-dimethyl-3,4-dillydro-lH 1,4-oxazinoC4,3-A~indol~, n~ (CDC~3) ~1.60 (3~), 2.30 ~3H)9 corre~ponding hydrobro~io acid r,ddition ~alt (hydroh.ro~ide) ha~ ~,p. 191 - 193a.~ a~t2r reory~talli~.atio~ from isopropanol-ether~
1,10-dimethyl-1-t2-ti~opropylamino)ethyl~_3,4_dihydro-lH-1,4-oxa~ino~4,3-a~ndvle, l,10-dim~thyl-1 C~ethYlamino)ethyl~ 394 dihydro ~ 4 oxazlno ~ C4~3-a~indole, nmr (C W l~) ~ l.S8 (~H), 2.32 (3~ corre~polldin~
hydrobro~ic a dd addition salt has m.p~ 196 - 198C.~ aftor ~ rocrystalllz~tion Prom i~opropanol-~ther~
1,10-dimethyl-1-~2~ pyrrolldinyl)othyl~-3,~i-dihydro~lH-1,4-oxazino[4,3~a]~ldole, nmr (CDCl~) ~1.60 (3~)~ 2,30 ~3~l), corre~ponding h~drochlori~ acld addltion ~alt ha~ m,p~ 223 - æ50c~
: after recry~tallization from isopropanol-ether, l~10-di~athyl-1-(2-piperidinoethyl)-3,4-dihydro-lH-1,4-oxa~ino-[4,3-a~i~dole, n~r (CDC13) ~1.61 (3H), 2~33 (3H), correspondinæ
hydrobromi~ acid addition ~alt ha~ m.p~ 253 - 255C., after recrystallizatio~ from methanol, l~10-dimetkyl-1-(2-morpholinoethyl~3,4-dihydro~ 1,4-oxaæino-. ~ .
C4~3-aJindole, nmr (GDC13) S1.60 (3~ 2~31 (3H)~ correspondin~
; hydroohloric acid addition Ralt ha~ m~p. 234 - 236C.~ after recry6talli7.ation from isopropanol-ether, and 1,10-dim~thyl~ 2-(4-methyl-1-piperazinyl)ethyl~-3,4-dihydro~
1,4-oxazinoC4,3-a~indolq, nmr (CDC13) ~1.62 (8~ 3H)~ 2.32 (8, 3~
: correspondin~ maleic acid addition 6~1t (dimaleate) has m.p. 196 -198C.~ aftor recrystallization fr ~ methanol, refipectively.
''~
.~ .

. -68- ;

P-57~6i5~2 1 36~ ~

- Ry ~ollowing the procedure of EY~mple 284 but u~in~
a6 eitartin~ material ~n equivalent a~o~lt oY o~e of the amid~
:~ compGund~ of formula V, described i.n Example~ 108 to 28~ ~ :
instead of ~ lO_trimethyl_3~1~_dihydro_1H_1,4_oxa~ino[4~3_a~- -indole-l-acetamide, then the corr~pondin~ coslpour~d6 of ormula I
~re obtained. ~.~ample6 o~ such compounds of formula I are ~ -l~Bted a6 product~ in Tables VII and VIII together with the appropriate starting material. In each ca~ie the etarting materlal i~ noted by the example in which it is prcpared.
~, :" :
.,'` ' . ' ..

.~ ` .
' ;
, .. . .
''' ' ' ', .", .... . .

~' . .' .

-69- :

7 ~ Y~, .... .
-r ~ 1g)36596 .: TA~ VIJ
: , .
:,. ~ ., ", . _ ,, .. ._ . . _ .... . .... . _ "'''` ' . . .
.,, _ NO. OF EXA~LE IN ~ICH PRODUCT: (PREFIX LISTED ~ELO~
~: STARTING ~ATERIAL IS 3,4-DI~YDRO-lH-1,4-OXAZXNOL4,3-a~-.~ E~UD~LE P~UEPARED IMDOLE
. ........ . ........... ___ _ ........... _ . 285 lC8 1~10-dimethyl-1-~3-(methylamino)_ . . propyl~, n~r (CDCl~) ~1.62 ~3H), . 2,32 (3~), corresp~ndi~g . . hydrochloric acid addition salt has :~
. . m.p. 193 - 195C., after recrystal_ ::
lization from isopropanol-ether . 286 109 1-(3-aminopropyl)-1~10-dimethyl~
. nmr(CDCl ) ~1.58 (3~), 1.90 (2~1), corre~po~ding hydroc}~oric acid addition ~alt has m.p. 204 - 206C~, . after recrystallizntion from . .. m~th~nol-c~her . 287 110 l,10-dimethyl~ C~-(dimot}lyl~mlno)_ . . propyl~, nmr (C~Cl.,) Çl.64 (3H)~
. 2,33 (3}1), 2,35 (4~)~ correspondin~
. . hydrochloric acid flddition salt has m.p. 200 _ 201C., after recrystal-: .. ization from methanol-ether ; 288 111 1,10-d~methyl-1-C3_(ethylamino)_ . . propyl~, nmr (CDCl~) ~1.61 (3~), . . . . 2.33 (3H), corresp~ndin~ hydrochlor c .. acid addition ~alt ha8 m.p. 220 _ 222C., after recrystallization from . 0 ethanol-ether .. 289 . 1-t3-(diethylamino)pro~ 1]-1,10-: _~ -~ di~ethyl, nmr.(CDCl~) 0.94 (t, 6H), .~ ~ .. 1.58 (8, 3H), corre~ponding .~ . hydrobromic acid additi.on salt has .~ . . .i m.p. 174 - 176C., after recry6tal-- . llzation from i~opropanol 290 113 l~10-dimethyl-1 C(methylamino)methYl 291 114 l-~Aminomethyl)-l,10-dimethyl ,';
.. . 292 115 l-~(dimethylamino)methyl]-l-ethyl~
: ~ ~ 1,3,10-trim~thyl ,~.
: 293 116 1,3-diisopropyl-8,10_dimethyl-1-. . . . . _ . . ~1 ~
.i i . .
.. . . .
';~, , .. . .
" ' .' , ' ' ' ' :
~, ~ ; ..
,. , . :
,, .

~ -70- ;

3~iS916 . -. . . ... ~ , ............ . . _ .... ..
... . , .
.. ~. NO. OP` EXAMPLE IN l;llIICH PRODUCT: (PREFIX LISTED BELO~
.- STARq~ING ~ATERIAL IS 3,4-~IHYDRO-lH-l,h-OXAZD~0[4 3-a~
EXA~IPIE PREPARED INl)OLE ~ -... . . . . . _ . .
294 117 1-(ethyla~ino)methyl-8-hydroxy_ . .
. . 1,3,3~10-tetramethyl Z95 118 6,10-dicthyl~ methylamino~methyl-. l-propyl 296 119 l-cyclopropyl-l-(dimethylamino)_ . . . methyl-4,10-i60propyl .. . 297 120 1-cyclopentyl-3,3-dimethyl-1-:. (dim~thylamino)mothyl-4,4,10-triethyl ~:
. ~ l 298 121 1 ~methylamino)ethyl-1,4~10-trimethyl 299 læ 1-~2-aminoethyl)-1-othyl-10-mothyl 300 12~ 1-C2-(dim~thylam~no)othyl]~l-othyl- ..
10-methyl 301 124 -eth~l-1-r2-~h~xyla~ino)ethyl-10- .

~ . 302 125 -[2-(dicthylamino)ethyl~-1-ethyl-10-:... . ethyl ... 303 126 10-methyl-1~2-(methylamino~ethyl~-. . I-propyl, nmr (CDCI7) ~ 0.84 (t, 3H), .- .30 (s, 3H), 4.03 ~m, 4H~, correspon .. .- - I ing hydrochloride addition salt . : as m.p. 229 - 230CC.
. 304 1~7 `; -(aminoethyl)-10-methyl-1-propyl 35 128 -t2-(d~Methylamino)ethyl]-lO-methyl-.: . -propyl, n~r (CDCl ) 1.64 ~31I), i 25 . . .34 ~3H)~ correspo~ding hydrobrom~c : . cid addition 6alt ha6 m.pO 196 -. . . . . . ;19~.C., afte~.rocry~tallization ~rom . . :isopropanol 306 !67b 1. ~2-~e~hylamino)e-~hyl}-10-me~hyl-1-. propyl, nmr ~CDCI ) 0.8~ (t, 3H~, : . ~ 1~26 ~t, 3H), 2.3~ (s, 3H), 4.03 . ~m, 3H), corresponding hydrochloric . _ _ acid addition salt has m.p. 212 -.~ .. _ . ., ' . ,~' , ! ~
.
, . ~ , . . .
_, .' ~ ~.

- AHP-5786/592l 3~596 ~` ~ ~ ,~ . ._ . NO. 0~ EXA~PLE IN ~n~IC~ PRODUCT: (PR~IX LISTED BELOW) : STARTING ~TERI~U1 IS 3,4-DI~YDRO~ 1,4-OXAZI~iO[~,3-a~-. EXAMPLE PREPAR~D _ INDOLE .
307 130 1-~2-(diethylamlno)ethyl]~l~methyl_ . l-pr~pyl, nmr (CDCl ) 1.62 (3~), 2,33 (3~), corrospo~ding hydrobre~ic . ~cid ~lddition ~alt has m.p. 165 _ 167~C " aftcr recry6talli~ation from i~opropanol : 308 131 1-isopropyl-10-methyl-1-r2-(methyl-amino)ethyl3 309 l3? 1-C2-tdi~thylflmino)ethyl~ .
l~opropyl-lO~methyl .
~10 133 3~10-dimethyl-l~C2-(mothyl~ino)_ othyl~-l~propyl 311 134 3,10-dlmethyl-1-C2-(dimothyl~mino)-': . ~thyl~-l-propyl 312 135 1,4-diethyl-1-~2_(diethylamino)-. cthyl~-3,10-dimethyl 313 136 1~10-di~ethyl-1-Cl-methyl-2-. . (methylamino)ethyl~
314 137 1-(2-amino-1-methylethyl3-1,10-. dimethyl : 20 315 ~ 138 . ltlO-dimethyl-1-~2-~dim~thylamino3-_ l-methylethyl ?
. . 316 1~9 1 cyclohe.Yyl-l-[l,l-dimethyl-2-.- . . ~ (ethyla~ino)ethylJ-10-ethyl .~ 317 140 1-t-butyl-10-methyl-1-~2-(methyl-.; 25 ami~o)ethyl] .
.~. ,. ,. .... ,.~ l 1~1 1-butyl-10-methyl-1-C2-(methyl-. amino)e~hyl~
319 142 10-ethyl-i-C2_(ethyla~1no)ethyl~-. ~ 6-methyl-1-propyl ' ' ' ' ' ` '`i~ ' :
, ; , . ~ .

