OXAZINOINDOLE-AND THIAZINOINDOLE DERIVATIVES

DERIVES D'OXAZINOINDOLE ET DE THIAZINOINDOLE

English 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.

Claims

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
<IMG> 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.
<IMG> III
in which R2, R3, R4, R5, R6 and R7 are as defined herein and X1 Is hydroxy,
with a compound of formula <IMG> 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,
99

(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
<IMG> 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
100

<IMG>
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
<IMG>
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
101

(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
102

subjecting the amine to optional N-alkylation with an appropriate
organic halide to the extent required and desired,
to obtain a compound of formula
<IMG>
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
<IMG>
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
103

<IMG>
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
<IMG>
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk and X are as defined
herein.
104

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 <IMG> 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
<IMG>
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.
105

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
<IMG> 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
<IMG>
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
106

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 <IMG> 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
107

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
<IMG>
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 <IMG> 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
108

<IMG>
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 <IMG> 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
<IMG>
in which R1, R2, R3, R4, R5, R6, R7, R8, R20, Alk and X are as
defined herein.
109

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 <IMG> 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
<IMG>
<IMG>
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, Alk and X are as
defined herein.
110

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 <IMG> 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 <IMG> 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.
111

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 <IMG> 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 <IMG>
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.
112

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 <IMG>
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 <IMG> 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.
113

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 <IMG>
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 <IMG>
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.
114

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 <IMG> 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 <IMG>
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 <IMG>
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.
115

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 <IMG> 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 <IMG>
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 <IMG> 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.
116

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 <IMG>
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 <IMG> 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 <IMG> 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.
117

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 <IMG>
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 <IMG> 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 <IMG> 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.
118

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 <IMG> 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 <IMG> 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 <IMG> 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.
119

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 <IMG> 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 <IMG> 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 <IMG>
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.
120

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 <IMG> 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 <IMG>
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 <IMG>
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.
121

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 <IMG>
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 <IMG> 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 <IMG> 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.
122

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 <IMG> 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
<IMG> 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
<IMG> 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
<IMG> 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 <IMG> 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]-
123

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 <IMG> 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 <IMG>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 <IMG> 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 <IMG> 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.
124

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
<IMG> 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 <IMG> 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 <IMG> 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
<IMG> is 5-(dimethylamino)-pentan-2-one.
125

550 A compound of formula I
<IMG>
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
126

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.
127

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.
128

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.
129

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.
130

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
. , .
:
,' ' ,
.
.:.~ . ' ' ~ '
.,.~ ;' .
~r ~ 7
:
. . . .

; 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
.;. ~ .
. .
. . .; , .
:'" ~ I , ..
; , I
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' ! `.; '.
, ,., : .
:':, ,:
. , .
;~: . ..
; ,.
g
.~ ,, . . . .. , ... . . . . ~

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~
'~, ;.. ',
; ' `:
,,~ ,. . .
,:, " ., :,
., ~ .
-13~
. ,: ,
.: . , ., ;, ,. . . . . , .. ;,, . ,, , . , .,~ ", .. , ;,. . . .. . . . . .
,. ; , .. , ., ,, ", .. ...

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
- 14--

~ ~ 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
, . . . .
'' ' , ~,':'
-15-

.
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~
.. . .
. . , - . ' ~ \ ~ .
.;
.~,~ .
. ~' ` ' ` " .
~` .. ,
21

!
; ~ AHP-5786J592i
; ..................... ~ .
1 036596
"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~ :

AIIP-5786/5921
:
, ~
' '':
1036596
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.
. .
'',''' ' ~
-28-
. ' , ,

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

:
AHP-5786 /592 1
'.','
- ~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.
.. . .
",~
'`I ''';' ''
; :~ '1 ... .... .
.. . ...
. ~ . , :.
,; - ' . .::
., -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
...
, .
' :
~ : .
-33-

~ ~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
.:....................................................................... .
., ' ' ''':
',' ,
:'.'~ .
".; . .
,
~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). :~
. ,' . ', .
,' ., ,,'~
.~ . ,,,,.. .,~
~,~
., . ,'. :,.
`: . , :
. ~ , .
: tt '" . ,
.. -36- ;

~ ~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
"
'.': "
,',, ~:
.''' ' .
, ................ . . .
,'~, ;:
..... .
,,,~.~ ..... .
..... .
;;,
.i~ . ~.
~ . . .
.. .... ..
''.:,
~ .
~' ' " '
.~ -37-
. .
~ ...... . .

AHP-5786/59~l ~
36596
.:, ':
,~''' ~ ' ' ',
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
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~ 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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;
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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
,,.,, .~
'., .,

AHP-5786 /592 1
.: " _~ . .
~ 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
,''' ,_ ." ~.
'' . ~
' :~'
:,~ . , ' "
:' . - ~'.
.. ~ ' ' .
2-
.

