ANTIPEPRESSANT INDOLEALKYL DERIVATIVES OF HETEROCYCLE-FUSED
BENZODIOXAN METHYLAMINES
Cross-Reference to Related Applications
[0001] This application is a continuation-in-part application of U.S. Application
Serial No. 60/410,347, filed September 12, 2002, the disclosure of which is
incorporated herein by reference in its entirety.
Background of the Invention
[0002] Major depression is a serious health problem affecting more than 5% of the
population, with a lifetime prevalence of 15-20%.
[0003] Selective serotonin reuptake inhibitors have produced success in treating
depression and related illnesses and have become among the most prescribed
drugs. They nonetheless have a slow onset of action, often taking several weeks to
produce their full therapeutic effect. Furthermore, they are effective in less than two-
thirds of patients.
[0004] Serotonin selective reuptake inhibitors (SSRIs) are well known for the
treatment of depression and other conditions. SSRIs work by blocking the neuronal
reuptake of serotonin, thereby increasing the concentration of serotonin in the
synaptic space, and thus increasing the activation of postsynaptic serotonin
receptors.
[0005] However, although a single dose of an SSRI can inhibit the neuronal
serotonin transporter which would be expected to increase synaptic serotonin, long-
term treatment is required before clinical improvement is achieved.
[0006] It has been suggested that the SSRIs increase the serotonin levels in the
vicinity of the serotonergic cell bodies and that the excess serotonin activates
somatodendritic autoreceptors, 5HTiA receptors, causing a decrease in serotonin
release in major forebrain areas. This negative feedback limits the increment of
synaptic serotonin that can be induced by antidepressants.
[0007] A 5HT1A antagonist would limit the negative feedback and should improve
the efficacy of the serotonin reuptake mechanism (Perez, V., et al., The Lancet,
349:1594-1597 (1997)). Such a combination therapy would be expected to speed up
the effect of the serotonin reuptake inhibitor.
[0008] Thus, it is highly desirable to provide improved compounds which both
inhibit serotonin reuptake and which are antagonists of the 5HT1A receptor.
Description of the Invention
[0009] In accordance with this invention, there is provided a group of novel
compounds of Formula I:

X is O, N=CH, CR7=CH or CR7=N, in which R7 is hydrogen or alkyl of 1 to 6
carbon atoms;
Z is O, S or NR8, in which R8 is hydrogen or alkyl of 1 to 6 carbon atoms;
R1, R5 and R6 are, independently, hydrogen, hydroxy, halo, cyano,
carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl,
alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2
to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or
di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,
alkanamido of 2 to 6 carbon atoms, alkanesulfonyl of 1 to 6 carbon atoms
or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen, halo, amino, mono- or di-alkylamino in which each alkyl
group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms;
R3 and R4 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms;
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
[0010] R1 is preferably hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon
atoms or alkoxy of 1 to 6 carbon atoms. More preferably, R1 is hydrogen, halo or
alkoxy of 1 to 6 carbon atoms. In still more preferred embodimants of the present
invention, R1 is hydrogen.
[0011] R2 is preferably hydrogen, amino or alkyl of 1 to 6 carbon atoms. More
preferably, R2 is hydrogen or alkyl of 1 to 3 carbon atoms.
[0012] R3, R4, R7 and R8 are preferably independently selected from hydrogen or
alkyl of 1 to 3 carbon atoms. More preferably, R3 is hydrogen or alkyl of 1 to 3
carbon atoms and R4 is hydrogen.
[0013] R5 and RB are preferably independently selected from hydrogen, hydroxy,
halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon
atoms. In still more preferred embodiments of the present invention R5 and R6 are
preferably independently selected from hydrogen, cyano or halogen.
[0014] X is preferably O or CR7=CH. When X is CR7=CH, R7 is preferably
hydrogen or alkyl of 1 to 3 carbon atoms.
[0015] Z is preferably NR8 . When Z is NR8, R8 is preferably hydrogen or alkyl of 1
to 3 carbon atoms.
[0016] n is preferably 2 or 3.
[0017] In other preferred embodiments of the invention is provided compounds of
Formula la:

wherein R1, R2, R3, R4, R5, R6, n, and Y are as described above.
[0019] This invention relates to both the R and S stereoisomers of the
aminomethyl-2,3-dihydro-1,4-dioxino[2,3-f]quinolines, -quinazolines, quinoxalines
and aminomethyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazoles as well as to
mixtures of the R and S stereoisomers. Throughout this application, the name of the
product of this invention, where the absolute configuration of the compounds of the
invention is not indicated, is intended to embrace the individual R and S enantiomers
as well as mixtures of the two. In some embodiments of the present invention the S
enantiomer is Drejerred^ Certain of the compounds of this invention (i.e., R4 is alkyl)
contain two stereogenic centers and thus may exist as diastereomers./This invention
relates to both provided substantially free of the corresponding enantiomer.
[0020] Where a stereoisomer is preferred, it may, in some embodiments be
provided substantially free of the corresponding enantiomer. Thus, an enantiomer
substantially free of the corresponding enantiomer refers to a compound which is
isolated or separated via separation techniques or prepared free of the
corresponding enantiomer. "Substantially free," as used herein, means that the
compound is made up of a significantly greater proportion of one stereoisomer. In
preferred embodiments the compound is made up of at least about 90% by weight of
a preferred stereoisomer. In other embodiments of the invention, the compound is
made up of at least about 99% by weight of a preferred stereoisomer. Preferred
stereoisomers may be isolated from racemic mixtures by any method known to those
skilled in the art, including high performance liquid chromatography (HPLC) and the
formation and crystallization of chiral salts or prepared by methods described herein.
See, for example, Jacques, et a/., Enantiomers, Racemates and Resolutions (Wiley
Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel,
E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H.
Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of
Notre Dame Press, Notre Dame, IN 1972).
[0021] "Alkyl," as used herein, refers to an aliphatic hydrocarbon chain and
includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-
butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and
isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.
[0022] "Alkanamido," as used herein, refers to the group R-C(=O)-NH- where R is
an alkyl group of 1 to 5 carbon atoms.
[0023] "Alkanoyl," as used herein, refers to the group R-C(=O)- where R is an alkyl
group of 1 to 5 carbon atoms.
[0024] "Alkanoyloxy," as used herein, refers to the group R-C(=O)-O- where R is an
alkyl group of 1 to 5 carbon atoms.
[0025] "Alkanesulfonamido," as used herein, refers to the group R-S(O)2-NH-
where R is an alkyl group of 1 to 6 carbon atoms.
[0026] "Alkanesulfonyl," as used herein, refers to the group R-S(O)2- where R is an
alkyl group of 1 to 6 carbon atoms.
[0027] "Alkoxy," as used herein, refers to the group R-O- where R is an alkyl group
of 1 to 6 carbon atoms.
[0028] "Carboxamido," as used herein, refers to the group NH2-C(=O)-.
[0029] "Carboalkoxy," as used herein, refers to the group R-O-C(=O)- where R is
an alkyl group of 1 to 5 carbon atoms.
[0030] "Halogen" (or "halo"), as used herein, refers to chlorine, bromine, fluorine
and iodine.
[0031] Pharmaceutically acceptable salts are those derived from such organic and
inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic,
malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric,
nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic,
salicylic, benzoic, and similarly known acceptable acids.
[0032] Specific examples of compounds of Formula I are:
N-[2-(5-Methoxy-1H-indol-3-yl)-ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)-amine;
N-[2-(5-Chloro-1H-indol-3-yl)ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2>3-
f]quinolin-2-ylmethyl)amine;
N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1l4]dioxino[2,3-
f]quinolin-2-ylmethyl)amine;
N-t2-(5-Fluoro-1H-indol-3-yl)ethyl]-N-(8-methyl-2,3-dihydro-t1,4]dioxino[2,3-f]quinolin-
2-ylmethyl)amine;
N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-(8-ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-
2-ylmethyl)amine;
N-[3-(1H-lndol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxinot2,3-f]quinolin-2-
ylmethyl)amine;
N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-methyl-N-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine;
N-[3-(7-Fluoro-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)amine;
N-[4-(1 H-l ndol-3-yl)butyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)amine;
N-[4-(5-Fluoro-1H-indol-3-yl)butyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-
2-ylmethyl)amine;
N-[4-(5-Fluoro-iH-indol-3-yl)-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
y!methyl)butan-2-amine;
N-[3-(5-Fluoro-1-methyl-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine;
N-[3-(5,7-Difluoro-iH-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)amine;
N-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-N-[3-(5-fluoro-1H-indol-3-
yl)propyl]amine;
N-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-N-[3-(5-fluoro-1H-indol-3-
yl)propyl]-N-methylamine;
N-[3-(5,7-Difluoro-1H-indol-3-yl)propyl]-N-methyl-N-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine;
N-[2-(1-Benzofuran-3-yl)ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)amine;
N-[3-(1-Benzofuran-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoIin-2-
ylmethyl)amine;
N-[3-(7-Methoxy-1-benzofuran-3-yl)propyl]-N-(8-methyl-2,3-dihydro-t1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)amine;
N-[3-(1-Benzothien-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)amine;
N-[2-(1-Benzothien-3-yl)ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)amine;
N-tS-ii-Benzothien-S-ylJpropyll-N-methyl-N^S-methyl^.S-dihydro-ti.^dioxinop.S-
f]quinolin-2-ylmethyl)amine;
N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-(2-methyl-7,8-dihydro-[1,4]dioxino[2r3-
g][1,3]benzoxazol-8-ylmethyl)amine;
N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-methyl-N-(2-rnethyl-7,8-dihydro-
[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)amine;
N-Ethyl-N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)amine;
N-[3-(5,7-Difluoro-1-methyl-1H-indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-fIquinolin-2-ylmethyl)amine;
N-[3-(5,7-Difluoro-1-methyl-1H-indol-3-yl)propyl]-N-methyl-N-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine;
N-^^i-Benzofuran-S-yObutylJ-N^S-rnethyl^.S-dihydro-ti^Jdioxinop.S-fJquinolin^-
ylmethyl)amine;
3-{3-[(8-Methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-propyl}-1H-
indole-5-carbonitrile;
SHS-^-Methyl-y.S-dihydro^i^ldioxino^.S-glti.Slbenzoxazol-S-ylmethyOamino]-
propyl}-1H-indole-5-carbonitrile;
3-{3-[Methyl-(2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)-
amino]-propyl}-1H-indole-5-carbonitrile;
3-{3-[Methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-
propyl}-1H-indole-5-carbonitrile;
[3-(6-Fluoro-indol-1-yl)-propyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)-amine;
[3-(6-Fluoro-indol-1-yl)-propyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)-amine;
[4-(5-Fluoro-1 -methyl-1 H-indol-3-yl)-butyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)-amine;
Ethyl-[3-(5-fluoro-1H-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-[1,4]dioxino[2,3-
g][1,3]benzoxazol-8-ylmethyl)-amine;
1-Methyl-3-{3-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-
propyl}-1H-indole-5-carbonitrile;
[4-(6-Fluoro-indol-1 -yl)-butyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
• ylmethyl)-amine;
3-{4-[(8-Methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-butyl}-1H-
indole-5-carbonitrile;
1-Methyl-3-{3-[methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-flquinolin-2-ylmethyl)-
amino]-propyl}-1H-indole-5-carbonitrile;
3-{4-[Methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-
butyl}-1 H-indole-5-carbonitrile;
[3-(5-Fluoro-1-methyl-iH-indol-3-yl)-propyl]-methyl-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine;
[4-(5-Fluoro-1H-indol-3-yl)-butyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxinot2,3-
f]quinolin-2-ylmethyl)-amine;
[4-(5-Fluoro-1 -methyl-1 H-indol-3-yl)-butyl]-methyl-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)-propyl-amine;
[3-(4-Fluoro-indol-1-yl)-propyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)-amine;
[4-(6-Fluoro-indol-1-yl)-butyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-
2-ylmethyl)-amine;
[3-(4-Fluoro-indol-1-yl)-propyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2)3-
f]quinolin-2-ylmethyl)-amine;
N-[4[(5-Chloro-1-benzothien-3-yl)butyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxinot2,3-
f]quinolin-2-yl]methyl};
N-[3-(5-Chloro-1-benzothien-3-yl)propyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[3-(5-Fluoro-1-benzothien-3-yl)propyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine; and
N-[4-(1-Benzofuran-3-yl)butyl]-N-ethyl-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-
f]quinolin-2-yl]methyl}amine.
[0033] Compounds of the present invention are prepared in accordance with the
following general description and specific examples. Variables used are as defined
for Formula I, unless otherwise noted. The 2,3-dihydro-1,4-dioxino[2,3-f|quinolin-2-
ylmethylamines in which R2 is H are prepared as illustrated in Scheme 1 below.
Specifically, the appropriately substituted nitroguaiacol (1) is alkylated with allyl
bromide in the presence of a suitable base such as sodium hydride and then
demethylated by a reagent such as sodium hydroxide. The resulting 4-nitro-2-
allyloxyphenol (3) is then alkylated with glycidyl tosylate or an epihalohydrin in the
presence of a base such as sodium hydride and heated in a high boiling solvent such
as mesitylene or xylene to effect both rearrangement of the allyl group and
cyclization of the dioxan ring. The resulting primary alcohol (5) is converted to the
tosylate by reaction with p-toluenesulfonyl chloride in the presence of a tertiary amine
or pyridine, or alternatively to a halide by reaction with carbon tetrabromide or carbon
tetrachloride in combination with triphenylphosphine. The allyl side chain is then
isomerized by treatment with catalytic bis-acetonitrile palladium (II) chloride in
refluxing methylene chloride or benzene. Allylic oxidation of 6 with selenium dioxide
in refluxing dioxane/water gives the o-nitrocinnamaldehyde, which upon reduction
with iron in acetic acid cyclizes to the 2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-
methyltosylate (7) or halide. Replacement of the tosylate or halide with the
appropriately substituted indolealkylamine in some high boiling solvent such as
dimethyl sulfoxide gives the title compounds of the invention.
Scheme 1
[0034] The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines of the invention
in which R2 is alkyl may be prepared from the nitro olefin described above in the
following manner (Scheme 2). The rearranged olefin (6) is treated sequentially with
ozone and a tertiary amine or with osmium tetroxide and sodium periodate to give the
o-nitrobenzaldehyde (8). Condensation with the appropriate
triphenylphosphorylidene ketone under Wittig conditions gives the o-nitrocinnamyl
ketone (9), which upon reduction by iron in acetic acid, cyclizes to the corresponding
2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyltosylate (10). Replacement of the
tosylate with the appropriately substituted indolealkylamine as above gives the title
compounds of the invention. Substitution of trimethyl phosphonoacetate for the
triphenylphosphorylidene ketone in the Wittig procedure above, followed by reduction
of the nitro group with tin (II) chloride and cyclization in acid gives the compounds of
the invention in which R2 is hydroxy. Treatment of the hydroxy derivative with an
inorganic acid chloride such as phosphoryl chloride or bromide gives the compounds
of the invention in which R2 is halo. Substitution of diethyl cyanomethylphosphonate
for the triphenylphosphorylidene ketone in the Wittig procedure above, followed by
reduction of the nitro group with tin (II) chloride and cyclization in acid gives the
compounds of the invention in which R2 is amino.
n

[0035] Compounds of the invention in which R1 is attached to position 6 of the 2,3-
dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines may be alternatively prepared by
a variation of the Skraup quinoline synthesis according to Scheme 3 below. The
appropriately substituted benzodioxan methyltosylate (11) is nitrated under standard
conditions with nitric acid in a solvent such as dichloroethane and the resulting nitro
compound (12) reduced by treatment with hydrogen in the presence of a catalyst
such as platinum on sulfide carbon. Treatment of the resulting aniline (13) with
acrolein in the presence of hydrogen chloride and an oxidant such as p-chloranil or
naphthoquinone gives the corresponding 2,3-dihydro-1,4-dioxino[2,3-f]quinoline (14).
Replacement of the tosylate with the appropriately substituted indolealkylamine as
above gives the title compounds of the invention.

[0036] The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of the
invention are prepared as illustrated below (Scheme 4). The o-nitrobenzaldehyde (8)
described above is converted to the oxime (15) by treatment with hydroxylamine
hydrochloride in the presence of a suitable base such as sodium acetate and the
nitro group reduced to the amine by hydrogenation over palladium on carbon.
Cyclization to the quinazoline N-oxide is effected by treatment at reflux with the
appropriate ortho ester according to the method of Ostrowski (Heterocycles, vol. 43,
No. 2, p. 389, 1996). The quinazoline N-oxide may be reduced to the quinazoline
(16) by a suitable reducing agent such as hydrogen over Raney-nickel. Alternatively,
an extended period of reflux in the ortho ester gives the reduced quinazoline directly
via a disproportionation reaction and the 2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-
methyltosylate or halide may be isolated by column chromatography. Replacement
of the tosylate or halide with the appropriately substituted indolealkylamine in some
high boiling solvent such as dimethyl sulfoxide gives the title compounds of the
invention.

Scheme 4
[0037] The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of the
invention may be alternatively prepared from the rearranged olefin described above
by the method outlined in Scheme 5 below. The nitro olefin (6) is first reduced to the
aniline by treatment with a suitable reducing agent such as stannous chloride
dihydrate in refuxing ethyl acetate and the resulting amine acylated with the
appropriate acyl halide or anhydride. The olefin (17) is then converted to the
aldehyde (18) by cleavage with catalytic osmium tetroxide in the presence of excess
sodium periodate. Cyclization directly to the 2,3-dihydro-1,4-dioxino[2,3-
f]quinazoline-2-methyltosylate (16) or halide is effected by treatment of the amido
aldehyde (18) with ammonia and replacement of the tosylate or halide with the
appropriately substituted indolealkylamine in some high boiling solvent such as
dimethyl sulfoxide as described above gives the title compounds of the invention.
[0038] The 2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-ylmethylamines of the
invention are prepared as illustrated in Scheme 6 below. The o-nitrobenzaldehyde
(8) described above is oxidized to the o-nitrobenzoic acid (19) by a suitable oxidant
such as chromium trioxide (Jones' oxidation) or sodium chlorite and the acid
converted to the o-nitroaniline (20) with diphenylphosphoryl azide (DPPA) in the
presence of a tertiary base such as diisopropylethylamine. Reduction of the resulting
nitroaniline to the diamine (21) with hydrogen and palladium on carbon and
cyclization by treatment with the appropriate dicarbonyl compound (for example,
glyoxal, 2,3-butanedione, 3,4-hexanedione) gives the 2,3-dihydro-1,4-dioxino[2,3-
f]quinoxaline-2-methyltosylate (22) or halide. Replacement of the tosylate or halide
with the appropriately substituted indolealkylamine in some high boiling solvent such
as dimethyl sulfoxide gives the title compounds of the invention.
Scheme 6
[0039] The o-nitrobenzaldehyde (8) used in the chemistry described above may be
alternatively prepared as shown in scheme 7 below. The appropriate mono-allylated
catechol (23) is elaborated with glycidyl tosylate as described above and rearranged
in refluxing mesitylene. Cyclization to the benzodioxan methanol (25) is effected by
treatment with sodium bicarbonate in ethanol and the alcohol is converted to the
tosylate (26) or halide as described above. After rearrangement of the double bond
by treatment with catalytic bis-acetonitrile palladium (II) chloride in refluxing
methylene chloride and cleavage with ozone or osmium tetroxide/sodium periodate
as described above, the resulting aldehyde (27) is regioselectively nitrated with a
combination of nitric acid and tin (IV) chloride.