'' i ~ :
. A~~5786 /5921 3L~)36596 TABI~E lTIT
. _ ~ .. .. _ ~_ . ~ ' .` , , .~ NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX LIS~ED BEIOW)_ . .
. ST~RT~JG MATERIAL IS 3,4-DIHYD~o ~ ~ ,~-a~-.. E3W ~PLE PREPAR~l3 INDOLE
_ ... _ . .. _ ........... .. .. ... _ 320 143 8-br~o~l,lO-diethyl-l-C2-(diethyl . :-mino)~hyl~
:. 5 321 144 1 l-t2-amin~othyl)-10-butyl-8-~ethoxy-. I -methyl .
322 145 ¦ -acetoxy-10-t-butyl-1-C2-(t-butyl-. I mino)othyl]-l-mothyl 323 146 1 -(2-aminoothyl)-8-benzyloxy 10-. isoprcpyl-l-mcthyl 324 147 ¦ ,10-dlm~thyl-1~2-(dlm~thylnm~no)_ . I thyl~ propyl . ...
325 148 L~r2-(diethylamino)ethyl]-7 . I imethyl-l-propyl 326 . 149 ,10-diprop~ E2-(hcxyla~i~o)-. . I thyl]-8-nitro 327 150 L-C2-~M~thylamino)ethyl]-l-propyl-,4,10-tximethyl .:
32B 151 cyclopropyl-3,3-dimethyl-1-. ¦ 2-ami~o-1,1-dim~hyl]-8-ethoxy-LO- ~:
. . thyl .
20 . 329 152 0-butyl-1-cyclohexyl-3,3-dimethyl-. . -Cl ~l-di~ethyl_2_(ethylamino)_. ~ thyl~-4,4,7-triethyl 33 153 ,10-dimethyl-1-ethyl-1-~1-methy~--(methylamino)ethyl~-4,4,9-tripropy 331 154 . -Cl,l-dimethyl-2-~dimethylamino)_ thyl~-10-othyl-1-propyl 332 155 -t-butyl-l_Cl,l-dii~opropyl-2- , .
., diethylamino)ethylJ-3,3,4,4~9910-. . . ex~ethyl " ~........ . . ._ .. ... ~
._ _ . .~
' ' ' ''\, .

;

~ . -73-:. `
1~)36596 ~ABIE VII
~: , _ ... .~ . .
::
,.- , , . ' NO. OF EXAI~LE IN WHICH PRODUCT: (PREFIX LI~T~3 BELOW) STARTING 2~ATERIAL IS 3,4-DI~YDRO-i~-1,4-O~AZI~JO~,3-a]-; ~ XXAMPLEPREPA~D _ INDO~
~3~` 156 9-iodo-1-isopropyl-10-~ethyl-1-:. ~3~ thylami~o)propyl]
: 334 157 1-Cl~l diethyl_3_(methylamino) : propyl~-7-hydroxy-10-methyl-1-propyl ~ 335 158 1-C3-amino-2-propylpropyl~-1-: ) cyclobutyl-3,10-dimethyl-6-nitro 336 159 1,10-di~thyl-4,4-dimethyl-1~
tl,l-dimethYl-3-~cthylnmino)pro~ylJ
337 160 1,3-dlpropyl-9~ethoxy-10-m~thyl-. l~ m~thyl~3-(propylamino)propyl~
: 338 161 1-cyclopropyl-7-ctho~-10-ethyl-:ij . . 1-~2-ethyl-3-tethylamino)propyl]
; 339 162 1,10-d~methyl-1_~4-(methylamlno)_ . . butyl~ nmr (CDCl ) ~ 1.54 (s, 3H), .', . ' . 2.28 (s, 3H), 4.~0 (m, 4H), corres-.' . ponding hydrochloride addition salt ~'', . , has m.p. 166 - 168C.
.,,, 340 163 IJ10-dimethyl-1-r4-(dimethylamino)-.. .. buty!l nmr (CDCI ) ~ 1.59 (s, 3H), ;,~ . ~-. . = 2.28 ts, 3H),,3~8 tm, 4H), corres- : -.i~ . . . ponding hydrochloride addition salt .
.~ . ,, has m.p. 194 - 196C. ,:
.: 341 164 . 1-buty~ 4-(butyla~ino)-1,2,3-tri~ethylbutyl~-3;10-diethyl-7-.~ ~itro 342 165 1 ~1,2-diethyl-4-(d~propyla~ino)-... . ~ butyl]-3,3-dimethyl~l,9,10-.l. . tripropyl ~ .343 166 10-butyl~ _(butylamino)-1,1,3,3- ::
.;.l . totramethyl_butyl~ etbyl-6- :
.~l . . hydroxy 344 167 . 10-t-butyl~ 4_(di_t_butylamino)-. 1~1,2,2,3,3-hex~methylbutyl~-9-i. . . othoxy-l~ethyl .,, . .. __ ___ ` ~

,~ _ , . ' ~ ~, .
.` " ! ~ :
.. . . .
7~- :
` . ^ ~ . ' ~HP-s7~6 /592 1 3LQ36596 :
: , TABLE YI~
. ,~ .
~ .~ ~ ~ ~ ,~
. , . , ,: .
NO. OF EXAMPLE IN WHICH PRODUGT: (PRE~IX LISTED ~FIOW)-., STA~rING MATERIAL IS 3,4-DXH~D~0-~-1 ~ ~ ,3-~J~
_ -. ~AMJ?.LJ~ E~ _N OI,~__ _ _ ___ 345 168 1,10-di~ethyl~ 3~tl-pyrrol.idinyl)-prVpyil nmr (CDCl ~ S1.61 (6,3~1), 4,03 (4EI), o~rre~o~ding hydro~ :.
.. bromic Rcid adcliti.on salt ha~ m,p.
: 154 - 156C.t a~tor recry~talliz~.: tio~ from i~opropanol ~:-. 10 . 346 169 l~10-dimethyl 1-(3-plperidinopropyll .
: n~r ~CDCl ) ~1.60 (~; 3H), 2~29 (8, 3~ orro~pond~ng~ hydrobro~i¢
ncid addition ~alt ha3 ~pO 205 -, 27~ ter rocry~tallizat~on fro~
,., . i80propanol .:
. 347 170 1,10-dimothyl-1~(3-lnorpholinoprol)yl) .' . . nmr (CDCl ) $`1060 (~ 02 (41l) ao~ro~pon~inK hydrochloric acid additlon ~alt hfl~ m.p~ 210 - 212C.
after recrystalli~.ation ~ro~
ioopropanol ~:
348 171 l,lO~di~thyl-l (3-pipera~opropyl) . . 349 172 1110~dimethyl-].-l:3_(4 ~2thyl~1-:, . pipera~ l)propyl~, n~r (CDC~ ) .~; . ~ 1063 (6, 3H)~ 2031 (3H) corr~spon-;.; 20 in~ hydr~bro~lc ~cid ~ddlti~n ~al~
,~ (dIhydrobro~de) ha~ ~.p, 260 - 262 , 9 .~. after rec~tallization fro~
~othanol 350 173 1- ~4-(2-hydroxyçthyl)-1-piper~ yl]propy~ -19 10-di~ethyl 351 174 l,10-dimet~yl-1~ pyrrolidinyl)-~;~ . . ~ethyl~
352 175 l~10-dimethyl-l~tmorpholinomethyl) 353 176 l~e~hyl~3,10-di~othyl-l~t4-mothyl-- . ~ . . .. _ _ _ l-piper~inyl)m~thyl~

;'``, .. .
. .

. ~ .

. . . . . ... . . . .

~HP 5786/5921 )3~596 TA~LE YIX

: ..... _ ._ ;

... ' ~
.. NO. 0~ E~XA~hE IN WHICH PRODUCT: (PR~FIX LIST~D B~LCW~_ STARTIN~ MATERIAI, IS 3,4-DIHYDRO-1~- ~ 93 EX~MPLE P~EPARED INDOLE
., ,. _ . . ,... , _ _ 354 177 1,4,10 trimsthyl-1-(2-piperidino-othy.l) 355 178 1-ethyl-lO ~ethyl-1-(2-~orpholino-. .5 ethyl) ..
. 356 179 1-ethyl-1-~2-C4-~3-hydroxyp.ropyl)- :~
l-piperazinyl~ethyl~-10-methyl 357 180 10-methyl-1-propyl-1-~2-(1-pyrrolidinyl)~thyl~
358 181 10-methyl-1-propyl-1-(2-morpholino-.. ethyl) .
.. 359 18~ L-i~opropyl~10-methyl-1_(2-piperi~inocthyl) 360 183 3,10-dimethyl-1-(2-piparazinoethylj- ~`
: l5 -propyl .
361 181t -ethyl-10 m~thyl-l-cl-m0thyl-2- .::
. . t4-methyl-1-pipera~inyl)ethyl] ::
36?. 185 -benzyloxy-10-i~opropyl-1-methyl-1- ::
. 2-(1-pyrrolidinyl)ethyl~ ~1 : 363 186 ,10-dimethyl-1 (2-ptpsridinoethyl)- : -;.~( 20 -propyl ~ 364 187 -cyclopropyl-1-(1,1-diethyl-2- .
:~ ~rpholinoethyl)-3,3-dimethyl-8-. thoxy-10-ethyl . 365 188 ~acetoxy-1~10-diethyl-3,3,4~4-.~ etramethyl-1-(2-msthyl-3-. $perazinopropyl) ~ 366 189 -oyolopropyl-l~,8,10-trimethyl-1~
., l3-CI~-(2-hytlroxyethyl)-l-piperazin-. 1]-1,1,2,2-tetram~thylpropyl~ :
., . , _ .,~, , `";' ':'' ' ';, .' , ;' ; ~ -' AHp-s786/s32l :~
. . --; .
; ~36596 : TABLE VII
,: ---- .,.. : .
:~ ,. ' ' ~. ~ ,_ ,., .____ . ~
' . '`
NO. OF ~XAMPLE IN ~ICH PRODUCT: (PREFIX L:~S5'~JD B~LOW)- ..
.. STA~TING MATERIAL IS 3~h~DIHYDRO-lH 1 ~ INoc4~3 A3-~XAMPLE P~ PAR~D INDOLE
~ .. .. _ ...... ~ , ~67 190 . 1,3,10-trir~ethyl-1-C2,2-dipropyl 3-; (l-pyrrolidinyl)propyl]
368 191 1~10-diethyl-4,4 dimethyl-l~
:: . dimethyl-3-morpholinopropyl-) ::
369 192 1-cyclopropyl-1-Cl,2-diethyl-3-(4-propyl-1-pipor~z"~n,yl)propyl~7 l thoxy-10-ethyl 37 193 1 l,10-dimethyl-l-CI~ (l-p~rrolid.~nyl)-: . butylJ
371 191~ 1,10-di~nothyl-1~.~4-~4-(hydroxy~ thy:
. l-pip~ru~inylJbu tyl~
.. 372 195 1-t(l,l-diethyl-4-piperidino)bu~yl3~-, 1-propyl-3 3,10 tri~c~hyl .~ 372a 167a l 10-ethyl-1-methyl-1-r3-(methyl-.. , amino)propyl], nmr (CDC13) ~S 1.22 . ~t, 3H), 1.62 (s, 3H), 3.98 (m, ~1-1), corresponding hydrochloric acid addition salt has m.p. 157 - 159~C.