A~-5786 /5921
, .
)36Sg6
,..... : .
. .~ . ~, - ... ~ `',`''
,.. 1 .
. `. 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
. ~ , ' ``,
., .
. I .
.. I .
l ~43- ~:

AHP-5786 /592 1
: . :
:::, ~ ,
~036596 `
,. ;.
q~ABIE^ I
:. ~ ,
. ., - ,.. :
, .~, . . _ ~. . . ~ ~, ': ''
'.":' .,''' . . '::
.. ; ; 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 .
.. . .
''I ' .
;`l `
'`'~ ; , :
_ A A_

5786/592 1
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 `~
'" , ' ^ :
i: ' ' ,, : `
.,.................. ~ . , , . ..... - '_ '~
. . 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/; ;~
,.'' . . . . .' . "~
~ . ~ . . .
. 30 .
:~ . . .
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. ' ' .
..
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. . . . .. ..

I AHP-5786/592l
36596
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 ~;
,~
`''I , .
.,, .:
~ 47- ;
,, ,, , . ", .

AHP-5786/5921
1036S96
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//
'.' . .__ _ . _ ~. ~ ~',""
~ . . ,' ' ~'.
~'~
~ 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 .:
~ ' ~ _ _ _ . .. __ _ ,,, . __ . .
:~'
:~ . , ; .
;,: .. . ..
,:'
:
~ ;
..,,~
,' '

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 ¦
. ~ . . . .... . !
. ' .~ ,.' ~ ~
''' . . . . . . ':
~ ' __ _ _. ..__1 . . ...~
, ~ .
,i . ,,
:. . . ~,
-50-
. . .
.. ;,. .
.' "~,~ , .

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), .
- .. .. ..... .. ..
. i .
~ ,:
., . '
~" ' , '
.
- ':. .~.':
-51-

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.
- . .
.
: .
.~
.
,
,
-52-
.... .. .....

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.
,: :
,"
,.
,
.`i
. !
:,; ' ,'; '
'
"'. ' .'` ' "
''": ~ ''
-"' '
: .`'
.
'. ~`'-:
'. ' ~'' ' ,
' ~ ` ' .`.'.":
',' ' ' ''"
.. . .
~ ' , .
:'~ ' ' '',
; :,, '.

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

AHP-5786 /592 1
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 . ~ - - . -
., ,,,, .,,~~
.
~ . .. ,..... .. . '
: . . ~... , :
. ... ., ~.,".. , ' . . ~, , . ~ . :
. . . .. _.. ~ =
. , ' _ ,. .. .. ~
. . . :
. :
~ ";., .
-63-

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 ~:
., ~ , ;~;.
., , . . .
,: . .
. ,,
, . . . ' '
65-
? , .

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~ ' :
, ; , . ~ .
''
72-

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-

AHP-5786 /592 1
:. `
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~
;'``, .. .
. .
. ~ .
-75-
. . . . . ... . . . .

~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.
,, I I` I
''``~,(' . .
' . . . . . I
.
~ .. -- - .. _.__. _., J :~'
!- - ~ ~
~" ,
`:
. .
..
, . . .
~ -77-

AT~-5'~59~ 1
'.. :. . ' :
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
\ :
. .
. .
.
~ '''''' ' ' '
'.',',,:,.
-80-

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.~
'' . ; :
.,~ ,1 , . .
.~
'; ~, ", .
.
'~ ' ' ' ' ' ' '' .
,: . . .. .
.
' ' . ,
s ~2- `
.. . . . . . ..

AT~P-5'i'~`6 ~592 1
3l~3659~
rrh?~ XII
.,~ ' .
:. ~.s __ _ . ... ____v_ ~_____.
.,.
." '
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~ . ' .''
:' ., ~ '' ' ~'
~'.:~ ` . ..... .
,.. . .
: ,- . :
.~ . , .
,. . ... ... .
: . - . , . ~ j ,
.. I I '.:'~ .
,
l \ ' ':.
.,1 ,, : , , Z ''.',;
., . " , .:
.'' ' ' .'.' ~,
: -84- ~ ,:
. ~ , , ~ .
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.
~ n~-57~ /59~
: ~36S96
. ` EXA~7hE 462
.. . .
: .
,' , ,
;;: , , .
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.
. ', . . ~
'1 ' ' . '
'' ,,,' ' ', ;.~ ~
.
` , ' ' . . .
~ 'AL`'~ '''"- .
-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~
.,j~ ~ . .
,f . ,, : '
.
f . ~ .
'-f' . ......
-: ~ ' ' ' ,~' :, .
. . ~ ' ' , "
,, .. ~ , .f~
:f . ':
.. ~ . ' ' . ,.
,, .... .. - - ' ' '' ' ''.
, "'
;''' ` ' '
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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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.,1
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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. .:
'., 30
:'~ ,
"'
':.`':
~,.",.
., .
,
. .
-90-

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 ' ~
.,'~ ' . '
'
:`
:
`; :
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;,
,`, ~ ~ .
. ' ,....
.
.
-93-

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- ~

AHP-5786 /5921
,
~ 103659~;
EXAMPLE 472
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.
',
~ ' `' ' .
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i, . . . . . .