Scheme 7
[0040] The 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethylamines of the
invention are prepared as illustrated in Scheme 8 below. The amido olefin (17)
described in Scheme 5 is cleaved to the corresponding o-amidobenzaldehyde (18)
by treatment with catalytic osmium tetroxide in the presence of sodium periodate.
The aldehyde is converted to the phenol (28) by treatment with meta-
chloroperoxybenzoic acid in a Baeyer-Villager reaction and cyclization to the 7,8-
dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (29) is effected by treatment at reflux with
an appropriate dehydrating agent such as an ortho ester or an acid catalyst such as
p-toluenesulfonic acid. Replacement of the tosylate or halide with the appropriately
substituted indolealkylamine in some high boiling solvent such as dimethyl sulfoxide
gives the title compounds of the invention.

[0041] Alternatively (Scheme 9), the nitro olefin (6) may be reduced with tin (II)
chloride as described in Scheme 5 above and protected with a suitable protecting
group such as carbobenzoxy (Cbz) before the olefin is cleaved to the aldehyde (31)
by treatment with osmium tetroxide/sodium periodate and the aldehyde converted to
a phenol (32) by the Baeyer-Villager procedure. Deprotection by treatment with
hydrogen over palladium on carbon gives the o-aminophenol, (33) which is cyclized
to the 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (29) by treatment with the
appropriate ortho ester, carboxylic acid or anhydride. Treatment of the o-
aminophenol
with cyanogen bromide or chloride or a suitably substituted carbamoyl chloride leads
to compounds of the invention in which R2 is amino. Treatment of the o-aminophenol
with carbonyl diimidazole gives the oxazolone which leads to compounds of the
invention in which R2 is halo via treatment with an inorganic anhydride such as
phosphoryl chloride or bromide. Replacement of the tosylate with the appropriately
substituted indolealkylamine as above gives the title compounds of the invention.

[0042] Compounds of the invention in which R1 is hydrogen and R2 is alkyl are
most conveniently prepared according to scheme 10 below. The appropriate 2',3\4'-
trihydroxyacylphenone (34) is regioselectively alkylated with glycidyl tosylate or an
epihalohydrin in the presence of a base such as sodium carbonate to give the
corresponding 7-acyl-8-hydroxybenzodioxan-2-methanol (35). Following conversion
of the ketone to the oxime (36) by reaction with hydroxylamine hydrochloride and
sodium acetate, cyclization to the oxazole (37) is effected by treatment with
phosphoryl chloride in the appropriate dimethylalkanoic acid amide. The resulting
7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene-8-methanol is converted to
the tosylate (38) by treatment with p-toluenesulfonyl chloride in pyridine and
combined with the appropriate indolealkylamines as described to give the title
compounds of the invention.

[0043] The compounds of the invention may be resolved into their enantiomers by
conventional methods or, preferably, the individual enantiomers may be prepared
directly by substitution of (2R)-(-)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for
the S benzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzene-sulfonate or
tosylate (for the R enantiomer) in place of epihalohydrin or racemic glycidyl tosylate
in the procedures above.
In yet another method, compounds of the present invention may be prepared in
accordance with Scheme 11. The synthesis of compound I is comprised of steps
that begin with halogenation of 39 where R' is alkyl of 1-6 carbon atoms, with
reagents such as N-halosuccinimide in acetonitrile to give 40 (where Hal is halogen
such as Br, Cl or I). Deprotecting 40 with Lewis acids such as boron tribromide,
boron trichloride, aluminum trichloride, ferric chloride, or trimethylsilyl iodide in a
suitable solvent such as methylene chloride, or with strong protic acids such as HBr
and HCI gives the salt 41. Free base 41 may be obtained by neutralization with an
Amberlyst A-21 resin slurry in polar solvents such as ethanol or methanol.
[0044] Alkylation of 41, either as the free base or as the salt, with benzyl or
substituted benzyl protected glycidyl ethers , where R" is benzyl,
substituted benzyl such as 4-bromobenzyl, 3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl,
or 4-methoxybenzyl) in suitable polar solvents such as DMSO, DMF, or DMA in the
presence of bases such as sodium carbonate, potassium carbonate, or triethylamine
gives 42. 42 was then cyclized using palladium catalysts such as
tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, or
palladium acetate with ligands from the group consisting of (±) BINAP and separate
enantiomers thereof, (±) Tol-BINAP and separate enantiomers thereof; 1-1'-
bis(diphenylphosphino) ferrocene, 1,3-bis(diphenylphosphino)propane, and 1,2
bis(diphenyl-phosphino)ethane in the presence of bases such as NaH, LiH, KH,
potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate,
potassium f-butoxide or potassium phosphate tribasic in suitable solvent such as
toluene, or alternatively, with copper catalyst such as copper iodide in the presence
of bases such NaH, LiH, KH in a suitable solvent such as toluene to afford 43.
[0045] Deprotection of quinoline 43 with Lewis acids such as boron tribromide,
boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodide in a
suitable solvent such as methylene chloride, or with strong protic acids such as HBr
and HCI or under reductive cleavage conditions using Pd catalyst and hydrogen
transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or
ammonium formate gives the heterocycle-fused benzodioxanmethanol 44. The
hydroxyl moiety of 44 can be activated with an aryl- or alkylsulfonyl chloride such as
p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitrobenzenesulfonyl
chloride, or 2- or 4-bromobenzenesulfonyl chloride in the presence of bases such as
triethylamine or pyridine in suitable solvents such as methylene chloride, THF, or
toluene to afford 45 where R'" is a sulfonate such as p-toluenesulfonate,
methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2- or 4-
bromobenzenesulfonate. The final coupling of 45 with indolealkylamines appropriate
to the invention, in the presence of bases such as Hunig's base (diisopropyl
ethylamine), potassium carbonate, or sodium carbonate in polar solvents such as
THF, dioxane, DMSO, DMF, or DMA affords the compounds of Formula I.
[0046] The compounds of the invention may alternatively be prepared from the
heterocycle-fused benzodioxan methyltosylate (45) by the method outlined below in
Scheme 11. The tosylate is heated with sodium azide in
an appropriate solvent such as DMF to give the azide 46, which is then reduced to
the primary amine (47) by a suitable reducing agent such as hydrogen over
palladium on carbon, sodium borohydride in isopropanol or triphenylphosphine. The
primary amine 47 may either be reductively alkylated by treatment with a suitably
substituted aldehyde or ketone in the presence of a reducing agent such as sodium
cyanoborohydride or alkylated with a suitably substituted indolealkyl halide,
alkylsulfonate or arylsulfonate in the presence of a base such as triethylamine or
Hunig's base to give the compounds of the invention in which R3 is hydrogen. The
secondary amines thus derived may be further alkylated if desired by treatment with
the appropriate alkyl halide in the presence of a tertiary base or alkanal in the
presence of a reducing agent such as sodium cyanoborohydride to give the
compunds of the invention in which R3 is alkyl.
Scheme 12
[0047] The guaiacols, catechols, 2'.3'4'-trihydroxyacylphenones and benzodioxan
methyltosylates appropriate to the above chemistry are known compounds or can be
prepared by one schooled in the art. The indole alkyl ketones, halides,
alkylsulfonates and arylsulfonates are known compounds or they can readily be
prepared by one schooled in the art using the procedures outlined by Smith, Yocca,
Yevich and Matson in EP 464 558 A1 or by Bathe and Tilly in WO 0035872 A1. The
indolealkylamines are known compounds or can readily be prepared by one schooled
in the art from the halides or sulfonates by treatment with sodium azide or sodium
cyanide, followed by reduction with hydrogen over the appropriate catalyst, either
palladium on carbon or rhodium on alumina. The benzofuranylalkylamines and
benzothiophenylalkylamines are known compounds or can readily be prepared by
one schooled in the art from the known alcohols by first converting them to the
bromides by treatment with triphenylphosphine and carbon tetrabromide, then
displacing the bromide with either sodium azide or sodium cyanide and finally by
reduction with hydrogen as described above for the indolealkylamines.
[0048] A protocol similar to that used by Cheetham et al. (Neuropharmacol. 32:737,
1993) was used to determine the affinity of the compounds of the invention for the
serotonin transporter. The compound's ability to displace 3H-paroxetine from male
rat frontal cortical membranes was determined using a Tom Tech filtration device to
separate bound from free 3H-paroxetine and a WaHac 1205 Beta Plate® counter to
quantitate bound radioactivity. Kj's thus determined for standard clinical
antidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and 67.6 nM for
zimelidine. A strong correlation has been found between 3H-paroxetine binding in rat
frontal cortex and 3H-serotonin uptake inhibition.
[0049] High affinity for the serotonin 5-HTiA receptor was established by testing the
claimed compound's ability to displace [3H] 8-OHDPAT (dipropylaminotetralin) from
the 5-HT1A serotonin receptor following a modification of the procedure of Hall ef al.,
J. Neurochem. 44, 1685 (1985) which utilizes CHO cells stably transfected with
human 5-HT1A receptors. The 5-HT1A affinities for the compounds of the invention
are reported below as Kj's.
[0050] Antagonist activity at 5-HT1A receptors was established by using a 35S-
GTPyS binding assay similar to that used by Lazareno and Birdsall {Br. J. Pharmacol.
109: 1120, 1993), in which the test compound's ability to affect the binding of ^S-
GTPyS to membranes containing cloned human 5-HT1A receptors was determined.
Agonists produce an increase in binding whereas antagonists produce no increase
but rather reverse the effects of the standard agonist 8-OHDPAT. The test
compound's maximum inhibitory effect is represented as the J^, while its potency is
defined by the JC50.
[0051] The results of the three standard experimental test procedures described in
the preceding three paragraphs were as follows:
anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as
anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol
addiction, sexual dysfunction (including but not limited to premature ejaculation),
incontinence (including, but not limited to fecal incontinence, urge incontinence,
overflow incontinence, passive incontinence, reflex incontinence, stress urinary
incontinence urinary exertional incontinence and urinary incontinence), and pain
(including, but not limited to migraine, chronic back pain, phantom limb pain,
neuropathic pain such as diabetic neuropathy, and post herpetic neuropathy) and
related illnesses. Moreover, the compounds of this invention have potent affinity for
and antagonist activity at brain 5HT1A serotonin receptors. Recent clinical trials
employing drug mixtures {e.g., fluoxetine and pindolol) have demonstrated a more
rapid onset of antidepressant efficacy for a treatment combining SSRI activity and
5HT1A antagonism (Blier and Bergeron, 1995; F. Artigas, et ah, 1996; M. B. Tome, et
a/., 1997). The compounds of the invention are thus exceedingly interesting and
useful for treating depressive illnesses.
[0053] Thus the present invention provides methods of treating, preventing,
inhibiting or alleviating each of the maladies listed above in a mammal, preferably in
a human, the methods comprising providing a pharmaceutically effective amount of a
compound of this invention to the mammal in need thereof.
[0054] Also encompassed by the present invention are pharmaceutical
compositions for treating or controlling disease states or conditions of the central
nervous system comprising at least one compound of Formula I, mixtures thereof,
and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier
therefore. Such compositions are prepared in accordance with acceptable
pharmaceutical procedures, such as described in Remington's Pharmaceutical
Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,
PA (1985). Pharmaceutically acceptable carriers are those that are compatible with
the other ingredients in the formulation and biologically acceptable.
[0055] The compounds of this invention may be administered orally or parenterally,
neat or in combination with conventional pharmaceutical carriers. Applicable solid
carriers can include one or more substances that may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants, compression aids,
binders or tablet-disintegrating agents or an encapsulating material. In powders, the
carrier is a finely divided solid that is in admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a carrier having the
necessary compression properties in suitable proportions and compacted in the
shape and size desired. The powders and tablets preferably contain up to 99% of
the active ingredient. Suitable solid carriers include, for example, calcium phosphate,
magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes
and ion exchange resins.
[0056] Liquid carriers may be used in preparing solutions, suspensions, emulsions,
syrups and elixirs. The active ingredient of this invention can be dissolved or
suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid
carrier can contain other suitable pharmaceutical additives such as solubiiizers,
emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents,
thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
Suitable examples of liquid carriers for oral and parenteral administration include
water (particularly containing additives as above, e.g. cellulose derivatives, preferably
sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols
and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration the carrier can also be an
oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used
in sterile liquid form compositions for parenteral administration.
[0057]' Liquid pharmaceutical compositions that are sterile solutions or suspensions
can be administered by, for example, intramuscular, intraperitoneal or subcutaneous
injection. Sterile solutions can also be administered intravenously. Oral
administration may be either liquid or solid composition form.
[0058] Preferably the pharmaceutical composition is in unit dosage form, e.g. as
tablets, capsules, powders, solutions, suspensions, emulsions, granules, or
suppositories. In such form, the composition is sub-divided in unit dose containing
appropriate quantities of the active ingredient; the unit dosage forms can be
packaged compositions, for example packeted powders, vials, ampoules, prefilled
syringes or sachets containing liquids. The unit dosage form can be, for example, a
capsule or tablet itself, or it can be the appropriate number of any such compositions
in package form.
[0059] The amount provided to a patient will vary depending upon what is being
administered, the purpose of the administration, such as prophylaxis or therapy, and
the state of the patient, the manner of administration, and the like. In therapeutic
applications, compounds of the present invention are provided to a patient already
suffering from a disease in an amount sufficient to cure or at least partially ameliorate
the symptoms of the disease and its complications. An amount adequate to
accomplish this is defined as a "therapeutically effective amount." The dosage to be
used in the treatment of a specific case must be subjectively determined by the
attending physician. The variables involved include the specific condition and the
size, age and response pattern of the patient. Generally, a starting dose is about 5
mg per day with gradual increase in the daily dose to about 150 mg per day, to
provide the desired dosage level in the human.
[0060] Provide, as used herein, means either directly administering a compound or
composition of the present invention, or administering a prodrug, derivative or analog
which will form an equivalent amount of the active compound or substance within the
body.
[0061] The present invention includes prodrugs of compounds of Formula I, la and
Ib. Prodrug, as used herein, means a compound which is convertible in vivo by
metabolic means (e.g. by hydrolysis) to a compound of Formula I. Various forms of
prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design
of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,
Academic Press (1985); Krogsgaard-Larsen, et al., (ed). Design and Application of
Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991),
Bundgaard, ef al., Journal of Drug Deliver Reviews, 8:1-38(1992), Bundgaard, J. of
Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.)
Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).
[0062] The following examples illustrate the production of representative
compounds of this invention.
INTERMEDIATE 1
3-AHvloxv-4-methoxynitrobenzene
[0063] 97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolved in one
liter of DMF and 1.5 equivalents of allyl bromide added. The reaction was heated to
65°C for two hours, after which time much of the dark color had discharged and tic
(1:1 CH2Cl2/hexane) indicated loss of starting material. The solvent was
concentrated in vacuum and the residue washed with water. The product was
isolated by filtration and dried in a vacuum. This gave 112 g of pale yellow solid. A
sample recrystallized from methanol, gave m.p. 93-94 °C.
INTERMEDIATE 2
2-Allvloxv-4-nitrophenol
[0064] To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueous sodium
hydroxide and the mixture was heated to 65°C. The pale yellow solid 3-allyloxy-4-
methoxynitrobenzene prepared above was added in portions over a 30 minute period
and then the temperature was raised to 95°C and maintained for 3 hours, after which
time the starting material had been consumed. The mixture was allowed to cool and
poured into a mixture of 1 L ice and 1 L 2 N HCI. 73 Grams of crude but
homogeneous (by tic 1:1 CH2Cl2/hexane) desired product was isolated as a light
brown solid by filtration. This material was subsequently dissolved in 1:1
hexane/methylene chloride and filtered through silica gel to give 68 g of pale yellow
solid, which, when recrystallized from ethyl/acetate/hexane, gave m.p. 61-62°C. The
aqueous mother liquors from the initial crystallization above were extracted with 2 L
of ethyl acetate. This was dried over sodium sulfate, filtered and evaporated to a
dark oil. Column chromatography on silica with 1:1 CH2Cl2/hexane gave an
additional 12 g of the title compound as a yellow solid. Elution with 2% MeOH in
CHCI3 gave 12 g of a dark oil which slowly crystallized in vacuum. This proved to be
the Claisen product, 3-allyl-4-nitrocatechol.
INTERMEDIATE 3
2-(2-Allvloxv-4-nitrophenoxymethvl)-oxirane
[0065] 20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two liter flask and
washed with 500 mL of hexane. 1 L of DMF was added, followed by 77 g (0.40
mole) of the 2-allyloxy-4-nitrophenol prepared in the previous step. Addition of the
phenol was performed in portions under argon. After stirring the mixture for 30
minutes at room temperature under argon, 108 g (0.48 moles) of (R)-glycidyl tosylate
was added and the mixture heated at 70-75°C under nitrogen overnight. Upon
cooling, the DMF was removed in vacuum and replaced with one liter of methylene
chloride. This was washed with 500 mL portions of 2 N HCI, saturated sodium
bicarbonate and saturated brine and dried over sodium sulfate. The mixture was
filtered, concentrated to an oil in vacuum and column chromatographed on silica gel
using 1:1 hexane/methylene chloride as eluant. This gave 43 g of product
contaminated with traces of the two starting materials, followed by 21 g of pure
product as a pale yellow solid. The impure material was recrystallized from 1.2 L of
10% ethyl acetate/hexane to give 34 g of pure (homogeneous on silica gel tic with
1:1 hexane/methylene chloride) (R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p.
64°C).
Elemental Analysis for: C12H13NO5
Calc'd: C, 57.37; H, 5.21; N, 5.58
Found: C, 57.50; H, 5.21; N, 5.43
INTERMEDIATE 4
(8-Allvl-7-nitro-2.3-dihvdro-benzo(1.4)dioxin-2-vlVmethanol
[0066] (R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmol) prepared
as above was heated at 155°C in mesitylene for 24 hours under nitrogen. Filtration
of the black solid that formed gave 1.5 g of very polar material. Evaporation of the
solvent in vacuum followed by column chromatography on silica gel with methylene
chloride as eluant gave 10 g of recovered starting material and 7.5 g of the desired
rearranged (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, which
slowly crystallized on standing in vacuum (m.p. 67°C). The yield based on recovered
starting material is 75%.
Elemental Analysis for: C12H13NO5
Calc'd: C, 57.37; H, 5.21; N, 5.58
Found: C, 57.26; H, 5.20; N, 5.35
INTERMEDIATE 5
Toluene-4-sulfonic acid 8-allvl-7-nitro-2,3-dihydro-benzo(1.4)dioxin-2-vlmethvl
ester
[0067] 9.55 g (38.0 mmol) of (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-
methanol was dissolved in 465 mL of pyridine, 29.0 g (152 mmol) of p-
toluenesulfonyl chloride was added and the mixture stirred at room temperature
under nitrogen overnight. Water was then added to quench the excess tosyl chloride
and the solvent was removed in vacuum and replaced with methylene chloride. This
solution was washed with 2 N HCI, with saturated sodium bicarbonate, and with
saturated brine, and dried over magnesium sulfate. Filtration, evaporation in vacuum
and column chromatography on silica gel with 1:1 hexane/methylene chloride as
eluant gave 12.6 g (92%) of toluene-4-sulfonic acid (R)-allyl-7-nitro-2,3-
benzo(1,4)dioxin-2-ylmethyl ester, which slowly crystallized to a tan solid (m.p. 60-62
°C) upon standing.