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36:~96 ~ABI~ VIII
--~ r~
;"' . ~
NOo OP` EXAMPIE IN WHICH PRODUCT: (PREFIX LISTED BFLI~OW)-STARq~ING MATERIAL IS ~ .DI~IYDllO-lll-~i ;~j~3-aJ~
5EXAMPL~_ P~EPARED ~ nL~
373 196 1~10-dimethyl-l~t3-~othyl~mino)_ -~
.. propyl~ :.
374 197 1-(3-aminopropyl)~l~10-dimethyl 375 198 1,10-dimothyl-1-[3-(di~ethylamino)~
. propyl~ :
376 199 1~lQ-di~s~thyl~ 3-(ethylamino)-propyl]
377 200 1~C3~(d~othyl~mlno)propylJ 1,10- ~`:
dimothyl . y78 201 l,lO~dim0thyl l-C~thylam~no)mothyl .!
379 202 l~(aminomethyl)-l,10-dimothyl `::
; 15 380 203 l-C(dlmethyla~ino)methyl~ ethy~-., 1,3,10-trlmethyl .
381 204 1,3-dli~opropyl-8,10-di~ethyl-1-.~ . C(hexylas~ino)methylJ
382 205 1-~ethylamino)methyl-8-hydro~y_ . ` 1,3~3,10-tetra~ethyl .::
383 206 6,10 di thyl~ r~thyl~Miuo~methyl- ~ ~:
384 207 l-cyclopropyl.l-(dimothylamino)_ methyl-4,10-diisopropyl . 385 208 1-cyolopontyl-3,3-dimethyl-1-;j (di~ethyl~mino)m~th~1-4,4,10-triethY1 386 ZO9 1-tmet~ ~m~nO)ethY~ 4~1O~tr1~

387 - ~ 1-t2-flminOethY1)-1-CthY1-1O-mOthY1 . _-- ........

.. . .
` 78-., A~-5786 /592l . . .
~36S~6 ~ABLE VIII
.
, .. _ , , __ , _ .. . _ ' ' ..... . , :. ~ . .
NO~ OF EXA~PLE IN ~ICII PRODUCT: (PREFlX LIS~ED BEIOW)_ . STAR5'ING MA~ERIAL IS ~,4-DIHYDRO-lH-i ~ ,3-~3-.: EXA~PLE PREP~EED INDOLE
,. ~ ~ ._ _ ........ ..
388 211 1-C2-(dimethylamino)ethyl~ ethyl-10-methyl 389 212 1-ethyl-1-r2-~h~xylam~no)ethyl]-10-.;^ 390 213 1_~2-(diethylamino~ethylJ-l-ethyl_ .~ 10-methyl . 391 214 10-methyl-1-t2-(mothylamlno)ethyl~-l-propyl 392 215 l-(~mlno~hyl)~10-methyl-1-propyl 393 216 l~C2-(dimethyl~ino)ethyl] 10_ , methyl-l-propyl ,. 394 217 1-~2-(hexylamino)othyl]-l~ethyl-1-. . propyl ` .
:~ l5 395 218 1-~2-~d~ethylamino)ethyl]-l~methyl-1-. . propyl 396 219 1-i~opropyl-10-methyl-1-~2-(methyl-ami~o)ethyl]
. 397 220 1~2-(diethylamino)ethyl]l-i~opropyl- .
. .= 10-~thyl 398 221 3,10-dimethyl-1-[2-(m~thyla~dno)-. ~ ethyl]-l-propyl 399 222 3~10-dim~thyl-l_r2-(dimethylamino)-ethyl3-1-propyl 400 223 1~4-diethyl-1-~2-(diethylamino)ethylJ .
:~ 3,10-dimethyl 401 æ4 1,10-dimethyl-~ methyl-2-(metilyl-am~no)~thyl3 .~ . 402 æ 5 1-(2-amino-1-methyl.ethyl)-1~10-.___ . . . di~ thyl ~_ ~r.

~.

~'` :', . ~ 1'' .
, : ~ -79-~HP-~7~6 /592l - ~36~i ' .. . ~ ._ .. _ .. . .
, , , NO. OF EXAMPLE IN WHICH PRODUCT: (PRÆFIX LISTED BELo~)_ E~UUD~LE _ STAKTING MATERIAL IS ~ ~
40~3 æ6 l~10-dimethyl -1-r2-(dimethylamino)_ . l-mothylethyl]
. 404 æ7 - 1-cyclohexyl-1-rl~l-dimethyl-2- ::
... (ethylaGino)othyl~-10-ethyl 405 æ 8 1-t-butyl-10-~ethyl-1-C2-(methyl-nm~no)ethyl~
406 229 1-butyl-~0-methyl-1-C2-tmothyl-. ~mino)~thyl]
, 407 23~ lO~othyl-1-~2-(ethylnn~no)othyl~-6_ .:
, . . . ~thyl-l-propyl : 408 231 8_bromo-1,10-dicthyl-1-t2-(diethyl-. amino)ethyl 409 232 1-~2-uminoethyl)-10-butyl-8-methoxy_ . . . . l-~ethyl .
. 410 233 8-acetoxy-10-t-butyl~l-r2-(t-butyl-. . , Amino)ethyl]-l-methyl 411 234 1-(2-aminoethyl)-8-benzyloxy-10-. ~opropyl-l-methyl 412 2~5 9~10-dimethyl_1_[2-.(dime~hylamino.)- : ~ .
.- ~ ethyl]-l-propyl 413 236 l-C2-(di~thylamino)ethyl~-7910-. ~ dimethyl-l-pro~yl 414 237 1910-dipropyl-1-~2-(hexylamino)ethyl~

415 238 . 1-~2-(methyl~mino)ethyl~ propyl-. 4~4,10-tri.~ethyl 416 239 1-oyolopropyl-3,3-d~ethyl-1-r2-. amino-l,l-dim~thylethyl~_8_ethoxy-~- I 10-ethyl \ :

. .

. .

.

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

AHP-~786 /592l ,' ' ~`
~L~3~596 T~BLE YIII
. _ , ~ , ,,, . ~
-' ~ , , _ .
. NO. OF ~XAMPLE IN ~ICH PROD~CT: (PR5FIX LISTED BEI~'.~)_ : STARTING 1~T~RIAL IS 3,4-DINIDRO-lN-1,~ AZ ~ ,3-a]-, EXAMPLE PR~PAREV INDOLE
_, . . . _ ._ .. . . . .~
417 240 10-butyl-1-cyclohexy1-3,3-dimethyl-. I-Cl,l-di~ethyl-2-(ethylamino)ethyl3-. . 4~4~7-triothyl 418 241 3~10-di~ethyl-1-ethyl~ 1-methyl-2-~methylamino)ethyl]-4~4~9-tripropyl 419 242 1-~1,1-dimethyl-2-(dimethyla~ino)-. ~thyl~-10-ethyl-1-propyl 420 243 . l-t-butyl-l-~l,l-dii60propyl-2-~ lO ~diethylamino)ethyl~-3,3,4,4~9~10-:: . 1~2l 2l~4 9-lodo~ opr~pyl-10-methyl-1-. ~. C3~(m~thylnn~no)propylJ
422 245 1-tl,l-diethyl-3-(ethyla~ino)-.. ~ . . propyl~-7-hydroxy-10-methyl-l~propyl ; I~ 423 246 1-~3-amino-2-propylpropyl~
. cyclobutyl-3,10-dimethyl-6-nitro . 424 247 1,10-di~thyl-4,4-dimethyl-1-~1,1-. dimethyl-3-(ethylamdno)propyl3 . 425 248 1,3-dipropyl-9-~etho~y-10-methyl-.20 -~ 1 ~1-methyl-3-tpropylami~o)propylJ
426 249 ~ 1-cyclopropyl-7-athoxy-10-ethyl-1-. . ~2-ethyl-3-(ethylamino)propyl~
427 ~5 l,10-dimethyl~ 4-(methylamino)-butyl~
. - -25 h28 251 1,lO~dimethyl-1_~4_tdimethylamino)_ .. . butyl~ .
.429 252 1-buty;_l-C4-(butyl~mino)-1,2,3-.~ . ¦ , trimethylbutyl~_3,10-diothyl-7-nitro 43 253 1-rl~2-di~thyl-4-(dipropyl~mino)b~ .
. _ . 3,3-dimcthyl-1,9,10-tripropyl "~ ' , ', ..
~ \~

.
:, .; , .~ , ~ i ~ 81-, A~-5786/592l i596 ~ABLE VIII
~' '~.'' __ . . _ _ :
~, ~ . ; , '' ' ,'. .~, . .~ , . "
. NO~ OF E5U~PLE IN ~EIC~ PRODUCT: (PR~FIX I~STED BELOW)_ STA~ING ~TEXI~L IS 3,4-DIHYD.lO_ ~ 0 ~ ,3-~]-.: EXhMPLE PREPARED INDOLE
. . . _ . . . ..
431 . 254 10-butyl-1-[4-(butyla~ino)-1,1,3,3_ . tetramethylbutylJ-1-ethyl-6-hydroxy 432 255 10-t-butyl-1-~4-(di-t-butyl~mi~o~_ :~
.. 5 1,1,2,2,~,3-hexamethylbutyl~-9-ethoxy-l-ethyl .. 433 256 1~10-~i.methyl-1-[3-~1-pyrrolidinyl)- ~.
propyl~
: 434 Z57 1~10-dimethyl-1-(3-piperidinopropyl) 435 258 1,10-d~mothyl-1w(3~Morpholinopropyl) 436 - 259 1,10-dimethyl-1-(3-piporazlnopropyl) 437 260 1~10-di~ethyl-1-C3-t4-methyl-1-pip~r~inyl)propyl]
4~8 261 1-j~3-t4-(2-hydroxyethyl)-1-piperazin . yl propyl~-l,10-dim~thyl 439 262 l,10-dimethyl-1-C(l-pyrrolidinyl~-' m~ Y~]
. 440 263 l~10-dimethyl-1-(morpholinomethyl) --.:~ 441 - 264 1-ethyl-3,10-dimethyl-1-[(4-~ethyl-. --_ l-p~peraz~nyl)~ethyl~
- 442 265 1,10-dimethyl-1-(2-piperidinoethyl) .i . 443 266 1-ethyl-10-methyl-1-(2-morpholino-ethyl) 444 267 1-ethyl~ 2-~4-(3-hydroxypropyl)-: 25 l-pip~razinyl~ethyl~-10-methyl .
445 268 10-~ethyl l~propyl-1-C2-(1-pyrrolidinyl)othyl3 ; 446 269 10-methyl_l_propyl_1_(2_morphol~no-.~ I eth.~

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AT~P-5'i'~`6 ~592 1 3l~3659~

rrh?~ XII
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.,.
." ' N`r C~ qPLE X~1 WHICH P~IODUCT: (PR~FIX LIST~ FLOW~_ STARTING MATEXIA1 IS ~4-DI~I~DRO-lH~ Oe4~3~ ::
EY.AMPIE ~ ~QI ~ . .__ :
: 44'~ 270 l-i~opropyl-10 ~ethyl-1-(2 pip~ridinoethyl~ :
448 2?1 l 710-dimethyl-1.~(2-.pip~razino~thyl)-l -prop~l 449 272 L-ethyl-10 ~ethyl-l-[l ~ethyl-2-~4-~ ethyl-l~pip~r~zinyl)ethyl~
.. 450 273 .. benzyloxy-10 l*opropyl~l-methyl-l-.. , ~, C2-(1-pyrx oJ.i(linyl)ethyl3 451 274 9~10-dl~othyl-1-~2-~iparldlno~hyl~-l~propyl . 452 2'~5 1-cyolopropyl~ dlothyl~2~
'.~ moxphol:lrlo~hyl)-~,3_di~thyl.,8-~th~xy_10-ethyl 453 276 6-Acetoxy-l,10-diethyl-393,4~4- ~.
.~ I5 totramethyl-1-(2-~thyl ~-piperaz~nopropyl) t54 2~7 1-cyclopropyl-4,8,10-trimethyl-1-~-~4-~2-hydro~yethyl)-l~pipqraæi.n-~ yl]-1,1,2,2-tetr~methylpropyl~
:;. 455 278 1~3,10~trimethyl-1 ~2,2-dipropyl-3-. (l-pyrrolidin~l)propyl] :~
456 279 1,10 diethyl-4,4-dim~thyl-1-(1,1 . dim~thyl-3 ~orpholinopropyl) .. 45? 280 l~cyclopropyl-l-[l ,2-di,et~yl-3- ~:
~4-propyl~l piperazinyl)propyl~-7-. 25 . . ethoxy-10 ethyl 458 281 1,10-dimethyl-1- [4- ~ l-pyrrolidinyl ) . butylJ
459 282 ~ l~10-dimethyl.~ ~ roxy~ethyl~
~ pipera~inyl~butyl3 .. l ; 460 283 1-C(l,l-diet}lyl-4 piperidino)butyl]-30 . ~ lcE~ropy~ 39lo-trimethyl _ .' .
" .

. A~-5786/592l 1~6S~
`
.~ EXA~L~ 461 . ~/dole-l-c~rboxa~lide - v; Rl and ~ C ~ "
_ and R H,_X = O and Z _ CON~

:. ;
By ~ollowing the procedure of ExAmple 4 (Procedure B) ;: .
but usin~ an equivalent amount of pyruvamide instead of levulinic ':
acid, the title compound, identicAl with the product of Example ',lO l14, i~ ~btained.
'~ ' In the 6ame manner but u~in~ an equivalent amount of , t"he appr~priate stAxtinb matorial o~ formula IXI in place of 3-methylindole-1-ethanol to6ether with the appropriata a~
or 6-keioamide~ the products listed in Example 107 and Tables lll, IV, V and Vl are obtained. For example, by usincZ 3-bu~yl-5-methoxyin- .
dole-l-ethanol and the ~ ketoamide, acetoacetamide in the procedure '' . , .. of th~s'eZxample~ 10-butyl-8-methoxy-1-methyl-3,4-dihydro-lH-1,4-i", oxazinot4~3-a~indoleZ-l-aoetA~ide~ identical to the product of .'.'~ , Ex~mple 144, i8 obtained.
.2~ . ' .'' :' ., ~ '' ' ~' ~'.:~ ` . ..... .

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: ~36S96 . ` EXA~7hE 462 .. . .

: .

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Procedure A: r The flcid ~ntermediate of for~ula ~ 10-dir.~thyl_ 3,4-dihydro-1~-1,4-oxazino~4,3_a]indole-1-propionic acid (10.4 g.), described in Example 4, in 100 ml. of rHF i8 ~lowly added to a 6tirred mixture of lithium alu~inum hydride (2 g.) in 100 mlO of T~DF, ~he reaetion ~ kept at 0C.
using un ice-water bath, Aftor additi.on of the acid, the exccss of th~ hydride i8 do~troy~d with water and the prooipit~tc i8 coll~cted on A filter pad, The ~lltr~tc i~
~v~porut~d, Tho re~idu~ i8 takon into oth~r and tha other . i . phuso i~ ~ashed ~rith water, dried (Na2S0~) flnd evaporatcd , . at reduced pre~6ure to af~ord an oil. Chromatography of the oil on cilica gcl u8in~ ethyl acetate-chloroform give~
' tho title co~poun.d,~ C~IC13 3610, 3450, 1080 cm~l.
:,` ~ B:
.. _ Alternatively, the title compound i8 ~18~ obtained ~ by follow$nz the procedure of Example 4 (Procedure A) but r~placi~g ethyl levulinate with an equivalent amount of the , . ~etoalcohol lower alkanoic acid ester, 5-acetoxypentan-2-one. Note ~ thflt the procedure of 6aid example include6 hydrolysis of ... ~ the intermediate ester.