Elemental Analysis for: C19H19NO7S
Calc'd: C, 56.29; H, 4.72; N, 3.45
Found: C, 56.13; H, 4.58; N, 3.44
INTERMEDIATE 6
(7-Nitro-8-ri-propenvn-2.3-dihvdro-1.4-benzodioxin-2-vl}methvl 4-
methvlbenzenesulfonate
[0068] To a solution of 10.0 g (24.0 mmol) of (R)-[8-allyl-7-nitro-2,3-dihydro-1,4-
benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 700 mL of benzene was added
1.03 g of bis(acetonitrile)dichloropalladium (II) and the mixture was refluxed under
nitrogen for 48 hours. The catalyst was then removed by filtration and the filtrate
concentrated in vacuum to a brown oil. Column chromatography on silica gel with
methylene chloride as eluent gave 7.2 g of the title compound as a mixture of E and
Z isomers. A sample of {(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzodioxin-
2-yl}methyl 4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106
°C) by evaporation of a pure E isomer-containing fraction.
Elemental Analysis for: C19H19NO7S
Calc'd: C, 56.29; H, 4.72; N, 3.45
Found: C, 56.12; H, 4.64; N, 3.39
INTERMEDIATE 7
(7-Nitro-8-r3-oxo-1-propenvn-2.3-dihvdro-1.4-benzodioxin-2-yl)methvl4-
methylbenzenesulfonate
[0069] .{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-
methy Ibenzenesulfonate (6.15 g, 15.2 mmol) was dissolved in 180 mL of dioxane.
Selenium dioxide (4.20 g, 37.9 mmol) was then added, followed by 0.70 mL of water.
The heterogeneous mixture was heated at reflux under nitrogen for 5 hours. Upon
cooling, the reaction was filtered and concentrated in vacuum to yield a dark yellow
solid. This was dissolved in minimal ethyl acetate and column chromatographed on
silica gel using 30% ethyl acetate in hexane as eluant to give 5.75 g of the (R)-
enantiomer of the title compound as a light yellow solid (m.p. 138-140 °C).
Elemental Analysis for: C19H17NO8S
Calc'd: C, 54.41; H, 4.09; N, 3.34
Found: C, 54.10; H, 3.85; N, 3.31
INTERMEDIATE 8
2,3-Dihvdrof1.4ldioxinor2.3-f1quinolin-2-vlmethyl4-methvlbenzenesulfonate
[0070] To a solution of {(2R)-7-nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-
benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (3.50 g, 8.35 mmol) in 200 mL of
acetic acid/ethanol (1:1) was added 2.35 g (42.1 mmol) of iron powder and the
mixture was heated at reflux under nitrogen for 8 hours. After the reaction was
complete, 150 mL of water was added and the mixture filtered through a pad of
celite. The filtrate was neutralized with saturated sodium bicarbonate and extracted
with ethyl acetate. The extract was dried over magnesium sulfate, filtered and
evaporated in vacuum. The residue was column chromatographed on silica gel
using a gradient elution commencing with 20% ethyl acetate/hexane and ending with
70% ethyl acetate/hexane to give 1.85 g of the (R)-enantiomer of the title compound
as a yellow oil. . 1H-NMR (CDCI3): doublet 8.8 8 (1 H); doublet 8.2 5 (1 H); doublet
7.8 8 (2 H); doublet 7.6 8 (1 H); multiplet 7.35 8 (1 H); multiplet 7.25 8 (3 H); multiplet
4.6 8 (1 H); multiplet 4.3-4.4 S (3 H); multiplet 4.2 8 (1 H); singlet 2.4 8 (3 H).
INTERMEDIATE 9
(8-Formvl-7- nitro-2.3-dihydro-1,4-benzodioxin -2-vl)methvl 4-
methvlbenzenesulfonate
[0071] {(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-
methy Ibenzenesulfonate (10.5 g, 25.9 mmol) dissolved in 400 mL of methylene
chloride was treated with excess ozone at -78°C. Diisopropylethylamine (11.5 mL,
66.0 mmol) was then added dropwise over 30 minutes and the mixture allowed to
come to room temperature and stir overnight under a nitrogen atmosphere. The
mixture was then diluted to 600 mL with methylene chloride, washed three times with
100 mL portions of 2N HCI (aq), twice with 200 mL portions of saturated aqueous
sodium bicarbonate and with 200 mL of saturated brine. The solution was dried over
magnesium sulfate, filtered and concentrated in vacuum to a crude brown oil, which
was column chromatographed on silica gel with 10% hexane/methylene chloride to
give 7.52 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR
(CDCI3): doublet 7.8 5 (2 H); doublet 7.62 5 (1 H); doublet 7.4 8 (2 H); doublet 7.0 5
(1 H); muitiplet 4.4-4.6 5 (2 H); multiplet 4.2 5 (3 H); singlet 2.4 5 (3 H).
INTERMEDIATE 10
(7-Nitro-8-f (E)-3-oxo-1 -butenvn-2.3-dihvdro-1.4-benzodloxtn-2-vl)methyl 4-
methvlbenzenesulfonate
[0072] To a solution of 3.00 g (7.37 mmol) of [(2R)-8-formyl-7- nitro-2,3-dihydro-
1,4-benzodioxin -2-yl]methy! 4-methylbenzenesulfonate in 250 mL of toluene was
added 2.90 g (9.10 mmol) of 1-triphenylphosphorylidene-2-propanone. The mixture
was stirred at room temperature under nitrogen for 5 hours, during which time some
product precipitated from solution. The solvent was removed in vacuum and the
crude residue was column chromatographed on silica gel with methylene chloride as
eluant to give 3.0 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-
NMR (CDCI3): doublet 7.8 5 (2 H); doublet 7.6 8 (1 H); doublet 7.5 5 (2 H); doublet
7.4 5 (2 H); doublet 6.95 6 (1 H); doublet 6.6 5 (1 H); multiplet 4.5 5 (1 H); doublet of
doublets 4.0 8 (1 H); multiplet 4.2 8 (3 H); singlet 2.45 S (3 H); singlet 2.4 5 (3 H).
INTERMEDIATE 11
(8-Methvl-2,3-dihvdroH .41dioxinof2.3-f1auinolin-2-vnmethvl 4-
methvlbenzenesulfonate
[0073] To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-
benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (3.40 g, 7.83 mmol) in 200 mL of
acetic acid/ethanol (3:2) was added 2.25 g (40.2 mmol) of iron powder and the
mixture was heated at reflux under nitrogen for 8 hours. After the reaction was
complete, 150 mL of water was added and the mixture filtered through a pad of
celite. The filtrate was neutralized with saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered
and evaporated in vacuum. The residue was column chromatographed on silica gel
using a gradient elution commencing with 20% ethyl acetate/hexane and ending with
70% ethyl acetate/hexane to give 2.5 g of the (R)-enantiomer of the title compound
as a yellow oil. 1H-NMR (CDCI3): doublet 8.1 5 (1 H); doublet 7.6 8 (2 H); doublet 7.45
5 (1 H); multiplet 7.2 8 (4 H); multiplet 4.6 S (1 H); multiplet 4.3 8 (3 H); multiplet4.1 8
(1 H); singlet 2.5 8 (3H); singlet 2.4 8 (3 H).
INTERMEDIATED
!7-Nitro-8-f(E>-3-oxo-1-Dentenvll-2.3-dihvdro-1.4-benzodioxin-2-vl)methvl 4-
methvlbenzenesulfonate
[0074] To a solution of 5.00 g (12.2 mmol) of [(2R)-8-formyl-7- nitro-2,3-dihydro-
1,4-benzodioxin -2-yl]methyl 4-methylbenzenesulfonate in 200 mL of toluene was
added 5.10 g (15.3 mmol) of 1-triphenylphosphorylidene-2-butanone. The mixture
was stirred at room temperature under nitrogen for 5 hours, after which time the
solvent was removed in vacuum and the crude residue was column
chromatographed on silica gel with methylene chloride as eluant to give 5.0 g of the
(R)-enantiomer of the title compound as a yellow solid (m.p. 114 °C).
Elemental Analysis for: C17H15NO8S
Calc'd: C, 56.37; H, 4.73; N, 3.13
Found: C, 56.81; H, 4.60; N, 3.01
INTERMEDIATE 13
(8-Ethvl-2.3-dihvdrof 1,41dioxinor2.3-f1auinolin-2-vl)methvl 4-
methvlbenzenesulfonate
[0075] To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1-pentenyl]-2,3-dihydro-1,4-
benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (1.57 g, 3.50 mmol) in 100 mL of
acetic acid/ethanol (1:1) was added 1.00 g (17.9 mmol) of iron powder and the
mixture was heated at reflux under nitrogen for 8 hours. After the reaction was
complete, 150 mL of water was added and the mixture filtered through a pad of
celite. The filtrate was neutralized with saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered
and evaporated in vacuum. The residue was column chromatographed on silica gel
using a gradient elution commencing with 20% ethyl acetate/hexane and ending with
70% ethyl acetate/hexane to give 0.94 g of the (R)-enantiomer of the title compound
as a yellow oil. 1H-NMR (CDCI3): doublet 8.2 8 (1 H); doublet 7.8 8 (2 H); doublet
7.55 6 (1 H); 7.2-7.3 5 (4 H); multiplet 4.6 5 (1 H); multiplet 4.2-4.4 5 (3 H); multiplet
4.1 5 (1 H); quartet 3.0 5 (2 H); singlet 2.4 S (3 H); triplet 1.4 5 (3 H).
INTERMEDIATE 14
1-r5-Hvdroxv-3-fhvdroxvmethvl)-2.3-dihvdro-1.4-ben2odioxin-6-vll-1-ethanone
[0076] To a solution of 2',3',4'-trihydroxyacetophenone (10.6 g, 63.0 mmol) in DMF
(75 mL) was added potassium carbonate (17.4 g, 126 mmol). After 5 minutes (R)-
glycidyl tosylate (9.67 g, 42.3 mmol) was added, then the heterogeneous mixture
was heated to 70°C for 3 hours. After removal of the solvent in vacuum, the residue
was taken into water (800 mL) and was then extracted with ethyl acetate (4 x 300
mL). The combined organic layers were dried over magnesium sulfate, filtered and
evaporate to dryness in vacuum. The crude brown oil thus obtained was column
chromatographed on silica gel with 40% hexane/ethyl acetate as eluant to give the
(S)-enantiomer of the title compound as a yellow oil which solidifies upon standing
(7.5 g, 78%). MS (ESI) m/z 223 (M-H)-.
Elemental Analysis for: CnH^Os'O.IO H2O
Calc'd: C, 58.46; H, 5.44
Found: C, 58.02; H, 5.09
INTERMEDIATE 15
1 -r5-Hvdroxv-3-(hvdroxvmethvl)-2.3-dihvdro-1.4-benzodioxin-6-vn-1 -ethanone
oxime
[0077] A solution of hydroxyiamine hydrochloride (2.38 g, 34.2 mmol) in 1:1
ethanol/pyridine (100 mL) was added to a solution of 1-[(3S)-5-hydroxy-3-
(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1 -ethanone (1.92 g, 8.57 mmol) in
ethanol (200 mL). It was then heated to reflux under nitrogen for 5 hours. Upon
cooling, the solvent was removed and replaced with ethyl acetate. The solution was
then washed with water (200 mL) and with aqueous 2N HCI (100 mL), dried over
magnesium sulfate, filtered and evaporated in vacuum to give 1.89 g (93%) of the
(S)-enantiomer of the title compound as a gray solid, m.p. 162°C. MS (ESI) m/z 240
(M+H)+.
Elemental Analysis for. CnH13NO5»0.35 H2O
Calc'd: C, 53.81; H, 5.62; N, 5.71 .
Found: C, 53.51; H, 5.30; N, 5.58
INTERMEDIATE 16
f2-Methvl-7.8-dihvdron.41dioxinor2.3-qiri.31benzoxazol-8-vnmethanol
[0078] 3.03 g (12.6 mmol) of 1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-
benzodioxin-6-yl]-1-ethanone oxime was dissolved in a mixture of 1:3 N,N-
dimethylacetamide/acetonitrile (100 mL). The solution was cooled in an ice/water
bath and a solution of phosphorus oxychloride (1.26 mL, 35 mmol) in 1:3 N,N-
dimethylacetamide/acetonitriie (30 mL) was added. The reaction mixture was stirred
under nitrogen over a period of 48 hours. It was then added to an ice cold, saturated
solution of sodium acetate, extracted with ethyl acetate, dried over magnesium
sulfate, filtered and evaporated in vacuum. The resulting crude oil was column
chromatographed on silica gel with 60% hexane/ethyl acetate to remove impurities
and the product eluted with 40% hexane/ethyl acetate. After evaporation of the
solvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the title compound was
obtained as a white solid, m.p. 120°C. MS (ESI) m/z 222 (M+H)+.
Elemental Analysis for: CnHnNO4'0.20 H2O
Calc'd: C, 58.77; H, 5.11; N, 6.23
Found: C, 58.93; H, 4.91; N, 6.14
INTERMEDIATE 17
[2-Methvl-7. 8-dihvdron .41dioxinof2.3-gin .31benzoxazol-8-vnmethyl 4-
methvlbenzenesulfonate
[0079] To a solution of [(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-
g][1,3]benzoxazol-8-yl]methanol (1.80 g, 8.14 mmol) in methylene chloride (100 mL)
was added p-toluenesulfonyl chloride (3.90 g, 20.4 mmol). The mixture was cooled in
an ice bath and a solution of diisopropylethylamine ( 3.55 mL, 20.4 mmol) in
methylene chloride (20 mL) was then added dropwise, followed by 4-
dimethylaminopyridine (0.65 g, 5.30 mmol). The solution was allowed to warm to
room temperature and was stirred under nitrogen overnight. The reaction was
diluted to 500 mL in volume with methylene chloride, then washed with aqueous 2 N
HCI (200 mL), with saturated aqueous sodium bicarbonate (200 mL), and with brine
(150 mL), dried over magnesium sulfate, filtered and evaporated in vacuum to a
yellow oil. The crude oil was column chromatographed on silica gel using methylene
chloride to remove impurities and 3% methanol/methylene chloride to elute the (R)-
enantiomer of the title compound, which becomes a white solid under vacuum (2.56
g, 84%), m.p. 123°C. MS (ESI) m/z 376 (M+H)+.
Elemental Analysis for: C18H17NO6S • 0.20 H2O
Calc'd: C, 57.04; H, 4.63; N, 3.70
Found: C, 56.75; H, 4.62; N, 3.51
INTERMEDIATE 18
5-Bromo-6-methoxv-2-methvlquinoline
[0080] A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) in acetonitrile
(1.77 L) was cooled to 0-3°C followed by portion-wise addition of N-bromo-
succinimide (200 g, 1.12 mol) over a period of 30 minutes while maintaining the
same temperature. The resulted brown slurry was warmed to ambient temperature
and stirred for an additional 6 hours. The reaction was then quenched by a 10%
NaHSO3 solution (211 mL). The reaction mixture was concentrated to a volume of
600 mL then slowly poured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred
at room temperature for 1 hour then filtered, washed with water (2x1 L) and dried in
a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid. R, =
0.39 (3:7) ethyl acetate:heptane; 1H NMR (DMSO) 5 8.30 (d, J=6.5 Hz, 1H), 7.98 (d,
J=6.9 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.5 Hz, 1H), 4.02 (s, 3H), 2.66 (s,
3H);
Elemental Analysis for: CnHioNOBr
Calc'd: C 52.40 H 3.97 N 5.56
Found: C 52.13 H 3.94 N 5.61
INTERMEDIATE 19
5-Bromo-2-methyl-6-quinolinol
[0081] A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48%
HBr (135 mL) was heated to reflux for 7 hours then cooled to 5°C in 1 hour to give a
brown and thick slurry. The slurry was stirred at 0-5°C for 1 hour then filtered,
washed with ethyl acetate (2 x 50 mL) and dried in a vacuum oven to give 34.9 g
(92%) of the hydrobromide of the title compound as a brown solid. 1H NMR (DMSO)
S 8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d,
J=8.7 Hz, 1H), 2.64 (s, 3H). A slurry of the hydrobromide salt of 5-bromo-2-methyl-6-
quinolinol (3.4 g, 10.5 mmol) and Amberlyst A-21 ion-exchange resin (1.7 g, pre-
washed with MeOH then dried in oven) in MeOH (35 mL) was stirred at room
temperature for 3 h. The mixture was then filtered and concentrated in vacuo to give
2.5 g (100%) of a yellow solid. R, = 0.36 (1:1) Ethyl acetate:heptane; 1H NMR
(DMSO) 5 8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.47 (t, J=9.1 Hz, 2H), 2.66
' (s, 3H).
INTERMEDIATE 20
(2S)-1-(BenzvloxvV3-r(5-bromo-2-methvl-6-quinolinv0oxv1-2-propanol
[0082] A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol), (R)-benzyl
glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g, 172 mmol) in DMA (200
mL) was heated in a 95-98°C oil bath for 2 days. The solution was cooled and
poured into water (300 mL) while stirring. The tan precipitate formed was filtered,
washed with water (100 mL) and dried in a vacuum oven to give 37 g (73%) of the
title compound as a tan solid. R, = 0.35 (ethyl acetate); 1H NMR (DMSO) 8 8.31 (d,
J=8.8 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.7Hz, 1H),
7.25-7.36 (m, 5H), 5.28 (d, J=5.1 Hz, 1H), 4.56 (s, 2H), 4.22-4.29 (m, 2H), 4.08-4.15
(m, 1H), 3.61 -3.73 (m, 2H), 2.66 (s, 3H); Specific rotation = +6.2 ° (c=1, CH3OH);
Elemental Analysis for: C2oH20BrN03
Calc'd: C 59.66 H 4.97 N 3.48
Found: C 59.43 H 4.97 N 3.55
INTERMEDIATE 21
(2S)-2r(Benzvloxv)methvl-8-methvl-2,3-dihvdron.41dioxino f2.3-flquinoline
[0083] To a mixture of (2S)-1 -(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-
propanol (100 g, 0.249 mol) and copper (I) iodide (47.4 g, 0.249 mol) in toluene (2 L),
NaH (10.9 g, 0.45 mol) was added in portions at 30-35°C over 20 minutes. The
reaction mixture was kept at 35°C for 30 minutes then heated to 110°C slowly. After
30 minutes, the reaction was cooled to 60°C, additional NaH (10.9 g, 0.45 mol) was
added. This was warmed to 110cC for an additional 2 hours then cooled to rt before
dropwise addition of water (200 ml_). After stirring for 15 minutes, the mixture was
filtered through a bed of celite then washed with toluene (3 x 50 mL) and water (50
mL). The two layers were separated. The organic layer was extracted with water
(100 mL), NH4OH (100 mL), 25% NaCI (100 mL) and concentrated in vacuoto give
387.6 g of the crude product as a brown syrup. The crude product was carried
through to the debenzylation step before purification.