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.
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-85~ t~l A~ 57~6 j5 92 1 .
~~~~ ~L~36S96 ~ro- -~ 2 -2 ~ ~
.: . . , ,- . ' ; 5 1,10-Dimethyl-3,4-d~hydro-1~-1,4-oxazino~4,3-a]indole-l-propanol (9.5 6.)- described in Exa~ple 462, iB di~BolVed in dry py~idine (20 ~1.), E~Tolu~ne~ulfonyl chlor~d~ (7.4 g.) i8 addod poltionwi~ to thc ~gorou~ly ~tirred and cool~d 601utio~.
Th~ mixturo iB ~tirred furthor at 0C. ~or 1 hr " ico and .0 water ~8 then Rdded and th~ aqueous ~ixture ifi ~xtractcd with ..
: other. ~ho combined oth~r oxtracts are wAshed with 10~ ico-cold hydrochloric acid, wfltor, 5% ~odium bicarbonato w~ter and .. dr~ed (Na2$0l~). Concontratlon o~ tho extracta ~forda .
1,10-dimothyl-3,4-dihydro-lN-1,4-oxazirlo~lt,3~ ndolo-1-propyl S tosyl~to, ~ C~Cl 1600~ 1370, 1190 and 1170 cm 1.
. Tho latt0r to~ylate (12.~ g.) iB dissol~d ~n dry occtonc (~00 ml.) and th~ r~sulting ~olution troatcd ~ith ; :
odlum iod~do (15 g.). The mixture 16 ~tirred at roo~
~, te~pcraturo ror 24 hr. Mo~t o~ tho acetono i8 r~moved at ,0 - reduced pressure, w~ter and i~e are addod and the re8ulting brown-colored ~olution i5 extr~ctod with ether. The combined :
~th~r extracts are wn~hod with 10% sodi~u~ thio6ulfato 801utio~
a~r and dried (Na2S04). Thè 601vent i8 ~aporated under ;- . reducod preB~ure to 6ivo a yellow oil. The o~ ub~ected ~o ..
~,S chro~atography on ~ilica gol and elu~d with benzono.
. ~ Concontration of the eluatc ~ffords 1,10-dimothyl-1-(3-i~dopropyl)-3,4-dihydro~ 1,4-oxazino~4,3-a~indolo, nmr (CDC13) & .59 (3M), 3.13 (2~). . .
A mixturo of tho lattor compound (10.2 ~,) in 10 ~HF and 40~ Aquoous methylflmine ~(199 ~1.) i6 ~tirred at ~.

roQm t~mper~turo for 6 hr. ~ost of tho totrahydrofuran i8 re~o~ed at reduced pre~auro~ th~ milXy wnter ~olution i8 ` ' ~

~ -86~
.. . . . .. . ... . . . . . . . . . .. . . . .

- AHP'5786/5921 :; 9.036S9~i extracted with ether and washed wifh water until the water .
tests neutral. The extract is dried (Na2S04) and evaporated .
to yield the title compound, identical to ;he product of .
Example ~85. .
. By following the procedure of Examples 462 and 463 in sequence but using as starting material in Example 462 an equivalent amount of the appropriate ester intermediate of formula V ~in the case of Procedure A) or an apprbpriate intermediate of formula 111 and appropriate ketoalcohol lower ~;
. Io alkyl ester of formula IV, described above, (in the case of ~
Procedure B); followed by the use of.an appropriate amine of :
formula HNR8Rg, for example the amtnes descrlbed In Example 107 i .
in the procedure o~ Example 463, then the respective compounds of formula 1, for examplo those described In Exampl~s 284 to 460, . 15 are obtaTned.
More speciflcally exempllfled, by following the . ~ procedure of Example 462,.(Procedure A) but replacing 1,10-dimethyl-3,4-dihydro-lH-1,4-oxazino r4 ,3-a]indole-1-propionic .. : acid with 1,10-dimethyl-3,4~dihydro-lH-1,4-oxazino[4,3-a]indole-I-butyric acid, described in Example 49~, then l,10-dimethyl-3,4-dihydro-lH-1,4-oxazino~4,3-a]indole-1-butanol, vcaHcl 3600 ~ and 3460 cm 1, is obtained. Thereafter, by following the :. procedure of Example 463, the latter compound is converted to its corresponding tosylate, ~cmHcl 1600, 1370, 1190~ 1170 cm 1, which in turn is treated with sodium 70dide to 9ive 1,10-d7methyl-1-(4-iodobutyl)-3,4-dlhyaro-lH-1,4-oxaz7no[4,~3-a]indole, m.p. 60 - 62C. Subsequent treatment of the latter compound with ethylamine gives l,10-dimethyl-1-[4-(ethylamino)butyl]-3,4-dih~dro-IH 1,4-oxazino~4,3-a]indole, nmr (CDC13) fi 1.54 (s, ;H), 2.25 (s, 3H), 3.98 (m, 4H), the corresponding hydrochloric acid addition saIt of which has m.p. 144 - 146C.

.
. .

AHP-5786 /592 l 36~ ; ExAMpIE 464 .~ I
'~ CI~CH~N(CH CH ~ ~

:: .
; ' 5 Jl fsolution of t~ th~rloxfonlunt fluoroboratf~f (~.5 g.~ ~ :
0.0185 molfofs) und the fsmlde o~ formul~ Y, N~N.;diff~t}url-10-methyl_ lfffffffpropyl-3~4-dihydro~ 4-oxazino~4,3_a~1ndol0 l-acetef~de . ~ 5.5 6.~ 0.016 ~oles), d~scrlbed ~n ExaDlple 130, ~ 100 ml. og ~5f~ :
' 1 s~eth~lene chloria~ `r8 eYaporsted at reduoed Fres~ure and the ; ! lo roeidue dissolved in 50 o~l. o~'' abf~olutfef et~anol. Sodi . boroh;rdrlde ~1.35 fff3~, 0.035 fff~ffolef~) lf8 ffldded in portionfs to th~
. j fst:Lrrf3d solution fl~ft 0C~ When the fadditif3fn i~ ooffnplfet~fff~ ..
l , fst~r~ng f~ff oofntinued ror 18 ~irff. fE~t ~soa. ~h~ f~foluticfffn i~ff ` ' ~ "f , ~ ~ , , :, pour~fd lnto 25a ml~ of'' wf~ter and extrefctet with 3 X 30 ml.
pcfrtionfs of ether. ~I!he combined extracts are wafsfhed ~ith WAter~
il. dri0d (Mf~f~4~ f~ffnd efYaporf~ffted yieldlng the titlfe compcu~d~
~ idf4fntical to thfaf pfroduct o~ E;xampfle 307f.
f. SllDilarly other f~ldde~s Or formula V, foi ffafxaf~,ole f ~ ' thosfsff described in Exa~pl~ ' to 28f3~ f~fy be reduced to their ~ :
, 20 corrff~sponding ox~ffzi~o~dolfafs of formulf~
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AHP-5786 ~592l 031E;59~
, :'' ~ ` ' .'.
: .
: l.10-Dimeth.yl-3,4-dihydro-lH-1!4-oxnzino_ , ' . . . ;_ .:
;, ,.
~ N~N_D~cyclohexylcarbod~imide (2.87 g.) i~ added to . a oooledg ~tirred aolution o~ the primary alcohol, l,10-dimeth~
.: 3,~-d~hydro-1~-1,4_oxazinoC4,~ a~indole_1~propanol (1.0 g.), -.-, .,. 10 .
;.~ described ~n Exampla 4629 in 10 ~lo of dimethyl sulroxide .;
b~nzeno (2:1) conta$nlng trirluoroac~t~c ac~d (0~18 ml.) and 1 . p~rldine (0.38 ml.)0 ~he reaction i8 stirred at room te~perature i under nitrogen for 5 hr. The roaotion mixture 1~ now diluted with ,, ! 100 ml~ 0~ ether~ followed b~ the dropwise addit~on o~ a ;'';1 .~ 801utio~ of oxalic Doid ~i.26 g,) in 6 ~1. o~ ~th~nol, A~ter . thirty ~dnute~, water (100 ml.) i8 added and th~ insoluble ...... 20 material i8 collected. ~he or6anic phase i8 wa~hed w~th water ! . ~2X), 5~ aqueous sodium bicarbonate (2X) and watcr (2X). A~ter ~, . i drylng (MgSQ4) the organic ph~e iB e~porated to yield an :~1 oil. The o~l i8 purified by chro~atography on sil~ca ~el~

¦ 25 Elution ~ith lq~ eth~r in benzene af~ord~ thc title co~pound 1 ~ an oil~ MxcXl 1720 c~
:
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. .. . ; . , . . ~ . , l~n~-s78~ss? 1 )3659~i ~,XAMPL~ 456 :` ., ~ e ~ dro- -: 5 .; The product of Example 465 is treated with dimethylamine and perohloric acld according to the method of NoJ~ ~eon~rd and J. VO Paukfttelis9 J. Org. Chem.~ 28~ 3021 (1963), to yield the correspondin~ i~monilua salt. Reduc~ion of the latter compound wlth ~odium borohydrlde accordlng to the procedure de~cribed by -.
; E, Schenkerl Angew, Chem" ~; 81 (1961), af.ford~ the : .
~:: title oo~pound~ ldentical to the produck o~ EXAmP1~ 287, ~
~y followlng the procedure o.~ ~xamples 46~, 465 and ,~ 466 in sequenae bu~ us:ln~ a~ 0tarting material in Examplo It62 an equivnlont Mmount o~ the apprOpriAte aoid int~medl.ate ~ Or formula V (in the ca~o Or ~rocedure A) or an approprlate ;,.. , 20 intermediAte of form~la III and tho appropriate ketoalcohol lower al~yl ester of forraula IV~ de~cribed above, (ln the . c~se of Procedure B), ~ollowed by the u~e o~ an appropri~te amine of formula HN~ R9, for example the ~mines de6cribed ~n Example 107, in the procedure o~ ExAmple 465, then the resp~tive co~pounds of for~ula I, for ~xample those de~cribed ..
~ - in Exa~ples 284 to 4~0, are obt~ined. .:

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h~~57~6 /592 1 `.~ 1036Sg~

~, . ' :
.
: Oxidation of l~lO~dimethyl-~,4~dihydro 1~194-oxa~no[l~,3-a]indole-l~propionaldehydo9 de~cribed ~ Ex~mple 465, : 5 with ~$1ve~ oxide accord~n~ to the method of D~l~pine and Bonn~t, citcd ~bove, Affords 1,10-dimethyl-3,4-d.ihydro-lH-1,4-ox~inoCI~93-a]indole-l~propionic ucid~ idonti~ll to the product of Example 40 i' ~y ~ollowing the proceduro of ~xa~ple~ 462, 465 u~d 467 in sequ~nce~ but u~ng h8 sturt-lng m~terlal in Exampl~ 462 un equlvulent amount of the ~ppropriate acid intormod-late of ; ~or~ulu V (ln the oaao of Procedure A) or ~n ~ppropriute torm~d~atc o~ ~ormulu IXI and appropriate koto~loohol lowor ~ kyl 0~ter of ror~ltlu IV~ de~oribed u~o~o~ ~ln tho ctl~e of,~ lS ~rooedure ~)~ than khe re~peo~ivo ao~-d co~pot~du of formml~ Y
ln whioh Z is COOI~ or AlklCOOH wherein Alkl lo a~ d~fined in tho fir~t in6ta~ce, for oxnmpl~ the prod~t¢t~ Or .~Yu~ples 5 to 10S ure obtuinedO

.' ' `, . , .

:,, , . ' hl~~5786/592l ~L036596 ~A ~ 466 : ~:
~ ~nd n7 = CH
~ nd AlkN ~ R9 - C~I~C~2 _2 '',' , :' .
A solution of th~ ~ldehyde~ l~10-dimethyl-3~4-dihydro-lH-1,4-oxazinoC4,3-a~indole-l~propionaldehyde(l.0 gO~ de~cribed in Exa~ple 465~ aqueous hydroxylamine hydrochloride (5 mlO of 5N) and aqusoua sodiu~ acetate (5.0 ml. of 5N) and methAnol . . .
(10 ml.) ie heated ~t 50 - 600C. for 5 min. and thon ~ept at ; 4C. for 16 ~. The precipitate i~ oollected n~d lecryst~ .ed from eth~nol wator to ~fford the oorro~pondln~ oxlme of tho abov0 ~ld~hyde.
;~ 15 ~he latter oompound (230 m~,) in dry ~'H~ (10 ~1.) 18 added dropwise to a stirred ~ixture of lithium ~luminum hydride (200 mg,) in 15 ml. of THF at ice bath temper~ture.
Th~ mixture i~ ~tirred for 1 hr.~ durin~ which tima it ie ~ ~llowed to ~ome to roo~ te~perature. Excese llthium ,, ~ . ..
- ~ 20 ~lu~inum hydride i8 de~troyed by the care~ul addition of H20/THF ~1 l)e In~oluble material is ~ollected o~ a filter and the f~ltrate 1~ conoentrated~ The co~centrate i~ taken up in ethqr. The ether ~olution i6 dried (M~S04)~ flltered i and ooncentrated to afford the title compoundj ldent~cal wlth the pr~duct of ~mple 286.
` ~y followin~ the proceduro~ of E~amplc~ 4629 465 and 468~ equ~noet but using a~ startin~ mater:LRl in ~.
Example 462 an equivHl~nt amount of the appropriate acld intermediate of formula Y ~in the case oY Prooodure A~ or an " . ;,.
. .
.. ~ . .. ..
'. , ,. , ' ``~
~ -92--:, A~ 57~Q)6/592 1 ~L~)36596 appropriate ~ntermediate of ~ormul~ together ~ith an appropriate ketoalc~hol lower ~11~1 e~t~r of ~ormNla IV9 described ~bove, then the re~pective pr~ary a~ine of formula I 1~ obtain~d. Morc specifically ex~mplifi~d, by roplaci~
1,lO_di~ethyl~3,4-dihydro~ oxRæino~4,3-a]indole-1~
propioni¢ ~cid wlth an equivule~t amoullt of 10-methyl 1- ~:
propyl-3~4-dihydro-~l-1,4~oxa3ino~4,3-a~indole~l~acetic ~cid~
described in Example 14, i~ the prooedure of Ex~ple 46~ and sub~ecting the product thereo~ to tho procedure~ of Example~
465 ~nd 46B, then l-~amlnoet.hyl~-10-metllyl-1-propyl-3,4-dihydro-lH-1~4-o~læinoC4,3-a~lndole, identlo~l to tho product o~ Examplc 30L~ ohtainedO

' ., i ' ~
.,'~ ' . ' ' :`
:
`; :
''~ . ' .

;, ,`, ~ ~ .
. ' ,....
.

.

A~IP-578~/592I
LiD365916 EX~PIF. ~

. j . . .
~4~d~h~ o~
, ~7 ^~- 7 , ~:
R R and R = H X - O and ~ = CH ~I CH I) _--~ 2 :,:
' ~0 A 801ution 0~ 3-methylindole-1-ethanol tl5 8.) .~. . .
in 150 ~1. of benzHne, 5-lodo~2_pant~none tl2 g,) 1B add~d.
qlhe mlxture i8 heated at ~oflux wlth 200 mg. of ~-toluenesulfonic acid and hydrAted alkali-alu~inum silicate (Molecul~r sieve8 No, 4). A~ter one hour 400 mg,mora of acid i~ added. Aftsr a ~otnl of two hour~ tho reaction i~ cooled, filter~d and , ~ washed with 5% ~odium bicarbonata~ wator ~nd dried oYer ~odi ~ ~ul~te. ~vnpor~tio~ undar reducad pres~urc a$ford~ ~n oil, ;; 15 ~hi~ o~l ia puri~ed by ohro~to~r~phy on sllioA ~ol~
,;, .~.
Elution with ben7.en~ ~nd conoentratlon oi the oluate give~ tho ~itla compound, identical to tha oompound of the 6a~e ~a~e ~, de~cribed in Example 463.
By ~ollowing the procedure of Examp~e 469 but u8in~
,. i .
a~ starting ~ateri~ls un appropriat~ intermediat0 of formula ~ :
III d~6cribed above, togeth~r with an ~ppropri~te ~, ~ or -h~loketono of formula IV de~cribed above, then the corre~pond-: ~
g lntermediate6 of ~oxmNla V (æ = Alk2-L in which A11~2 and L
ar~ a~ d~ecrib~d ln the ~ir~t lnstànce) are obta~ned, In turn the la~t sald intermediates of formula V ~y .:
~:' be treated aocording to condltion~ d~scribed ln Exampl~ 463 , with an appropriate a~ine of Sor~ula HNR8R9 in wbich R8 and R9 ;.
:, Are a~ de~cribed in the first instanco to yield the oorrespondln~
:' oxazinoindoles of for~lla I~ for instancfl the products of ~ ~o ~xample~ 284 to 289, and 386 to 438. `~

.' , .

.. . .
.-94-. ~ . .

AHP-5786/5~2l -f~ 3 6 5 g 6 .~ EXhMPLE 470 o)~ropyll-3 ~-d~ydr~-lH-l,~-oxRzino-~3-~Jindole (I-~ R
,'',., . ~

A mixture of 3-methyl~ndole-1-ethanol (4.2 g.) and 4- oxopentyl~cetamide (3~7 8), described by ~.P. Kuhn ~
J0 Am. Chem. Soc., 89, 3858 (1967), in 300 ml of dry benzene 1B stlrred and heated at re~lux. Water 18 collected in a De~n-St~rk trap. A~ter remov~l o~ the water five drops o~ boron tri nuoride-etherate ls added and the mixture refluxed 30 min.
~` using the water-separator agal~. A~ter stlrring at room temper-ature overnight the reactlon mixture i6 evaporated to dryhe88.
The solid re3idue iB dissolved in chloro~orm and washed ~uccessirely with l ~ a~ueous sodium blcarbonatff~ water~ and brlne. ~he chloro~orm BolUtion iB dried over ~gnesium ~ul~nte ~ , ~iltered, and evQpor~t~d to yield 1-~3-t~cetnmido)propyl}-l,~0-dimethyl~3~4-dihydro-IH-l,4-oxazlnot4,3-a~indole y CHC13 1650 cm-m~x The latter product (2.6 g) in 80 ml Or dry TEF is , added to a suspenslon of lithium aluminum hydride ln 200 ml ~; 25 ` o~ T~F. The resultant slurry i~ stirred and heated at ~

i re~lux ~or 2 hour6, cooled ~nd 2.4 g Or lithium ~luminum hydride i8 ~dded. The mixtuxe is heated at reflux ~or 16 hours. The mixture i8 then decomposed with 22.4~ml of water added dropwise , !
-1 o~er 3 ~our~ while Btirring ~nd cooling the mixture. The `~;3 30 precipitate is sepQrated by filtration. The filtr~te ls dried (MgS0~). Removal of the sol~ent affords the title compound~ identicsl to the product Or E~nmple 2e8.
'' .,., . ' '.

.~; . . ..
. , ': ~' ; . , , ' ' `1 t;~ - ~5 A'II)- 5~ 5'6~5921 , ' '~:

1~3~596 j;
By follcwing the procedure o~ Ex~npl~ 470, but uslng starting material an equivalent amount o~ the appropriate ~tarting material o~ formula III, for ex~mple, those de~cribed in Exa.mple~ 1 to 106 and u~ine an equlvalent amount of an ~ppropria~e ketoamido of ~ormula R~ Alk - NR8C0~ 0, described above, then the re~pective secondary amine compouras :~
: of formula I are obtained.
: ,''~ '' ,' , ;~''.
' ';'''.
'' .' ' '.

.,., , ;~, .

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

~..

.
;:
. -96- :

h~lP -5786 /5921 ~. _ 1~3659 , ~.
: ' 4_ Oxa~inOr4 3-a~indol~ (V R1 ~nd R7 ~ CH~ R2~L~
5 R5 ~nd R~ = H X = 0 and æ . CI~ CH N0 ) To a ~olution of 352 mg, o~ 3-methylindole-1-oth~ol and 273 mg. of the nitroketone, 5-nitro-2-pont~none, ~I. Sheohte~9 et ~1., cited above, in 100 ~1. of benzono i~ added 5 drop~ o~
boron trifluoride ether~te und threa drop~ of trifluoroacetic acid, The reaction mixtur0 i~ otlrred ~nd heated at reflux under u wator-~eparator fo~ 18 hr, The benzene ~o.lutio:. cooled~ wn~hed with 10~ ~odiu~ bicarbonato ~olllt~on, wuter~
nturatod br~lc ~olut~o~, und drled over n~ner.l~um ~ul~nto, The ~olvent iB removod und the re~idue i~ ~ubJeotod to chro~atoernphy on ~ilica gel. Elution with ohloroform ~Lve~
tbe tltlc compound,~ a~Ixl3 ~50~ 1550 cm lo Reductlon of the latter compound w~th llthium alu~inum hydride according to the procedure of Example 464 i,~ , .
: 20 af~orde 1-(3-a~inopropyl)-l,lO_di~ethyl-3,4-dihydro-lH-1,4-. oxazino~4~3-a~indole, identical to th~ product of Example 286c .: ~
By following the procedure of Example 471 includin~ :
the reductlo~ described therein but u~ing as starting ~ateri~l .~ an equivalent a~ount Or th~ appropri~te æt~rting material of formula III~ for example, those de~cribed in P`,xnmplea 1 to 106, and u~ing an equivalent amount of ~n appropri~to nitroketoIle of 1 formula R~ AlkN02, de~crlbed nbove, then the re~poct~ve :., prim~ry amine compounds of formulA I are obtained, .:.
.. . .. .......... . ...
: I . ,, , .. . .
.'' , . ~ ' ,: ~

-97- ~

, ~ 103659~;

I;lO-Dimethyl-l-r3-(methYlamino~DroPYll-3~4-dih~dr 1;4-oxazinor4;~-alindole ~l; R! and-R7 --~H~ -: - R ; R . R5 a n d R - H X =-O. Alk = ~H ~ ~ 2 ' ' ' ' F~ - H and-R = CH_) ~ ..
. . ,:~ ' To a solution of D-toluenesulfonic acid (2.28 9~ in toluene . . .
~40 ml), the starting' material of formula 111, 3-methylindole-l-ethanol "' ~1.6 9), and the aminoketone, 5-(methylamino)-2-pentanone (1.3 9~ ~' ;' are added. The mixture is evapo'rated under reduced pressure and the residue stirred under nitrogen at 130C. ~bath temperature) ' for 45 mln. The mixture is cooled, water (20 ml) added and the mixture extracted with toluene. The toluene extract is washed with 5~ sulfur7c acld (5 ml) and wlth water ~5 ml). The aqueous layer contalnlng a dark heavy oll Is combined with the aqueous washes.
Cdnc. NH40H (lO ml) is added and the mixture extracted with toluene ' 15 (lO ml and 2 x 5 ml). The combined toluene solution is washed with `~
' water ~2 x 5 ml), dried'(Na2S04), treated with charcoal and evaporated ' ' 'under reduced pressure to afford the title compound; identical to the product of Example 285.
;' In the same manner but replacing 3-methylindole-l~ethanol '' ~ 20 with an equivalent amount of sodium or potassium 3-methylindole-I-ethyl thiosulfate, the title compound is also obtained.
By following the procedure of Example 472, but using as';
starting material an equivalent amount of the appropriate starting material of formula 111, for example, those described in Example I to 106 and using an equivalent amount of the appropriate aminoketone of formula R C0-Alk-NR R wherein R , Alk, R and R are as defined in the first instance, then the corresponding oxazinoindoles of ~ormula I

are obtained.

', ~ ' `' ' .
_9~,_ i, . . . . . .

Claims (92)

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

1. A process for preparing a compound of formula I
I

In which R1 is lower alkyl; R2, R3, R4, R5 and R6 are hydrogen; R7 is lower alkyl; X is oxy; and Alk is CH2CH2, CH2CH2CH2 or CH2CH2CH2CH2 and R8 and R9 are selected from hydrogen and lower alkyl, or R8 and R9 together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperazino, morpholino, piperazino and 4-(lower alkyl)-1-piperazlnyl, comprising; reacting in the present of an acid catalyst a compound of the formula III.
III

in which R2, R3, R4, R5, R6 and R7 are as defined herein and X1 Is hydroxy, with a compound of formula in which R1 is lower alkyl and Z is selected from the group consisting of (a) COOR19 and Alk1-COOR18 in which R18 is hydrogen or lower alkyl and Alk1 is CH2, CH2CH2 or CH2CH2CH2, (b) CONR8R9 and Alk1-CONR8R9 in which R8 and R9 are either the same or different selected from the group consisting of hydrogen and lower alkyl, or R8 and R9 together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, piperazino and 4-(lower alkyl)-1-piperazinyl and Alk1 is as defined herein, (c) CH2OCOR19 and Alk1-CH2OCOR19 in which R19 is hydrogen or lower alkyl and Alk1 is as defined herein, (d) Alk2-L in which Alk2 is an alkylene selected from the group con-sisting of CH2CH2, CH2CH2CH2 and CH2CH2CH2CH2 and L is halo (e) Alk-NR8COR20 in which Alk is as defined herein, R8 is hydrogen or lower alkyl and R20 is hydrogen or lower alkyl containing one to five carbon atoms, (f) Alk-NO2 in which Alk is as defined herein, and (g) Alk-NR8R9 in which Alk, R8 and R9 are as defined herein, to obtain the corresponding compound of formula V
V

in which R1, R2, R3, R4 , R5 , R6 , R7 , X and Z are as defined herein; followed when said compound of formula V is different from said compound of formula I
by processes selected from the group consisting of A. subjecting the compound of formula V In which Z is COOR18 or Alk1-COOR18 as defined herein, to optional hydrolysis to the corresponding acid in the case where R18 is lower alkyl, subjecting the instant product to amidation with an appropriate amine of formula NHR8R9 in which R8 and R9 are as defined herein to give the corresponding amide, and reducing the amide with a suitable complex metal hydride to give a compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined herein, and Alk3 is CH2 or Alk1-CH2 wherein Alk1 is as defined herein; or B. subjecting the compound of formula V in which Z Is CONR8R9 or Alk-CONR8R9 as defined herein, to reduction with a suitable complex metal hydride to give a compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined herein, and Alk3 is CH2 or Alk1-CH2 wherein Alk1 is as defined herein; or C. subjecting the compound of formula V in which Z is CH2OCOR19 and Alk1-CH2OCOR as defined herein to hydrolysis with a suitable alkali to give the corresponding primary alcohol, treating said primary alcohol with (I) a suitable oxidizing agent to give the corresponding aldehyde, treating the aldehyde with either an amine of formula HNR8R9 in which R8 is hydrogen and R9 is hydrogen or lower alkyl to give the corresponding Schiff base or with an amine of formula HNR8R9 in which R8 and R9 are lower alkyl or together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, piperazino and 4-(lower alkyl)-1-piperazinyl, in the presence of perchloric acid to give the corresponding immonium salt, reducing the instant intermediate with sodium borohydride, (2) a suitable halogenating, mesylating or tosylating agent and reacting the intermediate obtained thereby with an amine of formula HNR8R9 in which R8 and R9 are as defined herein, (3) a suitable oxidizing agent to give the corresponding aldehyde, treating said aldehyde with a suitable oxidizing agent to give the corresponding acid subjecting said corresponding acid, subjecting the latter compound to amidation with an appropriate amine of formula HNR8R9 in which R8 and R9 are as defined herein to give the corresponding amide, reducing said amide with a suitable complex metal hydride.
(4) s suitable oxidizing agent to give the corresponding aldehyde, treating said aldehyde with hydroxylamine to give the corresponding oxime, reducing the oxime with a suitable complex metal hydride to give the corresponding amine, and is desired subjecting the amine to optional N-alkylation with an appropriate organic halide to the extent required and desired, to obtain a compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined herein, and Alk3 is CH2 or Alk1-CH2 wherein Alk1 is as defined herein; or D. reacting the compound of formula V in which Z is Alk2-L as defined herein with an amine of formula HNR8R9 in which R8 and R9 are as defined herein to give the corresponding compound of formula in which R1, R2 , R3, R4, R5, R6, R7, R8, R9, Alk2 and X are as defined herein; or E. reducing the compound of formula V in which is Alk-NR8COR20 as defined herein, with a suitable complex metal hydride to give the corresponding compound of formula R1, R2, R3, R4, R5, R6, R7, R8, R20, Alk and X are as defined herein; or F. reducing the compound of formula V in which Z is Alk-NO2 as defined herein, with a suitable complex metal hydride to give the corresponding amine, and subjecting said amine to optional N-alkylation with an appropriate organic halide to the extent required and desired to give a compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk and X are as defined herein.

2. The process of Claim 1 in which the compound of formula I is reacted with a pharmaceutically acceptable acid to obtain the corresponding pharmaceutically acceptable acid addition salt.

3. The process of Claim 1 for preparing a compound of formula I in which R1 , R2 , R3 , R4 , R5, R6 , R7 , R8, R9 and X are as defined therein and Alk is CH2 or Alk1-CH2 wherein Alk1 is as defined therein, comprising:
reacting in the presence of an acid catalyst a compound of formula III as defined therein with a compound of formula in which R1 is as defined therein and Z Is COOR18 or Alk1-COOR18 wherein R18 and Alk1 are as defined thereinto obtain the corresponding compound of formula V In which R1, R2, R3, R4, R5, R6, R7, and X are as defined herein and Z Is COOR18 or Alk1-COOR18 as defined herein, followed by subjecting the last named compound to optional hydrolysis to the corresponding acid in the case where R1 is lower alkyl, sub-jecting the Instant product to amidation with an appropriate amine of formula NHR8 R In which R and R9 are as defined herein to give the corresponding amide, and reducing the amide with a suitable complex metal hydride to give a compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined herein, and Alk3 is CH2 or Alk1-CH2 wherein Alk1 is as defined herein.

4. The process of Claim 1 for preparing a compound of formula 1 in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined therein and Alk is CH2 or Alk1-CH2 wherein Alk1 is as defined therein, comprising:
reacting in the presence of an acid catalyst a compound of formula III
as defined therein with a compound of formula in which R1 is as defined herein and Z is CONR8R9 or Alk1-CONR8R9 wherein R8, R9 and Alk1 are as defined herein to obtain the corresponding compound of formula V in which R1, R2, R3, R4, R5, R6, R7 and X are defined herein and Z is CONR8R9 or Alk1-CONR8R9 as defined herein, followed by subjecting the last named compound to reduction with a suitable complex metal hydride to give a compound of formula in which R1,R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined herein, and Alk3 is CH2 or Alk1-CH2 wherein Alk1 is as defined herein

5. The process of Claim I for preparing a compound of formula I in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined therein and Alk is CH2 or Alk1-CH2 wherein Alk1 is as defined therein, comprising:
reacting in the presence of an acid catalyst a compound of formula 111 as defined therein with a compound of formula in which R1 is as defined herein and Z is CH2OCOR19 or Alk1-CH2OCOR19 wherein R19 and Alk1 are as defined therein to obtain the corresponding compound of formula V in which R1, R2, R3, R4, R5, R6, R7 and X