INTERMEDIATE 22
r(2RV8-Methvl-2.3-dihvdrori.41dloxinor2.3-f|quinolin-2-vnmethanol
[0084] To a solution of (2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino
[2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene (0.5 mL)
then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated to reflux under N2 for
18 hours then cooled and filtered. The catalyst was rinsed with methanol and the
filtrate was concentrated in vacuo to afford 0.113 g (98%) of the title alcohol as an
off-white solid.
1H NMR (CD3OD) 5 8.46 (m, 1H), 7.47 (m, 1H), 7.38-7.31 (m, 2H), 4.40 (m, 1H), 4.36
(m, 1H), 4.18 (m, 1H), 3.91 (m, 2H), 2.68 (s, 3H).
INTERMEDIATE 23
r(2RV8-Methvl-2.3-dihvdron.41dioxinor2.3-f1auinolin-2-vnmethvl4-
bromobenzenesulfonate
[0085] A solution of [(2S)-8-rnethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-
methanol (4.0 g, 17.3 mmol), brosyl chloride (4.86 g, 19.0 mmol), dimethylamino
pyridine (20 mg, 0.16 mmol) and triethylamine (3.62 mL, 25.8 mmol) in toluene (40
mL) was stirred at 60°C for 6 hours. The reaction mixture was cooled to room
temperature then water (20 mL) was added. After 30 minutes, the two layers were
separated. The organic layer was extracted with 8% NaHCO3 (20 mL) and H2O (20
mL), dried over Na2SO4, filtered and concentrated in vacuo. The solid obtained was
dissolved in isopropyl alcohol (50 mL) and toluene (10 mL) at 80°C, cooled to room
temperature over 1 hour then filtered, washed with (5:1) IPA: toluene (2x5 mL) and
dried in a vacuum oven to give 5.99 g (76.9%) of the title compound as an off-white
solid. 13C NMR (CDCI3) 5 157.9, 144.3, 138.1, 134.7, 132.9, 129.7, 129.6, 129.0,
122.4, 121.7, 121.3,118.8, 70.7, 67.6, 64.5, 25.4
INTERMEDIATE 24
C-(8-Methvl-2.3-dihvdro-n.41dioxinof2,3-f1qulnolin-2-yl)-nnethvlamine
[0086] A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (0.45 g, 1.0 mmol) and sodium azide (0.33 g, 5.0 mmol) in
50 mL of DMF was heated at 60°C under nitrogen for 15 hours. The solvent was
removed in vacuum and the residue redissolved in 300 mL of methylene chloride and
washed with 300 mL portions of water and saturated brine, dried over magnesium
sulfate, filtered and concentrated in vacuum to 0.25 g of a yellow oil. The oil was
redissolved in 100 mL of methanol into which 100 mg of 10% Pd/C and 0.3 mL cone.
HCI had been added. The mixture was treated with hydrogen at 50 psi in a Parr
apparatus for 6 hours, then filtered through celite and concentrated in vacuum.
Recrystallization of the residue from ethanol gave 0.18 g of the (S)-enantiomer of the
title compound as a yellow dihydrochloride, m.p. > 250 °C.
Elemental Analysis for: Ci3H-|4N2C>2*2 HCI • H2O
Calc'd: C, 48.61; H, 5.65; N, 8.72
Found: C, 48.59; H, 5.51; N, 8.62
INTERMEDIATE 25
3-(3-Bromopropyl)benzofuran
[0087] To a 0°C solution of triphenylphosphine (2.07 g, 7.90 mmoi) in methylene
chrloride (20 ml_) was added bromine (0.4 mL, 7.90 mmol) dropwise. To the
resulting cloudy mixture was added a solution of 3-benzofuran-3-yl-propan-1-ol (1.16
g, 6.58 mmol) and pyridine (1.07 mL, 13.2 mmol) in methylene chloride (10 mL). The
reaction was stirred at room temperature for 4 hours, then was diluted with diethyl
ether (100 mL) and filtered. The ethereal solution was washed with 1 M aqueous
potassium hydrogen sulfate (50 mL), then with saturated aqueous sodium
bicarbonate (50 mL), and finally with brine (50 mL), then was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography on
SiO2 (CH2CI2) afforded 1.5 g (96%) of the title compound: 1H NMR (CDCI3, 400
MHz) 5 7.56 (d, J = 7.8 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 7.46 (s, 1 H), 7.7.22-7.35
(m, 2 H), 3.45 (t, J = 6.4 Hz, 2 H), 2.87 (t, J = 7.1 Hz, 2 H), 2.25 (quint, J = 7.2 Hz, 2
H).
INTERMEDIATE 26
3-(2-Bromoethvl)-7-methoxybenzofuran
[0088] This compound was prepared by the same method as for Intermediate 25,
using 4.15 g (21.6 mmol) of 2-(7-methoxybenzofuran-3-yl)-ethanol, 6.8 g (25.9 mmol)
of triphenylphosphine, 1.34 mL (25.9 mmol) of bromine, and 3.5 mL (43.2 mmol) of
pyridine in 70 mL of CH2CI2, to afford 2.87 g (52%) of the title compound after flash
chromatography on SiO2 (25% CH2CI2/hexanes to 100% CH2CI2 gradient): MS (ESI)
m/z 254 [M]Elemental Analysis for: CnHuBrO2
Calc'd: C, 51.79; H, 4.35
Found: C, 52.11; H, 4.07
INTERMEDIATE 27
4-Benzorb1thiophen-3-vl-butvronitrile
[0089] To a solution of 3-(3-bromopropyl)-benzo[b]thiophene (1.78 g, 6.97 mmol) in
anhydrous DMF (7 mL) under a nitrogen atmosphere was added sodium cyanide
(0.683 g, 13.9 mmol). The reaction was allowed to stir at ambient temperature for 2
days, then was poured into H2O (100 mL) and extracted with diethyl ether (3 x 100
mL). The combined organic layers were washed with 1:1 brine/H2O (2 x 100 mL) and
brine (100 mL), then were dried over anhydrous magnesium sulfate, filtered and
concentrated In vacuo, to afford 1.27 g (91%) of the title compound as a yellow oil.
INTERMEDIATE 28
3-Benzofuran-3-yl-propionitrile
[0090] This compound was prepared by the same method as for Intermediate 27,
using 1.98 g (8.8 mmol) of 3-(2-bromoethyl)benzofuran and 0.86 g (17.6 mmol) of
NaCN, to afford 1.5 g (quant.) of the title compound: MS (ESI) m/z 171 [M]+.
Elemental Analysis for: CnH9NO
Calc'd: C, 77.17; H, 5.30; N, 8.18
Found: C, 77.14; H, 5.45; N, 8.19
INTERMEDIATE 29
3-(7-Methoxybenzofuran-3-vO-propionitrite
[0091] This compound was prepared by the same method as for Intermediate 27,
using 2.87 g (11.25 mmol) of 3-(2-bromoethyl)-7-methoxybenzofuran and 1.1 g (22.5
mmol) of sodium cyanide, to afford 2.2 g (97%) of the title compound: MS (ESI) m/z
201 [M]+.
Elemental Analysis for: Ci2HnNO2
Calc'd: C, 71.63; H, 5.51; N, 6.96
Found: C, 71.57; H, 5.33; N, 6.62
INTERMEDIATE 30
3-Benzofuran-3-vl-propylamine
[0092] A mixture of 3-benzofuran-3-yl-propionitrile (0.87 g, 5.08 mmol) and 300 mg
of 5% rhodium on alumina in concentrated ammonium hydroxide (60 mL) and
ethanol (100 mL) was hydrogenated at 50 psi overnight. The catalyst was removed
by vacuum filtration through celite, washing with excess ethanol. The filtrate was
concentrated in vacuum. The residue was diluted with ethyl acetate, the aqueous
phase was removed, and the organic layer was dried over anhydrous magnesium
sulfate, then filtered and concentrated in vacuum. Flash chromatography on SiO2
(1/2/97 to 3/2/95 methanol / 2M NH3 in methanol / CH2CI2 gradient) afforded 700 mg
(85%) of the title compound: 1H NMR (CDCI3, 400 MHz): 5 7.53 (d, J = 8.1 Hz, 1H),
7.43 (d, J = 8.0 Hz), 7.18-7.30 (m, 2H), 2.78 (t, J = 7.0 Hz, 2H), 2.71 (t, J = 8.0 Hz,
2H), 1.85 (quint, J = 7.2 Hz, 2 H).
INTERMEDIATE 31
4-Benzofuran-3-yl-butvlamine
[0093] This compound was prepared by the same method as for Intermediate 30,
using 4-benzofuran-3-yl-butyronitrile (1.05 g, 5.67 mmol), 420 mg of 5% rhodium on
alumina, 100 mL of ammonium hydroxide, and 150 mL of ethanol, to afford 770 mg
(72%) of the title compound after chromatography: 1H NMR (CDCI3, 400 MHz) 5
7.52 (d, J = 8.2 Hz, 1 H), 7.43 (d, J = 8.1 Hz, 1 H), 7.38 (s, 1 H), 7.18-7.27 (m, 2 H),
2.72 (t, J = 7.0 Hz, 2 H), 2.67 (t, J = 7.3 Hz, 2 H), 1.73 (quint, J = 7.9 Hz, 2 H).
INTERMEDIATE 32
3-(7-Methoxvbenzofuran-3-vl)-propylamine
[0094] This compound was prepared by the same method as for Intermediate 30,
using 3-(7-methoxybenzofuran-3-yl-propionitrile (1.0 g, 4.97 mmol), 400 mg of 5%
rhodium on alumina, 100 mL of ammonium hydroxide, and 150 mL of ethanol, to
afford 770 mg (76%) of the title compound after chromatography: MS (ESI) m/z 206
[M+H]+.
Elemental Analysis for: Ci2H15NO2 • 0.4 H2O
Calc'd: C, 67.84; H, 7.50; N, 6.59
Found; C, 68.06; H, 5.42; N, 6.49
EXAMPLE 1
N-r2-(5-Methoxv-1H-lndol-3-vl)-ethvn-N-(8-methvl-2.3-dihvdro-n.41dioxinor2.3-
f|quinolin-2-ylmethvl)-amine
[0095] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yljmethyl 4-bromobenzenesulfonate (0.80 g, 1.8 mmol) and 2-(5-methoxy-1 H-indol-3-
yl)-ethylamine (1.05 g, 5.50 mmol) was added 10 mL of DMSO. The mixture was
stirred at 85°C for 4.5 hours. The solvent was evaporated at reduced pressure. The
residue was partitioned between 500 mL each of ethyl acetate and saturated
aqueous sodium bicarbonate. The ethyl acetate layer was washed with water 5
times (250 mL) and dried over anhydrous magnesium sulfate. Filtration and
concentration in vacuum gave 0.87 g of oil. This was chromatographed on silica gel
with gradient elution commencing with 1:1 ethyl acetate/hexane and ending with ethyl
acetate to give 0.39 g of the free base as an oil. The oil was dissolved in ethanol and
added to a solution of oxalic acid dihydrate (0.135 g, 1.07 mmol) in ethanol. Filtration
gave 0.426 g of the (S)-enantiomer of the title compound as an off-white oxalate,
m.p. dec > 240°C.
Elemental Analysis for: C24H25N3O3 • C2H2O4 • 2/3 H2O
Calc'd: C, 61.77; H, 5.65; N, 8.31
Found: C, 61.85; H, 5.41; N, 8.23
EXAMPLE 2
N-f2-(5-Chloro-1H-indol-3-vl)ethvn-N-(8-methvl-2,3-dihvdro-n.41dioxinor2,3-
f|quinolin-2-ylmethvl)amine
[0096] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (0.648 g, 1.48 mmol) and 2-(5-chloro-1 H-indol-3-
yl)-ethylamine (0.956 g, 4.14 mmol) was added sodium carbonate (0.87 g, 8.2 mmol)
and 10 mL of DMSO. The mixture was stirred at 85°C for 4.5 hours. The solvent
was evaporated at reduced pressure. The residue was partitioned between 500 mL
each of ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate
layer was washed with water 5 times (250 mL) and dried over anhydrous magnesium
sulfate. Filtration and concentration in vacuum gave 0.91 g of crude material. This
was chromatographed on silica gel with gradient elution commencing with 1:1 ethyl
acetate/hexane and ending with ethyl acetate to give 0.19 g of the free base as an
oil. This was dissolved in ethanol and added to a solution of oxalic acid dihydrate
(0.066 g, 0.520 mmol) in ethanol. Filtration gave 0.203 g of the (S)-enantiomer of
the title compound as an off-white oxalate, m.p. dec > 240°C.
Elemental Analysis for: C23H22CIN3O2 • C2H2O4 • 3/4 H2O
Calc'd: C, 58.71; H, 5.03; N, 8.22
Found: C, 58.71; H, 4.60; N, 7.79
EXAMPLE 3
N-r3-(5-Fluoro-1H-indol-3-vnpropvn-N-(8-methvl-2.3-dihvdro-ri.41dioxinor2.3-
f|quinolin-2-vlmethyl)amine
[0097] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (6.78 g, 15.1 mmol) and 2-(5-fluoro-1 H-indol-3-
yl)-propylamine (5.48 g, 28.5 mmol) was added sodium carbonate (5.07 g, 47.8
mmol) and 30 mL of DMSO. The mixture was stirred at 80°C for 18 hours. The
solvent was evaporated at reduced pressure. The residue was partitioned between
500 mL each of ethyl acetate and water. The ethyl acetate layer was washed with
water 3 times (250 mL) and dried over anhydrous magnesium sulfate. Filtration and
concentration in vacuum gave 9.00 g of crude material. This was chromatographed
on silica gel with gradient elution commencing with 1:1 ethyl acetate/hexane and
ending with ethyl acetate to give 3.77 g of the free base as a light tan oil. The oil was
dissolved in ethanol and added to a warm solution of fumaric acid (1.18 g, 10.2
mmol) in ethanol. Filtration gave 4.22 g of the (S)-enantiomer of the title compound
as a white fumarate, m.p. 207-209°C.
Elemental Analysis for: C24H24FN3O2 • C4H4O4
Calc'd: C, 64.48; H, 5.41; N, 8.06
Found: C, 64.37; H, 5.55; N, 7.98
EXAMPLE 4
N-r2-(5-Fluoro-1H-indol-3-vnethvn-N-(8-methvl-2.3-dihvdro-F1.41dloxinof2.3-
flauinolin-2-v!methvl)amine
[0098] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (0.71 g, 1.5 mmol) and 2-(5-f luoro-1 H-indol-3-yl)-
ethylamine (1.06 g, 4.94 mmol) was added sodium carbonate (1.05 g, 9.91 mmol)
and 10 mL of DMSO. The mixture was stirred at 85°C for 5 hours. The solvent was
evaporated at reduced pressure. The residue was partitioned between 500 mL each
of ethyl acetate and water. The ethyl acetate layer was washed with water twice
(250 mL) and dried over anhydrous magnesium sulfate. Filtration and concentration
in vacuum gave 0.75 g of oil. This was chromatographed on silica gel with 0-5%
methanol/ethyl acetate to give 0.14 g of the free base as a pure oil. This was
dissolved in ethanol and added to a solution of oxalic acid dihydrate (0.050 g, 0.40
mmol) in ethanol. Filtration gave 0.135 g of the (S)-enantiomer of the title compound
as a light yellow oxalate, m.p. dec. >245°C.
Elemental Analysis for: C23H22FN3O2 • C2H2O4 • 6/10 H2O
Calc'd: C, 61.00; H, 5.16; N, 8.54
Found: C, 60.98; H, 5.24; N, 8.48
EXAMPLE 5
N-r3-(5-Fluoro-1H-indol-3-vnpropvn-N-(8-ethvl-2.3-dihvdro-ri.4ldioxinor2.3-
f|quinolln-2-ylmethvl)amine
[0099] To a mixture [(2R)-8-ethyl-2,3-dihydro[i ,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-toluenesulfonate (0.46 g, 1.2 mmol) and 2-(5-fluoro-1H-indol-3-yl)-ethylamine
(0.428 g, 2.23 mmol) was added sodium carbonate (0.392 g, 3.70 mmol) and 1.5 mL
of DMSO. The mixture was stirred at 80°C for 18 hours. The solvent was
evaporated at reduced pressure. The residue was partitioned between 500 mL each
of ethyl acetate and water. The ethyl acetate layer was washed twice with water
(250 mL), once with saturated brine (250 ml_) and dried over anhydrous magnesium
sulfate. Filtration and concentration in vacuum gave 0.81 g of crude oil. This was
chromatographed on silica gel with a gradient of ethyl acetate and methanol to give
0.26 g of the free base. This was dissolved in ethanol and added to a solution of
oxalic acid dihydrate (0.076 g, 0.60 mmol) in ethanol. Filtration gave 0.256 g of the
(S)-enantiomer of the title compound as a white oxalate, m.p. dec. >230°C.
Elemental Analysis for: C25H26FN3O2 • C2H2O4
Calc'd; C, 63.61; H, 5.54; N, 8.24
Found: C, 63.31; H, 5.48; N, 8.06
EXAMPLE 6
N-r3-(1H-lndol-3-vnpropvn-N-(8-methvl-2.3-dihvdro-ri.41dioxinof2.3-f|quinolin-2-
vlmethvDamine
[0100] To a mixture of [^RJ-S-methyl^.S-dihydrofMJdioxinop.S-fJquinolin^-
y!]methyl 4-bromobenzenesulfonate (1.29 g, 2.86 mmol) and 2-(1 H-indol-3-yl)-
propylamine (0.97 g, 5.6 mmol) was added sodium carbonate (0.96 g, 9.1 mmol) and
5 mL of DMSO. The mixture was stirred at 85°C for 18 hours and then allowed to
stand at room temperature for 2 days. The solvent was evaporated at reduced
pressure. The residue was partitioned between 500 mL each of ethyl acetate and
water. The ethyl acetate layer was washed with water 3 times (250 mL) and dried
over anhydrous magnesium sulfate. Filtration and concentration in vacuum gave
1.61 g of dark oil. This was chromatographed on silica gel with 15% methanol in
ethyl acetate. The cleanest fractions were combined and evaporated to give 0.36 g
of the free base compound as an oil. This was dissolved in ethanol and added to a
solution of fumaric acid (0.120 g, 1.04 mmol) in ethanol. Filtration gave 0.399 g of
the (S)-enantiomer of the title compound as a tan fumarate, m.p. 202-203°C.
Elemental Analysis for: C24H25N3O2 • C4H4O4
Calc'd: C, 66.79; H, 5.80; N, 8.34
Found: C, 66,79; H, 5.91; N, 8.22
EXAMPLE 7
N-r3-(5-Fluoro-1H-indol-3-vl)propvn-N-methv[-N-(8-methvl-2.3-dihvdro-
ri.41dioxinor2.3-flquinolin-2-vlmethvl)amine
[0101] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (1.02 g, 2.27 mmol) and [3-(5-fluoro-1 H-indol-3-
yl)-propyl]-methyl-amine (0.54 g, 2.6 mmol) was added sodium carbonate (0.30 g,
2.8 mmol) and 7 mL of DMSO. The mixture was stirred at 100°C for 18 hours and
then at room temperature overnight. The solvent was evaporated at reduced
pressure. The residue was partitioned between 500 mL each of ethyl acetate and
water. The ethyl acetate layer was washed with water 4 times (250 mL) and dried
over anhydrous magnesium sulfate. Evaporation of the solvent gave 2.0 g of crude
material. This was chromatographed on silica gel with 0-5% methanol/ethyl acetate
to give 0.38 g of the free base as an oil. This was dissolved in ethanol and added to
a solution of fumaric acid (0.1173 g, 1.011 mmol) in ethanol. Filtration gave 0.374 g
of the (S)-enantiomer of the title compound as light yellow fumarate, m.p. 104-120°C.
Elemental Analysis for: C25H26FN3O2 • C4H4O4 • H2O
Calc'd: C, 62.92; H, 5.83; N, 7.59
Found: C, 62.71; H, 5.91; N, 7,42
EXAMPLE 8
N-r3-(7-Fluoro-1H-indol«3-vl)propvn-N-(8-methvl-2.3-dlhvdro-f1.41dioxinor2.3-
flquinolin-2-vlmethyl)amine
[0102] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (1.01 g, 2.24 mmol) and 3-(7-fluoro-1 H-indol-3-
yl)-propylamine (0.81 g, 4.2 mmol) was added sodium carbonate (0.75 g, 7.1 mmol)
and 4.5 mL of DMSO. The mixture was stirred at 108°C for 18 hours. The solvent
was evaporated at reduced pressure. The residue was partitioned between 500 mL
each of ethyl acetate and water. The ethyl acetate layer was washed with water 3
times (250 mL) and dried over anhydrous magnesium sulfate. Evaporation of the
solvent gave 1.36 g of oil. This was chromatographed on silica gel 0-10%
methanol/ethyl acetate to give 0.42 g of the free base as an oil. This was dissolved in
ethanol and added to a solution of fumaric acid (0.132 g, 1.14 mmol) in ethanol.
Filtration gave 0.367 g of the (S)-enantiomer of the title compound as a white
fumarate, m.p. 142-150°C.
Elemental Analysis for: C24H24FN3O2 * C4H4O4 • H2O
Calc'd: C, 62.33; H, 5.60; N, 7.79
Found: C, 62.10; H, 5.55; N, 7,83
EXAMPLE 9
N-r4-(1H-lndol-3-vnbutvn-N-(8-methvl-2.3-dihvdro-ri.41dioxinor2.3-f1quinolin-2-
vlmethvOamine
[0103] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (0.87 g, 1.9 mmol) and 4-(1 H-indol-3-yl)-
butylamine (0.63 g, 3.3 mmol) was added sodium carbonate (0.63 g, 5.9 mmol) and
10 mL of DMSO. The mixture was stirred at 80°C for 18 hours. The solvent was
evaporated at reduced pressure. The residue was partitioned between 500 mL each
of ethyl acetate and water. The ethyl acetate layer was washed with water (250 mL)
3 times and dried over anhydrous magnesium sulfate. Filtration and concentration in
vacuum gave 1.02 g of oil. This was chromatographed on silica gel with gradient
elution commencing with 1:1 ethyl acetate/hexane and ending with ethyl acetate to
give 0.38 g of the free base as an oil. This was dissolved in ethanol and added to a
solution of fumaric acid (0.115 g, 0.991 mmol) in ethanol. Filtration gave 0.336 g of
the (S)-enantiomer of the title compound as white solid hemifumarate, m.p. 208-
210°C.
Elemental Analysis for: C25H27N3O2 • O.5C4H4O4 • O.5H2O
Calc'd: C, 69.21; H, 6.45; N, 8.97
Found: C, 69.53; H, 6.47; N, 8.83
EXAMPLE 10
N-r4-(5-Fluoro-1H-indol-3-v»butvn-N-r8-methvl-2.3-dihvdro-ri.41dioxinor2.3-
f|quinolin-2-vlmethvl)amine
[0104] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yljmethyl 4-bromobenzenesulfonate (1.63 g, 3.62 mmol) and 4-(5-fluoro-1 H-indol-3-
yl)-butylamine (1.39 g, 6.74 mmol) was added sodium carbonate (1.18 g, 1.11 mmol)
and 8 mL of DMSO. The mixture was stirred at 105°C for 8 hours. The solvent was
evaporated at reduced pressure. The residue was partitioned between 500 mL each
of ethyl acetate and water. The ethyl acetate layer was washed with water (250 mL)
twice and dried over anhydrous magnesium sulfate. Filtration and concentration in
vacuum gave 1.77 g of oil. This was chromatographed on silica gel with 0-10%
methanol/ethyl acetate as eluant to give 0.42 g of the free base as an oil. This was
dissolved in ethanol and added to a solution of fumaric acid (0.197 g, 1.70 mmol) in
ethanol. Filtration gave 0.462 g of the (S)-enantiomer of the title compound as light
yellow fumarate, m.p. 138-154°C.
Elemental Analysis for: C25H26FN3O2 • C4H4O4 • H2O
Calc'd: C, 62.92; H, 5.83; N, 7.59
Found: C, 62.63; H, 5.87; N, 7.42
EXAMPLE 11
N-f4-(5-Fluoro-1H-indol-3-vl)-N-(8-methvl-2,3-dihvdro-n.41dioxinof2.3-
flquinolin-2-vlmethvPbutan-2-amine
ISOMER A
[0105] To a solution of 2S-C-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-
methylamine (0.70 g, 3.0 mmol) and 4-(5-fluoro-1 H-indol-3-yl)-butan-2-one (0.66 g,
3.2 mmol) in 30 mL of dichloromethane was added acetic acid (0.35 mL, 0.37 g, 6.1
mmol) and sodium triacetoxyborohydride (0.97 g, 4.6 mmol). The reaction was
stirred at room temperature for one day. The reaction mixture was shaken with 30
mL of 1 M NaOH. Water (30 mL) was added to this mixture and it was shaken again.
The layers were separated and the aqueous layer was extracted once with 100 mL of
methylene chloride. The organic layers were combined and dried over anhydrous
magnesium sulfate. Evaporation of the solvent gave 1.49 g of tan oil. A small
portion of this was eluted from a Chiralcel AD column with 90% EtOH and 10%
hexane which contained 0.1% diethylamine to give as an oil 0.073 g of the first
diastereomer to elute. This was dissolved in ethanol and added to a solution of
fumaric acid (0.022 g, 0.19 mmol) in ethanol. Filtration gave 0.073 g of the fumarate
of one diastereomer of the title compound as white solid, m.p. 145-154°C.
Elemental Analysis for: C25H26FN3O2 • C4H4O4 • 0.3 H2O
Calc'd: C, 64.39; H, 5.70; N, 7.77
Found: C, 64.38; H, 5.83; N, 7.51
1SOMER B
[0106] The separation of diastereomers in the last reaction also gave as an oil
0.042 g of the second diastereomer to elute. This was dissolved in ethanol and
added to a solution of fumaric acid (0.013 g, 0.11 mmol) in ethanol. This didn't yield
any crystals after prolonged standing. The residue after the solvent had been
allowed to evaporate was scraped loose, stirred with EtOH and filtered to remove a
lump of amorphous solid. Crystals formed in the ethanol solution. Filtration gave
0.017 g of the fumarate of the second diastereomer of the title compound as white
solid, m.p, 146-156°C.
Elemental Analysis for: C25H26FN3O2 • C4H4O4 • H2O
Calc'd: C, 62.92; H, 5.83; N, 7.59
Found: C, 62.81; H, 5.81; N, 7.52
EXAMPLE 12
N-r3-(5-Fluoro-1-methvl-1H-indol-3-vnpropvn-N-(8-methvl-2.3-dihvdro-
f1,41dioxinor2.3-flquinolin-2-ylmethvl)amine
[0107] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (2.29 g, 5.09 mmol) and 3-(5-fluoro-1-methyl-1H-
indol-3-yl)-propylamine (1.85 g, 8.97 mmol) was added sodium carbonate (1.57 g,
14.8 mmol) and 11 mL of DMSO. The mixture was stirred at 110°C for 7 hours and
then stirred at room temperature overnight. The solvent was evaporated at reduced
pressure. The residue was partitioned between 500 mL each of ethyl acetate and
water. The ethyl acetate layer was washed with water (250 mL) twice and dried over
anhydrous magnesium sulfate. Filtration through Celite and concentration in vacuum
gave 3.7 g of oil. This was chromatographed on silica gel 0-10% methanol/ethyl
acetate to give 1.32 g of the free base as a yellow oil. This was dissolved in ethanol
and added to a solution of fumaric acid (0.407 g, 3.51 mmol) in ethanol. Filtration
gave 1.44 g of the (S)-enantiomer of the title compound as nearly white fumarate,
m.p. 156-161 °C.
Elemental Analysis for: C25H26FN3O2 • C4H4O4 • 0.3 H2O
Calc'd: C, 64.39; H, 5.70; N, 7.77
Found: C, 64.38; H, 5.73; N, 7.68
EXAMPLE 13
N-r3-(5.7-Difluoro-1H-indol-3-vnproDvn-N-(8-methvl-2.3-dihvdro-
n.41dioxinor2.3-f|quinolin-2-vlmethvnamine
[0108] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (2.10 g, 4.66 mmol) and 3-(5,7-difluoro-1 H-indol-
3-yl)-propylamine (1.72 g, 8.18 mmol) was added sodium carbonate (1.43 g, 13.5
mmol) and 20 mL of DMSO. The mixture was stirred at room temperature for 4 days.
The solvent was evaporated at reduced pressure. The residue was partitioned
between 500 mL of ethyl acetate and water. The ethyl acetate layer was washed
with water (250 mL) twice and dried over anhydrous magnesium sulfate. Filtration
and concetration in vacuum gave 2.18 g of oil. This was chromatographed on silica
gel with 0-10% methanol/ethyl acetate as elusant to give 1.35 g of the free base as
an oil. This was dissolved in ethanol and added to a solution of fumaric acid (0.124
g, 1.07 mmol) in ethanol. Filtration gave 0.506 g of the (S)-enantiomer of the title
compound as white fumarate, m.p. 188-195°C.
Elemental Analysis for: C24H23F2N3O2 • C4H4O4 • 0.5 C2H5OH
Calc'd: C, 61.92; H, 5.37; N, 7.47
Found: C, 61.79; H, 5.46; N, 7.39
EXAMPLE 14
N-(2.3-Dihvdro-ri.4ldioxinor2.3-f1quinolin-2-ylmethvl)-N-r3-(5-fluoro-1H-indol-3-
vnpropyllamine
[0109] A solution of (2R)-toluene-4-sulfonic acid 2,3-dihydro-[1,4]dioxino[2,3-
/]quinolin-2-ylmethyl ester (0.6 g, 1.6 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine
(0.62 g, 3.2 mmol) and triethylamine (0.33 g, 3.2 mmol) in dimethylsulfoxide (20 mL)
was heated at 90°C under nitrogen for 9 hours. The reaction mixture was poured
into water (100 mL) and extracted with methylene chloride (3 x 100 mL). The organic
layer was washed with water (3 x 150 mL), dried over anhydrous sodium sulfate,
filtered and the solvent was removed under vacuum. The crude oil was column
chromatographed on silica gel (5% methanol/ethyl acetate). The product-containing
fractions were concentrated in vacuum to give 0.31 g of the (S)-enantiomer of the title
compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as
a yellow solid, m.p. 196-199°C.
Elemental Analysis for: CjaH^FNaCV 2 HCI • H2O
Calc'd: C. 57.27; H, 5.43; N, 8.71
Found: C. 57.32; H, 5.47; N, 8.48
EXAMPLE 15
N-(2.3-Dihvdro-n.41dloxinof2.3-f1auinolin-2-vlmethvl)-N-r3-(5-fluoro-1H-indol-3-
vDpropvn-N-methylamine
[0110] To a solution of (2S)-(2,3-dihydro-[1,4]dioxino[2,3-)]quinolin-2-ylmethyl)-[3-
(5-fluoro-1 H-indol-3-yl)-propyl]-amine (0.13 g, 0.33 mmol) and formaldehyde (37 wt.
% in water, 0.26 g, 3.3 mmol) in methanol (20 mL) was added sodium
cyanoborohydride (0.038 g, 0.59 mmol) and acetic acid (0.03g, 0.5 mmol) at room
temperature. The mixture was stirred at room temperature under nitrogen overnight,
then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene
chloride (3 x 50 mL). The organic layer was washed with water (3 x 50 mL), dried
over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum.
The crude oil was column chromatographed on silica gel (5% methanol-methylene
chloride). The product-containing fractions were concentrated in vacuum to give 0.1
g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt
was prepared in ethyl acetate as a yellow solid (decomposed at 78°C).
Elemental Analysis for: C24H24FN3O2 • 2 HCI • 3.25 H2O
Calc'd: C, 53.69; H, 6.10; N, 7.83
Found: C. 53.56; H. 6.16; N, 7.49
EXAMPLE 16
N-r3-(5.7-Difluoro-1H-lndol-3-vl>propvn-N-methvl-N-f8-methv>-2.3-dihvdro-
ri.41dioxinof2,3-flqulno»n-2-vlmethvl)amlne
[0111] To a solution of N-[3-(5,7-difluoro-1H-indol-3-yl)propyl]-N-{[(2S)-8-methyl-
2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl)amine (0.94 g, 2.2 mmol) in 4.3 mL
of methanol was added paraformaldehyde (0.0844 g, 2.81 mmol). 4.3 mL of a stock
solution of methanol/HCI (1 drop cone HCI in 16 mL of methanol) was added to
adjust the pH to approximately 5. Sodium cyanoborohydride (0.225 g, 3.58 mmol)
was added. The reaction was stirred at room temperature for 18 hours. One drop of
concentrated HCI was added. The solvent was evaporated at reduced pressure.
The residue was partitioned between 350 mL each of ethyl acetate and saturated
aqueous sodium bicarbonate. The ethyl acetate layer was washed with water (200
mL) twice and saturated brine once. It was dried over anhydrous magnesium sulfate.
Filtration and concentration in vacuum gave 1.00 g of crude residue. This was
chromatographed on silica gel with gradient elution commencing with 1:1 ethyl
acetate/hexane and ending with ethyl acetate to give 0.35 g of the free base as an
oil. This was dissolved in ethanol and added to a solution of excess HCI in methanol.
Filtration gave 0.343 g of the (S)-enantiomer of the title compound as a yellow
dihydrochloride, m.p. dec. >240°C.
Elemental Analysis for: C25H25F2N3O2 • 2 HCI • 0.2 H2O
Calc'd: C, 58.42; H, 5.37; N, 8.17
Found: C, 58.50; H, 5.44; N, 8.13
EXAMPLE 17
N-r2-(1-Benzofuran-3-vl)ethvl1-N-(8-methvl-2.3-dihvdro-n,41dioxinor2,3-
flqu8nolin-2-ylmethvnamine
[0112] To a stirred solution of 2-benzofuran-3-yl-ethylamine (390 mg, 2.42 mmol) in
3 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-
f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (363 mg, 0.807 mmol). The reaction
mixture was heated to 50°C overnight. The reaction was diluted with saturated
aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3x10 mL).
The combined organic layers were washed with brine (3 x 30 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash
chromatography on SiO2 (5% MeOH/CH2CI2) afforded 252 mg (83%) of the (S)-
enantiomer of the title compound as a yellow oil. The fumarate salt was prepared,
yielding 280 mg of a yellow solid, m.p. 210-214°C; MS (ESI) m/z375 [M+H]Elemental Analysis for: C23H22N2O3» 1.5 C4H4O4
Calc'd: C, 63.50; H, 5.15; N, 5.11
Found: C, 63.21; H, 5.19; N, 4.87
EXAMPLE 18
N-r3-n-Benzofuran-3-vnpropvn-N-(8-methvl-2.3-dihvdro-H.41dioxinor2.3-
flquinolin-2-vlmethv0amine
[0113] To a stirred solution of 3-benzofuran-3-yl-propylamine (700 mg, 4.34 mmol)
in 6 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-
f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (652 mg, 1.45 mmol). The reaction
mixture was heated to 50°C overnight. The reaction was diluted with saturated
aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3x10 mL).
The combined organic layers were washed with brine (3 x 30 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash
chromatography on SiO2 (5% MeOH/CH2CI2) afforded 510 mg (90%) of the (S)-
enantiomer of the title compound as a yellow oil. The fumarate salt was prepared,
yielding 93 mg of a yellow solid, m.p. 165-170°C; MS (ESI) m/z 389 [M+H]+.
Elemental Analysis for: C24H24N2O3 ^HA,
Calc'd: C. 66.66; H, 5.59; N, 5.55
Found: C. 64.56; H, 5.67; N, 5.05
EXAMPLE 19
N-f3-(7-MethoxY-1-benzofuran-3-yl)propyll-N-(8-methyl-2.3-dihvdro-
f1.41dioxinor2.3-flquinolin-2-vlmethvl)amine
[0114] To a stirred solution of 3-(7-methoxy-benzofuran-3-yl)-propylamine (770 mg,
3.75 mmol) in 5 mL of anhydrous DMSO was added [(2R)-8-methy!-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (563 mg,
1.25 mmol). The reaction mixture was heated to 50°C overnight. The reaction was
diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl
acetate (3x10 mL). The combined organic layers were washed with brine (3 x 30
mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum.
Rash chromatography on SiO2 (5% MeOH/CH2CI2) afforded 120 mg (23%) of the
(S)-enantiomer of the title compound as a yellow oil. The fumarate salt was
prepared, yielding 132 mg of a beige solid, m.p. 155-160°C; MS (ESI) m/z4i9
[M+H]+.
Elemental Analysis for: C25H26N2O4« C4H4CV 0.16 C4H8O2 • 0.09 H2O
Calc'd: C. 64.7; H, 5.76; N, 5.09
Found: C. 64.3; H, 5.55; N, 5.04
EXAMPLE 20
N-f3-f1-Ben2Othien-3-vnproDvn-N-f8-methvl-2.3-dihvdro-f1.41dioxinof2.3-
f1quinolin-2-vlmethyl)amine
[0115] To a stirred solution of 3-benzo[b]thiophen-3-yl-propylamine (382 mg, 2.0
mmol) in 1 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinoiin-2-yl]methyl 4-bromo-benzenesulfonate (300 mg,
0.67 mmol). The reaction mixture was heated at 40°C for 18 hours. The reaction
was diluted with H2O (10 mL), poured into saturated aqueous sodium bicarbonate (25
mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were
washed with 1:1 H2O/brine (40 mL) and brine (40 mL), then were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (2 x
20 cm SiO2, CH2CI2 to 3% MeOH/CH2CI2 gradient) afforded 221 mg (81%) of the (S)-
enantiomer of the title compound as a thick gum. The fumarate salt was prepared by
treating the amine in ethyl acetate with a solution of fumaric acid (63 mg , 0.54 mmol)
in methanol. The precipitated salt weighed 238 mg (m.p. 185-186 °C); MS (ESI) m/z
405 [M+H]+.