as defined herein and Z is CH2OCOR19 or Alk1-CH2OCOR19 are as defined herein, followed by subjecting the last named compound to hydrolysis with a suitable alkali to give the corresponding primary alcohol, treating said primary alcohol with (1) a suitable oxidizing agent to give the corresponding aldehyde, treating the aldehyde with either an amine of formula HNR8R9 in which R8 is hydrogen and R9 is hydrogen or lower alkyl to give the corresponding Schiff base or with an amine of formula HNR8R9 in which R8 and R9 are lower alkyl or together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, piperazino and 4-(lower alkyl)-1-piperazinyl, in the presence of perchloric acid to give the corresponding immonium salt, reducing the instant intermediate with sodium borohydride, (2) a suitable halogenating, mesylating or tosylating agent and reacting the intermediate obtained thereby with an amine of formula HNR8R9 in which R8 and R9 are as defined herein, (3) a suitable oxidizing agent to give the corresponding aldehyde, treating said aldehyde with a suitable oxidizing agent to give the corresponding acid subjecting said corresponding acid, subjecting the latter compound to amidation with an appropriate amine of formula HNR8R9 in which R8 and R9 are as defined herein to give the corresponding amide, reducing said amide with a suitable complex metal hydride, (4) a suitable oxidizing agent to give the corresponding aldehyde, treating said aldehyde with hydroxylamine to give the corresponding oxime, reducing the oxime with a suitable complex metal hydride to give the corresponding amine, and if desired subjecting the amine to optional N-alkylation with an appropriate organic halide to the extent required and desired, to obtain a compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined herein, and Alk3 is CH2 or Alk1-CH2 wherein Alk1 is as defined herein.

6. The process of Claim 1 for preparing a compound of formula I in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are defined therein and Alk is Alk2 as defined therein, comprising:
reacting in the presence of an acid catalyst a compound of formula III
as defined therein with a compound of formula in which R1 is as defined herein and Z is Alk2-L wherein Alk2 is as defined herein and L is halo to obtain the corresponding compound of formula in which R1, R2, R3, R4, R5, R6, R7 and X are as defined herein and Z is Alk2-L
as defined herein followed by reacting the last named compound with an amine of formula HNR8R9 in which R8 and R9 are as defined herein to give the corresponding compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk2 and X are as defined herein.

7. The process of Claim 1 for preparing a compound of formula I in which R1 , R2 , R3, R4, R5, R6, R7, R8, Alk and X
are as defined therein and R9 is CH2R20 wherein R20 is hydrogen or lower alkyl containing from one to five carbon atoms, comprising:
reacting in the presence of an acid catalyst a compound of formula III as defined therein with a compound of formula in which R1 is as defined herein and Z is Alk-NR8COR20 wherein Alk, R8 and R20 are as defined herein to obtain the corresponding compounds of formula V in which R1, R2, R3, R , R5, R6, R and X
are as defined herein and Z is Alk-NR8COR20 as defined herein followed by reducing the last named compound with a suitable complex metal hydride to give the corresponding compounds of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R20, Alk and X are as defined herein.

8. The process Claim I for preparing a compound of formula I in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk and X are as defined therein, comprising:
reacting in the presence of an acid catalyst a compound of formula III as defined herein with a compound of formula in which R1 is as defined herein and Z is Alk-NO2 wherein Alk is as defined herein to obtain the corresponding compound of formula V in which R1, R2, R3, R4, R5, R6, R7, and X are as defined herein and Z is Alk-NO2 as defined herein, followed by reducing the last named compound with a suitable complex metal hydride to give the corresponding amine, and subjecting said amine to optional N-alkylation with an appropriate organic halide to the extent required and desired to give a compound of formula in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk and X are as defined herein.

9. The process of Claim I for preparing a compound of formula I in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk and X are as defined therein, comprising:
reacting in the presence of an acid catalyst a compound of formula III
as defined therein with a compound of formula in which R1 is as defined herein and Z is Alk-NR8R9 wherein Alk, R8 and R9 are as defined herein to obtain the corresponding compound of formula I in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk and X are as defined herein.

10. The process of Claim 1 in which the acid catalyst is p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluorlde, zinc chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid or sulfuric acid.

11. The process of Claim 3 in which the compound of formula I is 1,10-dime1hyl-1-[2-(methylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-I-acetic acid ethyl ester, the amine is methylamine and the amide is N,1,10-trimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

12. The process of Claim 3 in which the compound of formula 1 is 1-(2-aminoethyl)-1,10-dimethyl-3-4-dihydro-1H-1,4-oxazino{4,3-a]indole, the acid catalyst is p-toluene-sulfonic acid, the compound of formula III is 3 methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino-[4,3-a]indole-1-acetic acid ethyl ester, the amine is ammonium hydroxide and the amide is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

13. The process of Claim 3 in which the compound of formula 1 is 1,10-dimethyl-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is dimethylamine and the amide is N,N,1,10-tetramethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

14. The process of Claim 3 in which the compound of formula I is 1-[2-(diethylamino)ethyl]-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III
is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is diethylamine and the amide is N,N-diethyl-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

15. The process of Claim 3 in which ths compound of formula I is 1,10-dimethyl-1-[2-(ethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, The acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is ethylamine and the amide is 1,10-dimethyl-N-ethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

16. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[2-(1-pyrrolidinyl)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is pyrrolidine and the amide is 1-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indol-1-yl)acetyl]pyrrolidine.

17. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-(2-piporicilnoethyl)-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is piperidine and the amide is 1-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indol-1-yl)]piperidine.

18. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-(2-morpholinoethyl)-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazinoC4,3-a]-indole-1-acetic acid ethyl ester, the amine is morpholine and the amide is 1-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]-indol-1-yl)acetyl]morpholine.

19. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[2-(4-methyl-1-piperazinyl)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl acetoacetate, the compound of formula V is 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is 1-methyl-piperazine and the amide is 1-methyl-4-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indol-1-yl)acetyl]piperazine.

20. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[3-(methylamino)propyl]-3,4-dihydro-lH-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is methylamine and the amide is N,1,10-trimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionamide.

21. The process of Claim 3 in which the compound of formula I is 1-(3-aminopropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is ammonium hydroxide and the amide is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]-indole-1-propionamide.

22. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid calalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate,the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl esier, the amine is dimethylamine and the amide is N,N,1,10-tetramethyl 3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionamide.

23. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[3-(ethylamino)propyl]-3,4-dihydro-1-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]-indole-1-propionic acid ethyl ester, the amine is ethylamine and the amide is 1,10-dimethyl-N-ethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionamide.

24. The process of Claim 3 in which the compound of formula I is 1-[3-[diethylamino)propyl]-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is diethylamine and the amide is N,N-diethyl-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionamide.

25. The process of Claim 3 in which the compound of formula I is 1-[2-(dimethylamino)ethyl]-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-me4thyl-indole-1-ethanol, the compound of formula is ethyl 3-oxohexanoate, the compound of formula V is 10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is dimethylamine and the amide is N,N-dimethyl-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

26. The process of Claim 3 in which the compound of formula I is 1-[2-(diethylamino)ethyl]-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methyl-indole-1-ethanol, the compound of formula is ethyl 3-oxohexanoate, the compound of formula V is 10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is diethylamine and the amide is N,N-diethyl-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

27. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[3-(1-pyrrolidinyl)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is pyrrolidine and the amide is 1-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionyl]-pyrrolidine.

28. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-(3-piperidinopropyl)-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is piperidine and the amide is 1-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionyl]piperidine.

29. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-(3-morpholinopropyl)-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluene-sulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is morpholine and the amide is 1-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionyl]morpholine.

30. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[3-(4-methyl-1-piperazinyl)-propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesuifonic acid, the compound of formula III is 3-methyl-indole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is 1-methyl-piperazine and the amide is 1-methyl-4-[(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionyl]piperazine.

31. The process of Claim 3 in which the compound of formula I is 10-methyl-1-[2-(methylamino)ethyl]-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-melhylindole-1-ethanol, the compound of formula is ethyl 3-oxohexanoate, the compound of formula V ts 10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, the amine is methylamine and the amide is N,10-dimethyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

32. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[4-(methylamino)butyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III
is 3-methylindole-1-ethanol, the compound of formula is ethyl 5-oxohexanoate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4 oxazino[4,3-a]indole-1-butyric acid ethyl ester, the amine is methylamine and the amide is N,1,10-trimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-butyramide.

33. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[4-(dimethylamino)butyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluene-sulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl 5-oxohexanoate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-butyric acid ethyl ester, the amine is dimethylamine and the amide is N,N,1,10-tetramethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-butyramide.

34. The process of Claim 3 in which the compound of formula I is 10-ethyl-1-methyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-ethylindole-1-ethanol, the compound of formula is ethyl levulinate, the compound of formula V is 10-ethyl-1-methyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, the amine is methylamine and the amide is N,1-dimethyl-10-ethy1-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionamide.

35. The process of Claim 3 in which the compound of formula I is 1-[2-(ethylamino)ethyl]-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl 3-oxohexanoate, the compound of formula V is 10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-I-acetic acid ethyl ester, the amine is ethylamine and the amide is N-ethyl-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

36. The process of Claim 3 in which the compound of formula I is 1,10-dimethyl-1-[4-(ethylamino)butyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is ethyl 5-oxohexanoate, the compound of formula V is 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-butyric acid ethyl ester, the amine is ethylamine and the amide is 1,10-dimethyl-N-ethy1-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-butyramide.