Elemental Analysis for: C24H24N2O2S • C4H4O4
Calc'd: C, 64.60; H, 5.42; N, 5.38
Found: C 64.29; H, 5.30; N, 5.23
EXAMPLE 21
N-r2-(1-Benzothlen-3-vnethvn-N-(8-methvl-2.3-dihvdro-ri.41dioxlnor2.3-
flquinolin-2-vlmethvl)amine
[0116] To a stirred solution of 2-benzo[b]thiophen-3-yl-ethylamine (354 mg, 2.0
mmol) in 1 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromo-benzenesulfonate (300 mg,
0.67 mmol). The reaction mixture was stirred at ambient temperature for 4 days.
The reaction was diluted with H2O (10 mL), poured into saturated aqueous sodium
bicarbonate (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined
organic layers were washed with 1:1 H2O/brine (40 mL) and brine (40 mL), then were
dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash
chromatography (2 x 20 cm SiO2l CH2CI2 to 3% MeOH/CH2CI2 gradient) afforded 225
mg (86%) of the (S)-enantiomer of the title compound as a thick oil. The fumarate
salt was prepared by treating the amine in ethyl acetate with a solution of 66 mg
(0.57 mmol) fumaric acid in methanol. The precipitated salt, a pale yellow solid,
weighed 190 mg (m.p. 124-127 °C); MS (ESI) m/z 391 [M+H]+.
Elemental Analysis for: C23H22N2O2S • C4H4O4 • 0.50 H2O
Calc'd: C, 62.90; H, 5.28; N, 5.43
Found: C, 62.55; H, 5.23; N, 5.34
EXAMPLE 22
N-I3-(1-Benzothien-3-vnproDvn-N-methvl-N-(8-methvl-2.3-dihvdro-
f1.41cHoxlnor2.3-flauinolin-2-vlmethvnamine
[0117] To a stirred solution of N-[3-(1-benzothien-3-yl)propyl]-N-{[(2S)-8-methyl-
2,3-dihydro[1,4]dioxinol2,3-f]quinolin-2-yl]methyl)amine (340 mg, 0.84 mmol) in 5 ml
of anhydrous THF was added formaldehyde (484 uL), acetic acid (96 nL, 1 -68 mmol),
and sodium triacetoxyborohydride (1.46 g, 6.9 mmol). The reaction mixture was
stirred at ambient temperature for 3 days. The reaction was quenched with 1 M
aqueous NaOH (10 mL), diluted with H2O (20 ml_), made basic with more 1 M
aqueous NaOH, and extracted with methylene chloride (3 x 40 mL). The combined
organic layers were washed with brine (3 x 120 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuum. Flash chromatography on SiO2 (5%
MeOH/CH2CI2) afforded 270 mg (77%) of the (S)-enantiomer of the title compound as
a yellow oil. The fumarate salt was prepared, yielding 189 mg of a beige solid, m.p.
123-127°C; MS (ESI) m/z 419 [M+H]+.
Elemental Analysis for: C25H2eN2O2S» C4H4O4 • 0.75 H2O
Calc'd: C, 63.55; H, 5.79; N, 5.11
Found: C, 63.40; H, 5.58; N, 4.81
EXAMPLE 23
N-[3-(5-Fluoro-1H-indol-3-vnproDvn-N-(2-methvl-7.8-dihvdro-n.41dioxino[2.3-
qiri,31benzoxazol-8-vlmethvl)amine
[0118J A solution of (2R)-toluene-4-sulfonic acid 2-methyl-7,8-dihydro-1,6,9-trioxa-
3-aza-cyclopenta[a]-napthalen-8-ylrnethyl)-ester (0.4 g, 1.1 mmol), 3-(5-fluoro-1H-
indol-3-yl)propylamine (0.41 g, 2.2 mmol) and triethylamine (0.29 g, 2.2 mmol) in
dimethylsulfoxide (20 mL) was heated at 90°C under nitrogen for 9 hours. The
reaction mixture was poured into water (100 mL) and extracted with methylene
chloride (3 x 80 mL). The organic layer was washed with water (3 x 100 mL), dried
over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum.
The crude oil was column chromatographed on silica gel (5% methanol-methylene
chloride). The product-containing fractions were concentrated in vacuum to give 0.14
g of the (S)-enantiomer of the title compound as a yellow oil. The hydrochloride salt
was prepared in ethyl acetate as an off-white solid, m.p. 91-93°C.
Elemental Analysis for: CzzHaaFNaOz* 1.5 HCI • 1.25 H2O
Calc'd: C. 55.91; H, 5.54; N, 8.89
Found: C. 56.04; H, 5.74; N, 8.59
EXAMPLE 24
N-f3-(5-Fluoro-1H-indol-3-vnpropvn-N-methvl-N-(2-methyl-7,8-dihvdro-
H .41dioxinor2.3-qin .31benzoxazol-8-ylmethvl)amine
[0119] To a solution of [3-(5-fluoro-1/+indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-
1,6,9-trioxa-3-aza-cyclopenta[a]napthalen-8-ylmethyl)-amine (0.05 g, 0.13 mmol) and
formaldehyde (37 wt. % in water, 0.1 g, 1.3 mmol) in methanol (10 mL) was added
sodium cyanoborohydride (0.014 g, 0.23 mmol) and acetic acid (0.01 g, 0.26 mmol) at
room temperature. The mixture was stirred at room temperature under nitrogen
overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with
methylene chloride (3 x 40 mL). The organic layer was washed with water (3 x 30
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (5%
methanol-methylene chloride). The product-containing fractions were concentrated
in vacuum to give 48 mg of the (S)-enantiomer of the title compound as a brown oil.
The dihydrochloride salt was prepared in ethyl acetate as a white solid, m.p. 136-
139°C.
Elemental Analysis for: Caa^FNaCb • 2 HCI • H2O
Calc'd: C. 55.21; H, 5.64; N, 8.40
Found: C. 55.40; H, 5.44; N, 8.29
EXAMPLE 25
N-Ethvl-N-f3-(5-Fluoro-1H-indol-3-vnproDvll-N-(8-methvl-2.3-dihvdro-
ri.41dioxinof2.3-f1auinolln-2-vlmethvnamine
[0120] N-[3-(5-Fluoro-1H-indol-3-yl)propyl]-N-{[(2S)-8-methyl-2,3-
dihydroti.^dioxinop.S-flquinolin^-yllmethylJamine (0.931 g, 2.30 mmol) was
dissolved in 4.6 ml_ of methanol with heat. The solution was then cooled in an ice-
bath. Acetaldehyde (0.20 ml_, 0.16 g, 3.6 mmol) was added. 4.6 ml_ of a stock
solution of HCI/methanol (one drop of cone HCI in 16 mL of methanol) was added to
adjust the pH to approximately 5. Sodium cyanoborohydride (0.266 g, 4.23 mmol)
was added. The reaction was stirred at room temperature and was complete in 4
hours. One drop of concentrated HCI was added. The solvent was evaporated at
reduced pressure. The residue was partitioned between 350 mL each of ethyl
acetate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was
washed with water (200 mL) twice and saturated brine once. It was dried over
anhydrous magnesium sulfate. Filtration and concentration in vacuum gave 1.00 g of
yellow oil. This was chromatographed on silica gel with gradient elution commencing
with 1:1 ethyl acetate/hexane and ending with ethyl acetate to give 0.18 g of the free
base as a clear colorless oil. Another 0.26 g was collected contaminated with one
impurity. The pure portion was dissolved in ethanol and excess EtOH/HCI added.
Filtration gave 0.075 g of the (S)-enantiomer of the title compound as a yellow
dihydrochloride, m.p. 158-175 °C.
Elemental Analysis for: C26H28FN3O2 • 2 HCI • 1.5 H2O
Calc'd: C, 58.54; H, 6.23; N. 7.88
Found: C, 58.55; H, 5.99; N, 7.56
EXAMPLE 26
N-r3-(5.7-Difluoro-1-methyl-1H-indol-3-vl)propvn-N-(8-methvl-2.3-dihvdro-
f1.41d239°C.
Elemental Analysis for: C25H25F2N3O2 • 2 HCI • 1/3 H2O
Calc'd: C, 58.15; H, 5.40; N, 8.14
Found: C, 58.09; H, 5.28; N, 8.01
EXAMPLE 27
N-r3-(5.7-Difluoro-1-methvl-1H-indol-3-vnpropvn-N-methvl-N-(8-methvl-2.3-
dihvdro-T1.41dioxlnof2,3-f|quinolin-2-vlmethvl)amine
[0122] To 3-(5,7-difluoro-1-methyl-1 H-indol-3-yl)-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}propan-1-amine (0.57 g, 1.3 mmol) was
added a warm suspension of paraformaldehyde (0.0625 g, 2.08 mmol) in 2.3 mL of
methanol. 2.3 mL of a stock solution of HCI/methanol (one drop cone HCI in 16 mL
of methanol) was added to adjust the pH to approximately 5. Sodium
triacetoxyborohydride (0.48 g, 2.3 mmol) was added and the mixture was stirred at
room temperature till the evolution of gas ceased. There was still starting material
present. Excess HCI/methanol (2.3 mL) was added. NaBH4 (0.42 g, 11 mmol) was
added slowly. Sufficient methanol was added to allow efficient stirring. The reaction
was stirred at room temperature for 1 day. HCI was added dropwise until no more
gas was evolved. The solvent was evaporated in vacuum. The residue was
partitioned between 500 mL each of ethyl acetate and saturated aqueous sodium
bicarbonate. The ethyl acetate portion was washed with water (350 mL) twice.
Drying over magnesium sulfate, filtration and evaporation of the solvent gave 0.65 g
of oil. This was chromatographed on silica gel with a gradient of ethyl acetate and
methanol to give 0.53 g of the free base as a colorless oil. This was dissolved in
ethanol. An excess of saturated HCI/ethanol was added. Filtration gave 0.542 g of
the (S)-enantiomer of the title compound as a yellow solid dihydrochloride, m.p. 190-
204 °C.
Elemental Analysis for: C26H27F2N3O2 • 2 HCI • 1.25 H2O
Calc'd: C, 57.10; H, 5.80; N, 7.68
Found: C, 57.05; H, 5.81; N, 7.59
EXAMPLE 28
N-r4-(1-Ben20furan-3-vnbutvn-N-f8-methvt-2.3-dihvdro-n.4Tdioxinof2.3-
flquinolln-2-vlmethvQamlne
[0123] To a stirred solution of 4-benzofuran-3-yl-butylamine (770 mg, 4.07 mmol) in
6 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro(1,4]dioxino[2,3-
f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (611 mg mg, 1.36 mmol). The
reaction mixture was heated to 50°C overnight. The reaction was diluted with
saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x
10 mL). The combined organic layers were washed with brine (3 x 30 mL), dried
over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash
chromatography on SiO2 (5% MeOH/CH2CI2) afforded 403 mg (74%) of the (S)-
enantiomer of the title compound as a yellow oil. The fumarate salt was prepared,
yielding 285 mg of a beige solid, m.p. 127-130°C; MS (ESI) m/z403 [M+H]+.
Elemental Analysis for. CpsH^NpQa* 0.8 &H4O4
Calc'd: C. 68.38; H, 5.94; N, 5.66
Found: C. 68.06; H, 5.95; N, 6.04
EXAMPLE 29
3-{3-r(8-Methvl-2.3-dihvdro-ri,41dioxinor2,3-f1quinolin-2-vlmethvn-aminol-
propvl)-1 H-l ndole-5-carbon Itrile
[0124] A solution of (2R)-4-bromobenzenesulfonic acid 2,3-dihydro-
[1,4]dioxino[2,3-/)quinolin-2-ylmethyl ester (1.13 g, 2.5 mmol), 3-(5-cyano-1 H-indol-3-
yl)propylamine (0.65 g, 3.2 mmol) and triethylamine (0.7 mL, 5.0 mmol) in
dimethylsulfoxide (40 mL) was heated at 90°C under nitrogen for 16 hours. The
reaction mixture was quenched with 1N sodium hydroxide and extracted with
methylene chloride (3 x 100 ml_). The organic layer was washed with water (3 x 150
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (10%
methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.54 g of the (S)-enantiomer of the title compound as a brown oil.
The dihydrochloride salt was prepared in ethyl acetate as a yellow solid, m.p. 170-
174°C.
Elemental Analysis for: C25H24N4O2» 2 HCI • 1.75 H2O
Calc'd: C. 58.09; H, 5.75; N, 10.84
Found: C. 58.00; H, 5.91; N, 10.82
EXAMPLE 30
3-(3-r(2-Methvl-7.8-dihvdro-ri.4ldioxinor2,3-q1f1.31benzoxazol-8-
vlmethyl)amino1-propvlT-1H-indole-5-carbonitrile
[0125] A solution of (2R)-toluene-4-sulfonic acid 2-methyl-7,8-dihydro-1,6,9-trioxa-
3-aza-cyclopenta[a]-napthalen-8-ylmethyl)-ester (1.0 g, 2.7 mmol), 3-(5-cyano-1 H-
indol-3-yl)propylamine (0.7 g, 3.5 mmol) and triethylamine (0.75 mL, 5.4 mmol) in
dimethylsulfoxide (20 mL) was heated at 90°C under nitrogen for 16 hours. The
reaction mixture was quenched with 1N sodium hydroxide and extracted with
methylene chloride (3 x 100 mL). The organic layer was washed with water (3 x 150
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (10%
methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.56 g of the (S)-enantiomer of the title compound as a brown oil.
The hydrochloride salt was prepared in ethyl acetate as an white solid, m.p. 148-
151°C.
Elemental Analysis for: C23H22N4O3» 1.5 HCI • 0.75 H2O
Calc'd: C, 58.70; H, 5.35; N, 11.90
Found: C. 58.90; H, 5.72; N, 11.77
EXAMPLE 31
3-{3-fMethvl-(2-methvl-7.8-dihvdro-n.41dloxinor2.3-Qif1,31benzoxazol-8-
vlmethvl)-amino1-propvl>-1H-indole-5-carbonitrile
[0126] To a solution of [3-(5-fluoro-1H-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-
1,6,9-trioxa-3-aza-cyclopenta[a]napthalen-8-ylmethyi)-amine (0.45 g, 0.11 mmol) and
formaldehyde (37 wt. % in water, 0.9 g, 1.1 mmol) in methanol (20 mL) was added
sodium cyanoborohydride (0.13 g, 0.2 mmol) and acetic acid (0.13 mL, 2.2 mmol) at
room temperature. The mixture was stirred at room temperature under nitrogen
overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with
methylene chloride (3 x 60 mL). The organic layer was washed with water (3 x 60
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (5%
methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.23 g of the (S)-enantiomer of the title compound as a brown oil.
The hydrochloride salt was prepared in ethyl acetate as a white solid, m.p. 140°C (d).
Elemental Analysis for: CwHaMCV 1.5 HCI • H2O
Calc'd: C, 58.93; H, 5.67; N, 11.45
Found: C. 59.20; H, 5.90; N, 11.40
EXAMPLE 32
3-(3-FMethvl-(8-methvl-2.3-dihvdro-ri.41dloxinof2,3-flqulnolin-2-vlmethvl)-
amino1-propvH»1H-indole-5-carbonitrile
[0127] To a solution of (2S)-3-{3-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-rjquinolin-
2-ylmethyl)-amino]-proyl}-1H-indole-5-carbonitrile (0.2 g, 0.48 mmol) and
formaldehyde (37 wt. % in water, 0.39 g, 4.8 mmol) in methanol (20 mL) was added
sodium cyanoborohydride (0.05 g, 0.72 mmol) and acetic acid (0.06 mL, 0.96 mmol)
at room temperature. The mixture was stirred at room temperature under nitrogen
for 4 hours, then quenched with 1N NaOH (5 mL). The mixture was extracted with
methylene chloride (3 x 60 mL). The organic layer was washed with water (3 x 50
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (5%
methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.18 g of the (S)-enantiomer of the title compound as a brown oil.
The dihydrochloride salt was prepared in ethyl acetate as a yellow solid
(decomposed at 158 °C).
Elemental Analysis for: CzeHasN^* 2 HCI • 3 H2O
Calc'd: C. 56.42; H, 6.19; N, 10.12
Found: C, 56.15; H, 6.09; N, 9.89
EXAMPLE 33
r3-(6-Fluoro-indol-1-vn-propvn-(8-methvl-2.3-dihvdro-n.41dioxinof2.3-
flquinolin-2-vlmethvO-amine
[0128] A solution of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate_(0.56 g, 1.2 mmol) in 35 mL of dimethyl sulfoxide
and 0.35 mL of triethylamine was added to 3-(6-fluoro-indol-1-yl)-propylamine (0.6 g,
3.1 mmol). The mixture was heated under nitrogen at 90°C for 4 hours. The mixture
was cooled to room temperature, made basic with 1N sodium hydroxide and then
extracted with 400 mL of methylene chloride. The methylene chloride phase was
washed with 300 mL each of water and saturated brine, dried over magnesium
sulfate, filtered and concentrated in vacuum. The residue was then column
chromatographed on silica gel using first 3.5 L of 55% ethyl acetate/45% hexane to
remove the impurities. The product was then eluted using 5% methanol in 95%
methylene chloride. The product-containing fractions were then concentrated under
vacuum to give 0.83 g of a light brown oil, which was dissolved in ethyl acetate and
treated with excess hydrochloric acid in ether to give 0.050 g of the (S)-enantiomer of
the title compound as a tan solid dihydrochloride, m.p. 154-156°C.
Elemental Analysis for: Qwr^FNaOz • 3.25 H2O • 2 HCI
Calc'd: C, 53.69; H, 6.10; N, 7.83
Found: C, 53.67; H, 5.81; N, 7.73
EXAMPLE 34
r3-(6-Fluoro-indol-1-vlVpropvn-methvl-(8-methvl-2.3-dihvdro-n.41dioxinor2.3-
f|quinolin-2-ylmethvl)-amine
[0129] A solution of [3-(6-fluoro-indol-1-yl)-propylH(2S)-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl]-amine (0.53 g, 1.3 mmol) in 1.05 mL of
formaldehyde, 0.11 mL of acetic acid and 20 mL of methanol was added to 95%
sodium cyanoborohydride (0.13 g, 1.9 mmole). The mixture was allowed to stir at
room temperature under nitrogen overnight. The mixture was partitioned between
400 mL each of methylene chloride and water. The organic portion was washed with
saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum.
The residue was then column chromatographed on silica gel using 55% ethyl
acetate/44% hexane/1% methanol as eluant. The product-containing fractions were
concentrated under vacuum to give a yellow oil, which was dissolved in ethyl acetate
and treated with excess HCI in ether to give 0.040 g of the (S)-enantiomer of the title
compound as a yellow hydrochloride, m.p. 75.9-83.7°C.
Elemental Analysis for: C25H26FN3O2 • 0.7 H2O • 3.0 HCI
Calc'd: C, 55.31; H, 6.24; N, 7.74
Found: C, 55.56 H, 5.95; N, 7.30
EXAMPLE 35
r4-(5-Fluoro-1-methvl-1H-indol-3-vn-butvn-(8-methvl-2.3-dihvdro-
H.41dioxinof2.3-flquinolin-2-vlmethvh-amine
[0130] To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate (3.69 g, 8.19 mmol) and 4-(5-fluoro-1-methyl-1H-
indol-3-yl)-butylamine (2.21 g, 10.0 mmol) was added sodium carbonate (2.47 g, 23.3
mmol) and 20 mL of DMSO. The mixture was stirred at room temperature for 4 days.
The solvent was evaporated at reduced pressure. The residue was partitioned
between 500 mL each of ethyl acetate and water. The ethyl acetate layer was
washed with water (250 mL) 3 times and dried over anhydrous magnesium sulfate.
Filtration and concentration in vacuum gave 3.49 g of oil. This was chromatographed
on silica gel with 0-10% methanol/ethyl acetate to give 1.29 g of the free base as a
clear, colorless oil. A 0.49 g portion was dissolved in ethanol. An excess of
saturated HCI/ethanol was added. Filtration gave 0.256 g of the (S)-enantiomer of
the title compound as a yellow dihydrochloride, m.p. 229-235°C.
Elemental Analysis for: C26H28FN3O2 • 2 HCI • 0.9 H2O
Calc'd: C, 59.75; H, 5.96; N, 8.04
Found: C, 59.71; H, 6.17; N, 7.93
EXAMPLE 36
Ethvl-r3-(5-fluoro-1H-indol-3-vl)-propvn-(2-nnethvl-7.8-dihvdro-ri.41dioxinor2.3-
giri,31benzoxazol-8-vlmethvO-amine
[0131] To a solution of [3-(5-fluorcMH-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-
1,6,9-trioxa-3-aza-cyclopenta[a]napthalen-8-ylmethyl)-amine (0.13 g, 0.32 mmol) and
acetaldehyde (0.18 ml_, 3.2 mmol) in methanol (20 mL) was added sodium
cyanoborohydride (0.07 g, 0.57 mmol) and acetic acid (0.04 mL, 0.32 mmol) at room
temperature. The mixture was stirred at room temperature under nitrogen overnight,
then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene
chloride (3 x 50 mL). The organic layer was washed with water (3 x 50 mL), dried
over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum.
The crude oil was column chromatographed on silica gel (5% methanol-methylene
chloride). The product-containing fractions were concentrated in vacuum to give 145
mg of the (S)-enantiomer of the title compound as a yellow oil. The dihydrochloride
salt was prepared in ethyl acetate as a white solid, m.p. 115°C d.
Elemental Analysis for: C24H24FN3O3 • 2 HCI • 0.25 H2O
Calc'd: C. 57.55; H, 5.73; N, 8.39
Found: C. 57.83; H, 5.76; N, 8.28
EXAMPLE 37
1-Methvl-3-{3-r(8-methvl-2.3-dihvdro-ri.4Tdioxinor2.3-flquinolin-2-vlmethvl)-
aminoi-propylHH-indole-5-carbonitrile
[0132] A solution of (2R)-4-bromobenzenesulfonic acid-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-/]quinolin-2-ylmethyl ester (0.5 g, 1.1 mmol), 3-(5-cyano-i-methyl-
indol-3-yl)propylamine (0.33 g, 1.4 mmol) and triethylamine (0.23 ml_, 2.2 mmol) in
dimethylsulfoxide (20 mL) was heated at 90°C under nitrogen for 16 hours. The
reaction mixture was quenched with 1N sodium hydroxide and extracted with
methylene chloride (3 x 100 mL). The organic layer was washed with water (3 x 150
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (10%
methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.2 g of the (S)-enantiomer of the title compound as a brown oil. The
dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at
148 °C).
Elemental Analysis for: CasHajl^CV 2 HCI • 2.75 H2O
Calc'd: C. 56.88; H, 6.15; N, 10.21
Found: C. 56.72; H, 5.93; N, 10.08
EXAMPLE 38
r4-(6-Fluoro-indol-1-vn-butvn-(8-methvl-2.3-dlhvdro-f1,41dioxinof2.3-f1quinolln-
2-ylmethvl)-amine
[0133] A solution of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl 4-bromobenzenesulfonate_(1.57 g, 3.5 mmol) in 105 mL of dimethyl
sulfoxide and 0.97 mL of triethylamine was added to 4-(6-fluoro-indol-1-yl)-
butylamine (1.8 g, 7.3 mmol). The mixture was heated under nitrogen at 90°C for 4
hours. The mixture was cooled to room temperature, made basic with 1N sodium
hydroxide and then extracted with 400 mL of methylene chloride. The organic
portion was washed with 300 mL each of water and saturated brine, dried over
magnesium sulfate, filtered and concentrated in vacuum. The residue was column
chromatographed on silica gel using first 55% ethyl acetate/44% hexane/1%
methanol to wash off some impurities and then 5% methanol/methylene chloride to
elute the product off the column. The product-containing fractions were then
concentrated under vacuum to give 0.225 g of a yellow oil. The oil was dissolved in
ethyl acetate and treated with excess ethereal HCI to give 0.060 g of the (S)-
enantiomer of the title compound as a yellow dihydrochloride, m.p. 122-127°C.
Elemental Analysis for: C2SH26FN3O2 • 2 HCI • 0.50 H2O
Calc'd: C, 59.88; H, 5.83; N, 8.38
Found: C, 59.55; H, 5.87; N, 8.05
EXAMPLE 39
3-(4-r(8-Methvl-2.3-dihvdro-ri,41dioxinor2,3-f1quinolin-2-vlmethyl)-amino1-
butvll-1 H-indole-5-carbonitrile
[0134] A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-/]quinolin-2-ylmethyl ester (0.84 g, 1.8 mmol), 3-(5-cyano-1 H-indol-3-
yl)butylamine (0.6 g, 2.8 mmol) and triethylamine (0.52 mL, 3.6 mmol) in
dimethylsulfoxide (40 mL) was heated at 90°C under nitrogen overnight. The
reaction mixture was quenched with 1N sodium hydroxide and extracted with
methylene chloride (3 x 100 mL). The organic layer was washed with water (3 x 150
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (10%
methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.25 g of the (S)-enantiomer of the title compound as a brown oil.
The dihydrochloride salt was prepared in ethyl acetate as a yellow solid
(decomposed at 105 CC).
Elemental Analysis for: CasH^N^* 2 HCI • 2.25 H^O
Calc'd: C. 57.83; H, 6.07; N, 10.38
Found: C. 57.81; H, 5.93; N, 10.34
EXAMPLE 40
1-Methvl-3-f3-rmethvl-(8-methvl-2.3-dihvdro-ri.4ldioxlnof2,3-f1quinolin-2-
vlmethvn-aminoi-propylM H-indole-5-carbonitrile
[0135] To a solution of (2S)-1-methyl-3-{3-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
/)quinolin-2-ylmethyl)-amino]-proyl}-1/-/-indoie-5-carbonitrile (0.1 g, 0.23 mmol) and
formaldehyde (37 wt. % in water, 0.19 g, 2.3 mmol) in methanol (20 mL) was added
sodium cyanoborohydride (0.026 g, 0.41 mmol) and acetic acid (0.027 mL, 0.46
mmol) at room temperature. The mixture was stirred at room temperature under
nitrogen for 2 hours, then quenched with 1N NaOH (5 mL). The mixture was
extracted with methylene chloride (3 x 50 mL). The organic layer was washed with
water (3 x 50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was
removed under vacuum. The crude oil was column chromatographed on silica gel
(5% methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The
dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at
165°C).
Elemental Analysis for: C27H28N4O2 • 2 HCI • 4 H2O
Calc'd: C, 55.39; H, 6.54; N, 9.57
Found: C. 55.51; H, 6.35; N, 9.57
EXAMPLE 41
3-(4-fMethvl-(8-methvl-2.3-dihvdro-n.41dioxinor2.3-flquinolin-2-vlmethvh-
aminoi-butvlHH-indole-5-carbonitrile
[0136] To a solution of (2S)-3-{4-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-/)quinolin-
2-ylmethyl)-amino]-butyl}-1H-indole-5-carbonitrile (0.13 g, 0.30 mmol) and
formaldehyde (37 wt. % in water, 0.24 g, 3.0 mmol) in methanol (20 mL) was added
sodium cyanoborohydride (0.35 g, 0.54 mmol) and acetic acid (0.035 mL, 0.6 mmol)
at room temperature. The mixture was stirred at room temperature under nitrogen
for 4 hours, then quenched with 1N NaOH (5 mL). The mixture was extracted with
methylene chloride (3 x 50 mL). The organic layer was washed with water (3 x 50
mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed
under vacuum. The crude oil was column chromatographed on silica gel (5%
methanol-ethyl acetate). The product-containing fractions were concentrated in
vacuum to give 0.11 g of the (S)-enantiomer of the title compound as a brown oil.
The dihydrochloride salt was prepared in ethyl acetate as a yellow solid
(decomposed at 155 °C).
Elemental Analysis for: C27H28N4O 2 HCI • 3 H2O
Calc'd: C. 57.14: H. 6.39: N. 9.87
Found: C. 57.35; H, 6.37; N, 9.76
EXAMPLE 42
r3-(5-Fluoro-1-methvl-1H-indol-3'Vl)-propvn-methvl-(8-methvl-2.3-dihvdro-
n.41dloxinof2.3-nquinolin-2-vlmethyl)-amine
[0137] To a solution of N-[3-(5-fluoro-1-methyl-1H-indol-3-yl)propyl]-N-{[(2S)-8-
methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine (1.05 g, 2.50 mmol) in
100 mL of methanol was added an aqueous 37% formaldehyde solution (2 ml_, 0.8 g,
30 mmol). Acetic acid (0.2 mL, 0.2 g, 3 mmol) and then sodium cyanoborohydride
(0.28 g, 4.5 mmol) were added. The reaction was stirred at room temperature for 3
hours. No amine starting material remained. One drop of concentrated HCI was
added. The mixture was allowed to stir for 2 days. The solvent was evaporated at
reduced pressure. The residue was partitioned between 500 mL each of ethyl
acetate and water. The ethyl acetate layer was washed with water (250 mL) twice.
Saturated brine was added as needed to break up the emulsion. Drying over
anhydrous magnesium sulfate, filtration and evaporation of the solvent gave 1.08 g of
oil. This was chromatographed on silica gel with gradient elution commencing with
1:1 ethyl acetate/hexane and ending with ethyl acetate to give 0.85 g of the free base
as a colorless and almost pure oil. This was dissolved in ethanol. An excess of
saturated HCI/ethanol was added. Filtration gave 0.316 g of the (S)-enantiomer of
the title compound as a yellow solid dihydrochloride, m.p. 274-275 °C.
Elemental Analysis for: C26H28FN3O2 • 2 HCI
Calc'd: C, 61.66; H, 5.97; N, 8.30
Found: C, 62.26; H, 5.93; N, 8.21
EXAMPLE 43
r4-(5-Fluoro-1H-indol-3-vl)-butvn-methvl-(8-methvl-2.3-dihvdro-n.41dioxinor2.3-
f]quinolin-2-ylmethvl)-amine
[0138] To a mixture of N-[4-(5-fluoro-1H-indol-3-yl)butyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine (0.87 g, 2.1 mmol) and N-[4-(5-
fluoro-1H-indol-3-yl)butyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl}amine dihydrochloride (0.46 g, 9.3 mmol) in 100 mL of methanol was added
an aqueous 37% formaldehyde solution (2.39 mL, 0.964 g, 32.1 mmol). Acetic acid
(0.1 mL, 0.1 g, 2 mmol) and then sodium cyanoborohydride (0.25 g, 4.0 mmol) were
added. The reaction was stirred at room temperature for 18 hours. The solvent was
evaporated at reduced pressure. The residue was partitioned between 500 mL each
of ethyl acetate and water. The ethyl acetate layer was washed with water (250 mL)
3 times. Drying over anhydrous magnesium sulfate, filtration and evaporation of the
solvent gave 1.64 g of oil. This was chromatographed on silica gel with gradient
elution commencing with 1:1 ethyl acetate/hexane and ending with ethyl acetate to
give 0.86 g of the free base as a colorless oil. This was dissolved in ethanol. An
excess of saturated HCI/ethanol was added. Filtration gave 0.771 g of the (S)-
enantiomer of the title compound as a yellow solid dihydrochloride, m.p. 274-275°C.
Elemental Analysis for: C26H28FN3O2 • 2 HCI • 0.5 H2O
Calc'd: C, 60.58; H, 6.06; N, 8.15
Found: C, 60.78; H, 5.84; N, 7.95
EXAMPLE 44
r4-(5-Fluorc-1-methvl-1H-indol-3-vn-butvn-methvl-(8-methvl-2.3-dihvdro-
ri,41dioxinor2.3-flquinolin-2-ylmethvO-amine
[0139] To a solution of N-t4-(5-fluoro-1H-indol-3-yl)butyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl)amine (0.83 g, 2.0 mmol) in 79 mL of
methanol was added an aqueous 37% formaldehyde solution (1.6 mL, 0.65 g, 21
mmol). Acetic acid (1.5 mL, 1.6 g, 26 mmol) and then sodium cyanoborohydride
(0.22 g, 3.5 mmol) were added. The reaction was stirred at room temperature for 5
days. Only a trace of amine starting material remained. The solvent was evaporated
at reduced pressure. The residue was partitioned between 500 mL each of ethyl
acetate and water. The ethyl acetate layer was washed with water (250 mL) twice.
Drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent
gave 0.79 g of oil. This was chromatographed on silica gel with ethyl acetate and
then 2.5% methanol in ethyl acetate to give 0.74 g of the free base as an oil. This
was dissolved in ethanol. An excess of saturated HCI/ethanol was added. Filtration
gave 0.760 g of the (S)-enantiomer of the title compound as a yellow solid
dihydrochloride, m.p. 275-276 °C.
Elemental Analysis for: C27H30FN3O2 • 2 HCI
Calc'd: C, 62.31; H, 6.20; N, 8.07
Found: C, 62.11; H, 6.04; N, 7.93
EXAMPLE 45
r3-(5-Fluoro-1H-indol-3-vn-propvn-(8-methvl-2.3-dihvdro-f1.41dioxinor2.3-
f|quinolin-2-vlmethvl)-propy|-amine
[0140] To a solution of N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quino!in-2-yl]methyl}amine (0.39 g, 0.96 mmol) in 4.9 mL of
methanol was added propionaldehyde (0.15 mL, 0.12 g, 2.1 mmol). 4.9 mL of a
stock solution of HCI/methanol (one drop cone HCI in 16 mL of methanol) was added
to adjust the pH to approximately 5. Sodium cyanoborohydride (0.12 g, 1.9 mmol)
was added. The reaction was stirred at room temperature and was complete in 3
hours. One drop of concentrated HCI was added. The mixture was stirred overnight.
The solvent was evaporated at reduced pressure. The residue was partitioned
between 500 mL each of ethyl acetate and water. The ethyl acetate layer was
washed with water (250 mL) twice. Saturated brine was added as needed to break
up the emulsion. Drying over anhydrous magnesium sulfate, filtration and
evaporation of the solvent gave 0.39 g of yellow oil. This was chromatographed on
silica gel with gradient elution commencing with 1:1 ethyl acetate/hexane and ending
with ethyl acetate to give 0.27 g of the free base as a clear oil. This was dissolved in
ethanol. An excess of saturated HCI/ethanol was added. Filtration gave 0.234 g of
the (S)-enantiomer of the title compound as a yellow solid dihydrochloride, m.p. 164-
170°C.
Elemental Analysis for: C27H30FN3O2 • 2 HCI • 2.75 H2O
Calc'd: C, 56.89; H, 6.63; N, 7.37
Found: C, 56.81; H, 6.35; N, 7.29
EXAMPLE 46
f3-f4-Fluoro-indol-1-yl>-propvlH8-methYl-2.3-dihvdro-ri.41c»oxinor2.3-
f|quinolin-2-ylmethvl)-amine
[0141] A solution of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yljmethyl 4-bromobenzenesulfonate_(1.56 g, 3.5 mmol) in 97.5 mL of dimethyl
sulfoxide and 0.97 mL of triethylamine was added to 3-(4-fluoro-indol-1 -yl)-
propylamine (1.67 g, 8.7 mmol). The mixture was heated under nitrogen at 90°C for 5
hours. The mixture was cooled to room temperature, made basic with 1N sodium
hydroxide and then diluted with 400 mL of methylene chloride. The mixture was
washed with 300 mL portions of water and saturated brine, dried over magnesium
sulfate, filtered and concentrated in vacuum. The residue was column
chromatographed on silica gel using 70% ethyl acetate/25% hexane/5% methanol to
elute the product off the column. The product-containing fractions were then
combined and concentrated under vacuum to give a clear oil. The oil was dissolved
in ethyl acetate and treated with excess ethereal HCI to give 0.088 g of the (S)-
enantiomer of the title compound as a white hydrochloride, m.p. 203-206°C.
Elemental Analysis for: C24H24FN3O2 • HCI • 0.25 H2O
Calc'd: C, 53.66; H, 5.43; N, 7.45
Found: C, 53.67; H, 5.81; N, 7.73
EXAMPLE 47
r4-(6-Fluoro-indol-1-vl)-butvn-methvl-(8-methvl-2.3-dihvdro-n.41dioxinor2.3-
fiQuinolin-2-ylmethvn-amine
[0142] A solution of [4-(6-fiuoro-indol-1-yl)-butyl]-[(2S)-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl]-amine (0.23 g, 0.5 mmol) in 0.45 mL of
formaldehyde, 0.05 mL of acetic acid and 10 mL of methanol was added to 95%
sodium cyanoborohydride (0.05 g, 0.5 mmol). The mixture was allowed to stir at
room temperature under nitrogen for 4.5 hours. The mixture was partitioned between
400 mL each of ethyl acetate and water. The organic portion was washed with
saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum.
The residue was column chromatographed on silica gel using 15% methanol in ethyl
acetate as eluant. The product-containing fractions were concentrated under
vacuum to give a yellow oil. The oil was dissolved in ethyl acetate and treated with
excess ethereal HCI to give 0.40 g of the (S)-enantiomer of the title compound as a
yellow solid dihydrochloride, m.p. 182-188°C.
Elemental Analysis for: C24H24FN3O2 • 2.0 HCI • 3.0 H2O
Calc'd: C, 55.72; H, 5.47; N, 7.50
Found: C, 53.67; H, 6.07; N, 7.46
EXAMPLE 48
f3-(4-Fluoro-indol-1-vn-propvll-methvl-(8-methvl-2.3-dihvdro-n.41dloxlnof2.3-
flquinolin-2-ylmBthvl)-amine
[0143] A solution of [3-(4-fluoro-indol-1-yl)-propyl]-(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine (0.19 g, 0.5 mmol) in 0.71 mL of
formaldehyde, 0.07 mL of acetic acid and 18 mL of methanol was added to 95%
sodium cyanoborohydride (0.09 g, 1.3 mmol). The mixture was allowed to stir at
room temperature under nitrogen for 4 hours. The mixture was diluted to 400 mL with
methylene chloride, washed with 300 mL each of water and saturated brine, dried
over magnesium sulfate, filtered and concentrated in vacuum to a yellow oil. The
residue was column chromatographed on silica gel using 75% ethyl acetate and 25%
hexane as eluant. The product-containing fractions were concentrated under
vacuum to give a yellow oil and the oil was dissolved in ethyl acetate and treated with
excess ethereal HCI to give 0.060 g of the (S)-enantiomer of the title compound as a
yellow dihydrochloride, m.p. 125-137°C.