37. The process of Claim 4 in which the compound of formula I is 1,10-dimethyl-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-t oluenesulfonic acid, the compound of formula III is 3-melhylindole-1-ethanol, the compound of formula is N,N-dlmethylacetoacetamide, and the compound of formula V is N,N,1,10-tetramethy1-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide.

38. The process of Claim 5 in which the compound of formula I is 1,10-dimethyl-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is 4-acetoxybutan-2-one, the compound of formula V is 1-methyl-3,4 dihydro-1H-1,4-oxazino[4,3-a]indole-1-ethanol acetate, the tosylating agent is p-toluenesulfonyl chloride and the amine is dimethylamine.

39. The process of Claim 6 in which the compound of formula I is 1,10-dimethy1-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is 4-chloro-butan-2-one, the compound of formula V is 1-(2-chloroethyl)-1,10-dimethyl-3,4-dihydro-1H-1-1,4-oxazino[4,3-a]-indole and the amine is dimethylamine.

40. The process of Claim 7 in which the compound of formula I is 1,10-dimethyl-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catialyst is p-toluenesulfonic acid, the compound of forrnula III is 3-methylindole-1-ethanol, the compound of formula is N-methyl-N-(3-oxobutyl)formamide, the compound of formula V is 1-[(N-methyl)formamidoethyl]-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole and the complex metal hydride is lithium aluminum hydride.

41. The process of Claim 8 in which the compound of formula I is 1,10-dimethyl-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula 111 is 3-methyl-indole-1-ethanol, the compound of formula is 4-nitro-2-butanone, the compound of formula V is 1-(2-nitroethyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the complex metal hydride is lithium aluminum hydride, the corresponding amine is 1-(2-aminoethyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole and the organic halide is methyl iodide, methyl bromide or methyl chloride.

42. The process of Claim 9 in which the compound of formula I
is 1,10-dimethyl-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol and the compound of formula is 4-(dimethylamino)-butan-2-one.

43. The process of Claim 4 in which the compound of formula I
is 1,10-dimethyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is N-methyl-4-oxovaleramide, and the compound of formula V is N,1,10-trimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propionamide.

44. The process of Clatm 5 in which the compound of formula I
is 1,10-dlmethyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, the acid calalysl is p-toluenesulfonic acid, the compound of formula III is 3-melhylindole-1-elhanol, the compound of formula is 5-acetoxypentan-2-one, the compound of formula V is 1-methyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propanol acetate, the tosylating agent is p-toluenesulfonyl chloride and the amine is methylamine.

45. The process of Claim 6 in which the compound of formula I
is 1,10-dimethyl-1[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is 5-chloro-pentan-2-one, the compound of formula V is 1-(3-chloropropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]-indole and the amine is methylamine.

46. The process of Cla1m 7 In which the compound of formula I is 1,10-dimethyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is-N-(4-oxopentyl)formamide, the compound of formula V
is 1(formamidopropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]-indole and the complex metal hydride is lithium aluminum hydride.

47. The process of Claim 8 in which the compound of formula I is 1,10-dimethyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is 5-nitro-2-penianone, the compound of formula V is 1-(3-nitiropropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the complex metal hydride is lithium aluminum hydride, the corresponding amine is 1-(3-aminopropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole and the organic halide is methyl iodide, melhyl bromide or metilyl chloride.

48. The process of Claim 9 in which ihe compound of formula I
is 1,10-dimelhyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, the acid catalyst is p-ltoluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol and the compound of formula Z is 5-(methylamino)-pentan-2-one.

49. The process of Claim 4 in which the compound of formula I
is 1,10-dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formuia is N,N-dimethyl-4-oxovaleramide, and the compound of formula V is N,N,1,10-tetramethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]-indole-1-propionamide.

50. The process of Claim 5 in which the compound of formula I
is 1,10-dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indiole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is 5-acetoxypentan-2-one, the compound of formula V is 1-methyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propanol acelate, the tosylating agent is P-toluenesulfonyl chloride and the amine is dimethylamine.

51. Tne process of Claim 6 in which the compound of formula I
is 1,10-dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is 5-chloro-pentan-2-one, the compound of formula V is 1-(3-chloropropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]-indole and the amine is dimethylamine.

52. The process of Claim 7 in which the compound of formula I is 1,10-dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is N-methyl-N-(4-oxopentyl)formamide, the compound of formula V is 1-[(N-methyl)formamldopropyl]-1,10-dimethyl-3,4 dihydro-1H-1,4-oxazino[4,3-a]indole and the complex metal hydrido is lithium aluminum hydride.

53. The process of Claim 8 in which the compound of formula I is 1,10-dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol, the compound of formula is 5-nitro-2-pentanone, the compound of formula V is 1-(3-nitropropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, the complex metal hydride is lithium aluminum hydride, the corresponding amine is 1-(3-aminopropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole and the organic halide is methyl iodine, methyl bromide or methyl chloride.

54. The process of Claim 9 in which the compound of formula I
is 1,10-dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, the acid catalyst is p-toluenesulfonic acid, the compound of formula III is 3-methylindole-1-ethanol and the compound of formula is 5-(dimethylamino)-pentan-2-one.

125 550 A compound of formula I

in which R1 is lower alkyl; R2, R3, R4, R5 and R6 are hydrogen; R7 is lower alkyl; X is oxy; and Alk is CH2CH2, CH2CH2CH2 or CH2CH2CH2CH2 and R8 and R9 are selected from hydrogen and lower alkyl,or R8 and R9 together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consistng of 1-pyrrolidinyl, piperazino, morpholino, piperazino and 4-(lower alkyl)-1-piperazinyl, when prepared by the process of Claim 1, or an obvious chemical equivalent thereof.

56. A pharmaceutically acceptable acid addition salt or the compound of formula 1, as claimed in Claim 55, when prepared by the process of Claim 2.

57. A compound of formula 1, as claimed in Claim 55, in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined in Claim 55 and Alk is CH2 or Alk1-CH2 wherein Alk1 is an alkylene selected from the group consisting of CR10CR11, CR10R11CR12R13 and CR10R11CR12R13CR14R15 wherein R10, R11, R12, R13, R14 and R15 are hydrogen or lower alkyl, when prepared by the process of Claims 3, 4 or 5, or an obvious chemical equivalent thereof.

58. A compound of formula I, as claimed in Claim 55, in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined in ClaiM 55 and Alk is Alk2 wherein Alk2 is an alkylene selected from the group consisting of CR10R11CHR12,CR10R11CR12R13CHR14 and CR10R11CR12R13CR14R15CHR16 wherein R10, R11, R12, R13, R14 R15 and R16 are hydrogen or lower alkyl, when prepared by the process of Claim 6, or an obvious chemical equivalenl thereof.

59. A compound of formula 1, as claimed in Claim 55, in which R1, R2, R3, R4, R5, R6, R7, R8, Alk ancl X are as defined in Claim 55, and R9 is CH2R20 in which R20 is hydrogen or lower alkyl coniaining from on to five carbon atoms, when prepared by the process of Claim 7, or an obvious chemical equivalent thereof.

60. A compound of formula I, as claimed in Claim 55, when prepared by the process of Claims 8, 9 or 10 or an obvious chemical equivalent thereof.

61. 1,10-Dimethyl-1-[2-(methylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 11, or an obvious chemical equivalent thereof.

62. 1-(2-Aminoethyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino-[4,3-a]indole, when prepared by the process of Claim 12, or an obvious chemical equivalent thereof.

63. 1,10-Dimethyl-1-[(2-dimethylamino)ethy]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 13, or an obvious chemical equlvalent thereof.

64. 1-[2-(Diethylamino)ethyl]-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 14, or an obvious chemical equivalent thereof.

65. 1,10-Dimethyl-1-[2-(ethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 15, or an obvious chemical equivalent thereof.

66. 1,10-Dimethyl-1-[2-(1-pyrrolidinyl)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 16 or an obvious chemical equivalent thereof.

67. 1,10-Dimethyl-1-(2-piperidinoethyl)-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process ot Claim 17, or an obvious chemical equivalent thereof.

68. 1,10-Dimethyl-1-(2-morpholinoethyl)-3,4-dihydro-1H-1-1,4-oxazino[4,3-a[indole, when prepared by the process of Claim 18, or an obvious chemical equivalent thereof.

69. 1,10-Dimethyl-1-[2-(4-methyl-1-piperazinyl)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 19, or an obvious chemical equivalent thereof.

70. 1,10-Dimethyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 20, or an obvious chemical equivalent thereof.

71. 1-(3-Aminopropyl)-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 21, or an obvious chemical equivalent thereof.

72. 1,10-Dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 22, or an obvious chemical equivalent thereof.

73. 1,10-Dimethyl-1-[3-(ethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 23, or an obvious chemical equivalent thereof.

74. 1- [3-(Diethylamino)propyl]-1,10-dimethy1-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 24, or an obvious chemical equivalent thereof.

75. 1-[2[(Dimethylamino)ethyl]-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process oc Claim 25, or an obvious chemical equivalent thereof.

76. 1- [2- (Diethylamino)eihyl]-10-methyl-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 26, or an obvious chemical equivalent thereof.

77. 1,10-Dimethyl-1-(3-(1-pyrrolidinyl)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 27, or an obvious chemical equivalent thereof.

78. 1,10-Dimethyl-1-[3-piperidinopropyl)-3,4-dihydro-1H-1-4-oxazino[4,3-a]indole, when prepared by the process of Claim 28, or an obvious chemical equivalent thereof.

79. 1,10-Dimethyl-1-(3-morpholinopropyl)-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 29, or an obvious chemical equivalent thereof.

80. 1,10-Dimethyl-1-[3-(4-methyl-1-piperazinyl)-propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 30, or an obvious chemical equivalent thereof.

81. 10-Methyl-1-[2-(methylamino)ethyl]-1-propyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 31, or an obvious chemical equivalent thereof.

82. 1,10-Dimethyl-1-[4-(methylamino)butyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 32, or an obvious chemical equivalent thereof.

83. 1,10-Dimethyl-1-[4-(dimethylamino)butyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 33, or an obvious chemical equivalent thereof.

84. 10-Ethyl-1-methyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 34, or an obvious chemical equivalent thereof.

85. 1-[2-(Ethylamino)ethyl]-10-methyl-1-propy1-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 35, or an obvious chemical equivalent thereof.

86. 1,10-Dimethyl-1-[4-(eihylamino)butyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claim 36, or an obvious chemical equivalent thereof.

87. 1,10-Dimethyl-1-[(2-dimethylamino)ethyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claims 37, 38 or 39, or an obvious chemical equivalent thereof.

88. 1,10-Dimethyl-1,[(2-dimethylamino)ethyl]-3,4-dihydro-1,4-oxazino[4,3-a]indole, when prepared by the process of Claims 40, 41 or 42,or an obvious chemical equivalent thereof.

89. 1,10-Dimethyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claims 43, 44 or 45, or an obvious chemical equivalent thereof.

90. 1,10-Dimethyl-1-[3-(methylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claims 46, 47 or 48, or an obvious chemical equivalent thereof.

91. 1,10-Dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claims 49, 50 or 51, or an obvious chemical equivalent thereof.

92. 1,10-Dimethyl-1-[3-(dimethylamino)propyl]-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole, when prepared by the process of Claims 52, 53 or 54, or an obvious chemical equivalent thereof.