Elemental Analysis for: C24H24FN3O2 • 2.0 HCI • 1.0 HZO • 0.2 C4H8O2
Calc'd: C, 58.75; H, 5.98; N, 8.09
Found: C, 58.78; H, 5.91; N, 8.04
EXAMPLE 49
N-r4r(S-Chloro-1-benzothien-3-vnbutvn-N-{r(2S>-8-methvl-2.3-
dihvdrori.41dioxinof2.3-flguinolin-2-vnmethvl}amine
[0144] A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (250 mg, 0.556 mmol) and 4-(5-chloro-benzo[b]thiophen-
3-yl)-butylamine (400 mg, 1.67 mmol) in anhydrous dimethylsulfoxide (3 mL) was
heated at 40°C for three days. The cooled reaction was diluted with saturated
aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 20 mL).
The combined organic layers were washed with brine (30 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica
gel (3/97 2 M ammonia in methanol/methylene chloride) did not provide clean
product. Re-chromatography on silica gel (90/5/5 ethyl acetate/hexane/triethylamine)
afforded 236 mg (94%) of the title compound as a yellow viscous oil, which was
converted to its fumarate salt as a yellow solid: mp 140-144°C; MS (ES) m/z 453
[M+H]+; [cc]D -28.9° (c 1.0, DMSO).
Elemental Analysis for: C24H24FN3O2 • C4H4O4 • 0.1 C4H8O2 • H2O
Calc'd: C, 59.26; H, 5.38; N, 4.70
Found: C, 59.05; H, 5.07; N, 4.35
EXAMPLE 50
N-r3-(5-Chloro-1-benzothien-3-vl)propvn-N-{r(2S)-8-methvl-2.3-
dihvdrori.41dioxinor2.3-f|quinolin-2-vnrnethv[)arnine
[0145] A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (406 mg, 0.90 mmol) and 3-(5-chloro-benzo[b]thiophen-3-
yl)-propylamine (610 mg, 2.7 mmol) in anhydrous dimethylsulfoxide (4 mL) was
heated at 40°C overnight. The cooled reaction was diluted with saturated aqueous
sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 x 25 mL). The
combined organic layers were washed with brine (40 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica
gel (3/2/95 methanol / 2 M ammonia in methanol / methylene chloride) afforded 340
mg (86%) of the title compound as a yellow viscous oil, which was converted to its
fumarate salt as a yellow solid: mp 193-196°C; MS (ES) m/z 439 [M+H]+; [a]0 -26.9°
(d.O, DMSO)
Elemental Analysis for: C24H23CIN2O2S • C4H4O4 • 0.7 C4H8O2 • H2O
Calc'd: C, 58.28; H, 5.49; N, 4.41
Found: C, 57.91; H, 5.28; N, 4.44
EXAMPLE 51
N-r3-(5-Fluoro-1-benzothien-3-vnpropvn-N-fr(2S)-8-methvl-2.3-
dihvdron.41dloxinor2.3-flquinolin-2-vl1methvl)amine
[0146] A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (151 mg, 0.669 mmol) and 3-(5-fluoro-benzo[b]thiophen-3-
yl)-propylamine (140 mg, 0.335 mmol) in anhydrous dimethylsulfoxide (7 mL) was
stirred at ambient temperature for three days without any apparent reaction
occurring. The reaction was then heated at 40°C for two days, resulting in complete
conversion. The cooled reaction was diluted with saturated aqueous sodium
bicarbonate (35 mL) and extracted with ethyl acetate (3 x 35 mL). The combined
organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography on silica gel (2/2/96
methanol / 2 M ammonia in methanol / methylene chloride) afforded 90 mg (63%) of
the title compound as a yellow viscous oil, which was converted to its fumarate salt
as a yellow solid: mp 117-120°C; MS (ES) m/z 423 [M+H]+; [a]D -29.1° (c 0.94,
DMSO)
Elemental Analysis for: C24H24FN3O2 • C4H4O4 • 0.5 H2O
Calc'd: C, 61.41; H, 5.15; N, 5.12
Found: C, 61.07; H, 5.03; N, 4.89
EXAMPLE 52
N-r4-(1-Benzofuran-3-vl)butvn-N-ethvl-N-(r(2S)-8-methvl-2.3-
dihvdrof1.41dioxinor2,3-flquinolin-2-yllmethvl)amlne
[0147] To a solution of N-[3-(1-benzofuran-3-yl)propyl]-N-{[(2S)-8-rnethyl-2,3-
dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl]methyl)amine (206 mg, 0.512 mmol) in
anhydrous tetrahydrofuran (3 ml_) was added acetaldehyde (206 u.L, 3.67 mmol),
sodium triacetoxyborohydride (445 mg, 2.1 mmol), and glacial acetic acid (41 u.L,
0.716 mmol). The reaction was allowed to stir at ambient temperature overnight,
then was quenched with 1 M aqueous sodium hydroxide (5 mL) and diluted with
water (10 mL). The aqueous mixture was extracted with methylene chloride (3 x 25
mL). The combined organic layers were washed with brine (50 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (50/45/5 ethyl acetate/hexane/triethylamine) afforded
120 mg (55%) of the title compound as an orange oil, which was converted to its
fumarate salt as a brown solid: mp 87-92°C; MS (ES) m/z 431 [M+H]+; [ot]D -8.58° (c
1.0, DMSO).
Elemental Analysis for: C27H3oN203» 1.3 C4H4O4 • 0.7 H2O
Calc'd: C, 65.10; H, 6.21; N, 4.72
Found: C, 65.56; H, 6.43; N, 4.33
[0148] When ranges are used herein for physical properties, such as molecular
weight, or chemical properties,' such as chemical formulae, all combinations and
subcombinations of ranges specific embodiments therein are intended to be
included.
[0149] The disclosures of each patent, patent application, and publication cited or
described in this document are hereby incorporated herein by reference, in their
entirety.
[0150] Those skilled in the art will appreciate that numerous changes and
modifications can be made to the preferred embodiments of the invention and that
such changes and modifications can be made without departing from the spirit of the
invention. It is, therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of the invention.
WE CLAIM :
1. A compound of Formula I:

X is O, N=CH, CR7=CH or CR7=N, in which R7 is hydrogen or alkyl of 1 to 6
carbon atoms;
Z is O, S or NR8, in which R8 is hydrogen or alkyl of 1 to 6 carbon atoms;
R1, R5 and R6 are, independently, hydrogen, hydroxy, halo, cyano,
carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl,
alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2
to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or
di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,
alkanamido of 2 to 6 carbon atoms, alkanesulfonyl of 1 to 6 carbon atoms
or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen, halo, amino, mono- or di-alkylamino in which each alkyl
group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms;
R3 and R4 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms;
n is 1,2 or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound of Formula I as claimed in claim 1, wherein X is CR7=CH where
R7 is hydrogen or alkyl of 1 to 3 carbon atoms.
3. A compound as claimed in claim 1 of Formula la:

la
or a pharmaceutically acceptable salt thereof.
4. A compound as claimed in claim 1 of Formula Ib:

Ib
or a pharmaceutically acceptable sialt thereof.
5. A compound as claimed in any one of claims 1 to 4, wherein R1 is hydrogen,
halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy,of 1 to 6 carbon
atoms.
6. A compound as claimed in any one of claims 1 to 4, wherein R1 is hydrogen,
halo or alkoxy of 1 to 6 carbon atoms.
7. A compound as claimed in any one of claims 1 to 4, wherein R1 is hydrogen.
8. A compound as claimed in any one of claims 1 to 7, wherein R2 is hydrogen,
amino or alkyl of 1 to 6 carbon atoms.
9. A compound as claimed in any one of claims 1 to 7, wherein R2 is hydrogen
or alkyl of 1 to 3 carbon atoms.
10. A compound as claimed in any one of claims 1 to 9, wherein R?. aqd R4 are
independently selected from hydrogen or alkyl of 1 to 3 carbon atoms.
11. A compound as claimed in any one of claims 1 to 10, wherein R4 is hydrogen.
12. A compound as claimed in any one of claims 1 to 11, wherein R7 and R8 are
independently selected from hydrogen or alkyl of 1 to 3 carbon atoms.
13. A compound as claimed in any one of claims 1 to 12, wherein R5 and R6 are
independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of 1
to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms.
14. A compound as claimed in any one of claims 1 to 12, wherein R5 and R6 are
independently selected from hydrogen, cyano or halogen.
15. A compound as claimed in any one of claims 1 to 14, wherein Z is NR8
16. A compound as claimed in claim 15, wherein R8 is hydrogen or alkyl of 1 to 3
carbon atoms.
17. A compound as claimed in any one of claims 1 to 16, wherein n is 2 or 3.
18. A compound as claimed in claim 1, wherein R1 hydrogen, halo, cyano,
trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.
19. A compound as claimed in claim 1, wherein R1 is hydrogen, halo or alkoxy of
1 to 6 carbon atoms, R2, R3, R7 and R8 are hydrogen or alkyl of 1 to 3 carbon atoms,
R4 is hydrogen, R5 and R6 are independently hydrogen, cyano or halogen, Z is NR8
and n is 2 or 3.
20. The compound as claimed in claim 1 which is N-[2-(5-methoxy-1 H-indol-3-yl)-
ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof. "' "
21. The compound as claimed in claim 1 which is N-[2-(5-chloro-1H-indbK£yl)
ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
22. The compound as claimed in claim 1 which is N-[3-(5-fluoro-1H-indol-3-yl)
propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine
or a pharmaceutically acceptable salt thereof.
23. The compound as claimed in claim 1 which is N-[2-(5-fluoro-1 H-indol-3-yl)
ethyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
24. The compound as claimed in claim 1 which is N-[3-(5-fluoro-1 H-indol-3-yl)
propyl]-N-(8-ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
25. The compound as claimed in claim 1 which is N-[3-(1H-indol-3-yl)propyl]-N-
(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
26. The compound as claimed in claim 1 which is N-[3-(5-fluoro-1 H-indol-3-yl)
propyl]-N-methyl-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine
or a pharmaceutically acceptable salt thereof.
27. The compound as claimed in claim 1 which is N-[3-(7-fluoro-1 H-indol-3-yl)
propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
28. The compound as claimed in claim 1 which is N-[4-(1H-indol-3-yl)butyl]-N-(8-
methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a pharmaceutically
acceptable salt thereof.
29. The compound as claimed in claim 1 which is N-[4-(5-fluoro-1 H-indol-3-yl)
butyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
30. The compound as claimed in claim 1 which is N-[4-(5-fluoro-1H-indol-3-yl)-N-
(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)butan-2-amine or a
pharmaceutically acceptable salt thereof.
31. The compound as claimed in claim 1 which is N-[3-(5-fluoro-1-methyl-1H-
indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)
amine or a pharmaceutically acceptable salt thereof.
32. The compound as claimed in claim 1 which is N-[3-(5,7-difluoro-1 H-indol-3-yl)
propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
33. The compound as claimed in claim 1 which is N-(2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]amine or a pharmaceutically
acceptable salt thereof.
34. The compound as claimed in claim 1 which is N-(2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-ylmethyl)-N-[3-(5-fluoro-1 H-indol-3-yl)propyl]-N-methylamine or a
pharmaceutically acceptable salt thereof.
35. The compound as claimed in claim 1 which is N-[3-(5,7-difluoro-1 H-indol-3-yl)
propyl]-N-methyl-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine
or a pharmaceutically acceptable salt thereof.
36. The compound as claimed in claim 1 which is N-[2-(1-benzofuran-3-yl)ethyl]-
N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
37. The compound as claimed in claim 1 which is N-[3-(1-benzofuran-3-yl)
propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
38. The compound as claimed in claim 1 which is N-[3-(7-methoxy-1-benzofuran-
3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
39. The compound as claimed in claim 1 which is N-[3-(1-benzothien-3-yl)propyl]-
N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
40. The compound as claimed in claim 1 which is N-[2-(1-benzothien-3-yl)ethyl]-
N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
41. The compound as claimed in claim 1 which is N-[3-(1-benzothien-3-yl)propyl]-
N-methyl-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
42. The compound as claimed in claim 1 which is N-[3-(5-fluoro-1H-indol-3-yl)
propyl]-N-(2-methyl-7,8-dihydro-[1,4]dioxino[2)3-g][1,3]benzoxazol-8-ylmethyl)amine
or a pharmaceutically acceptable salt thereof.
43. The compound as claimed in claim 1 which is N-[3-(5-fluoro-1 H-indol-3-yl)
propyl]-N-methyl-N-(2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazol-8-
ylmethyl)amine or a pharmaceutically acceptable salt thereof.
44. The compound as claimed in claim 1 which is N-ethyl-N-[3-(5-Fluoro-1H-
indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)
amine or a pharmaceutically acceptable salt thereof.
45. The compound as claimed in claim 1 which is N-[3-(5,7-difluoco-1-methyl-1H-
indol-3-yl)propyl]-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)
amine or a pharmaceutically acceptable salt thereof.
46. The compound as claimed in claim 1 which is N-[3-(5,7-difluoro-1-methyl-1H-
indol-3-yl)propyl]-N-methyl-N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-
ylmethyl)amine or a pharmaceutically acceptable salt thereof.
47. The compound as claimed in claim 1 which is N-[4-(1-benzofuran-3-yl)butyl]-
N-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)amine or a
pharmaceutically acceptable salt thereof.
48. The compound as claimed in claim 1 which is 3-{3-[(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-propyl}-1 H-indole-5-carbonitrile or a
pharmaceutically acceptable salt thereof.
49. The compound as claimed in claim 1 which is 3-{3-[(2-methyl-7,8-dihydro-
[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)amino]-propyl}-1 H-indole-5-carbonitrile
or a pharmaceutically acceptable salt thereof.
50. The compound as claimed in claim 1 which is 3-{3-[methyl-(2-methyl-7,8-
dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)-amino]-propyl}-1 H-indole-5-
carbonitrile or a pharmaceutically acceptable salt thereof.
51. The compound as claimed in claim 1 which is 3-{3-[methyl-(8-methyl-2,3-
dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-propyl}-1 H-indole-5-carbonitrile
or a pharmaceutically acceptable salt thereof.
52. The compound as claimed in claim 1 which is [3-(6-fluoro-indol-1-yl)-propyl]-
(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof.
53. The compound as claimed in claim 1 which is [3-(6-fluoro-indoM-yl)-propyl]-
methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof. ^ •" '
54. The compound as claimed in claim 1 which is [4-(5-fluoro-1-methyl-1H-indol-
3-yl)-butyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof.
55. The compound as claimed in claim 1 which is ethyl-[3-(5-fluoro-1H-indol-3-yl)-
propyl]-(2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl)-amine or
a pharmaceutically acceptable salt thereof.
56. The compound as claimed in claim 1 which is 1-methyl-3-{3-[(8-methyl-2,3-
dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-propyl}-1H-indole-5-carbonitrile
or a pharmaceutically acceptable slat thereof.
57. The compound as claimed in claim 1 which is [4-(6-fluoro-indol-1-yl)-butyl]-(8-
methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof.
58. The compound as claimed in claim 1 which is 3-{4-[(8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-butyl}-1 H-indole-5-carbonitrile or a
pharmaceutically acceptable salt thereof.
59. The compound as claimed in claim 1 which is 1-methyl-3-{3-[methyl-(8-
methyl^.S-dihydro-fi^JdioxinoP.S-flquinolin^-ylmethyO-aminohpropylJ-IH-indole-S-
carbonitrile or a pharmaceutically acceptable salt thereof.
60. The compound as claimed in claim 1 which is 3-{4-[methyl-(8-methyl-2,3-
dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-butyl}-1H-indole-5-carbonitrile
or a pharmaceutically acceptable salt thereof.
61. The compound as claimed in claim 1 which is [S-fS-fluoro-i-rhethyl-iH-indol-
3-yl)-propyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-
amine or a pharmaceutically acceptable salt thereof.
62. The compound as claimed in claim 1 which is [4-(5-fluoro-1 H-indol-3-yl)-
butyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmetfiyl)-amine or a
pharmaceutically acceptable salt thereof.
63. The compound as claimed in claim 1 which is [4-(5-fluoro-1-methyl-1H-indol-
3-yl)-butyl]-methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine
or a pharmaceutically acceptable salt thereof.
64. The compound as claimed in claim 1 which is [3-(5-fluoro-1H-indol-3-yl)-
propyl]-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-propyl-amine or a
pharmaceutically acceptable salt thereof.
65. The compound as claimed in claim 1 which is [3-(4-fluoro-indol-1-yl)-propyl]-
(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof.
66. The compound as claimed in claim 1 which is [4-(6-fluoro-indol-1-yl)-butyl]-
methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof.
67. The compound as claimed in claim 1 which is [3-(4-fluoro-indol-1-yl)-propyl]-
methyl-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine or a
pharmaceutically acceptable salt thereof.
68. The compound as claimed in claim 1 which is N-[4[(5-Chloro-1-benzothien-3-
yl)butyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amineor
a pharmaceutically acceptable salt thereof.
69. The compound as claimed in claim 1 which is N-[3-(5-Chloro-1-benzothien-3-
yl)propyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine
or a pharmaceutically acceptable salt thereof.
70. The compound as claimed in claim 1 which is N-[3-(5-Fluoro-1-benzothien-3-
yl)propyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine
or a pharmaceutically acceptable salt thereof.
71. The compound as claimed in claim 1 which is N-[4-(1-Benzofuran-3-yl)butyl]-
N-ethyl-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f|quinolin-2-yl]methyl}amineor
a pharmaceutically acceptable salt thereof.
72. A compound as claimed in claim 1 which is the S enantiomer, substantially
free of the R enantiomer of said compound.
73. A pharmaceutical composition comprising a compound of Formula I as
claimed in any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable carrier or excipient.
74. A pharmaceutical composition as claimed in claim 73 for treating a subject
suffering from a condition selected from depression, anxiety, panic disorder, post- traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder,
obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder,
obesity, eating disorders, vasomotor flushing, cocaine and alcohol addiction, and
sexual dysfunction.
75. A pharmaceutical composition as claimed in claim 74, wherein the condition
is depression.
76. A pharmaceutical composition as claimed in claim 74, wherein the condition ]
is selected from the group consisting of obsessive compulsive disorder, panic /
attacks, generalized anxiety disorder, and social anxiety disorder. /
77. A compound as claimed in any one of claims 1 to 72 ^abaple of being used inv^^Jthe preparation of a medicament for the treatmerTroi-^pression, anxieTyrp^n1c"~"^>
disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention-/«
deficit disorder, obsessive compulsive disorder, social anxiety disorder, generalized"
anxiety disorder, obesity, eating disorders, vasomotor flushing, cocaine and alcohol
addiction, and sexual dysfunction. I
78. A compound as claimed in claim 77, wherein the condition is depression. 79. A compound as claimed in claim 77, wherein the condition is selected from /
the group consisting of obsessive compulsive disorder, panic disorder, generalized
anxiety disorder, and social anxiety disorder.

Compounds of the Formula: are useful for the
treatment of depression ( including but not limited to major
depressive disorder, childhood depression and dysthymia). Anxiety,
panic disorder, post-traumatic stress disorder, premenstrual
dysphoric disorder (also known as premenstrual syndrome),
attention deficit disorder ( with and without hyperactivity),
obsessive compulsive disorder, social anxiety disorder, generalized
anxiety disorder, obesity, eating disorders such as anorexia nervosa,
bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction,
sexual dysfunction and related illnesses.