U.S. patent application number 12/254118 was filed with the patent office on 2009-02-12 for antidepressant piperidine derivatives of heterocycle-fused benzodioxans.
This patent application is currently assigned to Wyeth. Invention is credited to Magda Asselin, Deborah A. Evrard, Gary Paul Stack, Michael Byron Webb.
Application Number | 20090042895 12/254118 |
Document ID | / |
Family ID | 31994047 |
Filed Date | 2009-02-12 |
United States Patent
Application |
20090042895 |
Kind Code |
A1 |
Webb; Michael Byron ; et
al. |
February 12, 2009 |
Antidepressant Piperidine Derivatives of Heterocycle-Fused
Benzodioxans
Abstract
Compounds of the Formula: ##STR00001## 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 pre-menstrual syndrome),
attention deficit disorder (with and without hyperactivity),
obsessive compulsive disorder, social anxiety disorder, generalized
anxiety disorder, obesity, eating disorders such as anorexia
nervosa and bulimia nervosa, vasomotor flushing, cocaine and
alcohol addiction, sexual dysfunction and related illnesses.
Inventors: |
Webb; Michael Byron;
(Levittown, PA) ; Stack; Gary Paul; (Ambler,
PA) ; Asselin; Magda; (Mahwah, NJ) ; Evrard;
Deborah A.; (Hamilton Square, NJ) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP/WYETH
CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET
PHILADELPHIA
PA
19104-2891
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
31994047 |
Appl. No.: |
12/254118 |
Filed: |
October 20, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11142787 |
Jun 1, 2005 |
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12254118 |
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10659160 |
Sep 10, 2003 |
6939877 |
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11142787 |
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60410033 |
Sep 12, 2002 |
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Current U.S.
Class: |
514/250 ;
514/291; 514/338; 544/345; 546/271.7; 546/90 |
Current CPC
Class: |
A61P 25/32 20180101;
A61P 25/24 20180101; A61P 43/00 20180101; C07D 491/04 20130101;
A61P 15/10 20180101; A61P 25/20 20180101; A61P 25/36 20180101; A61P
25/22 20180101; A61P 25/28 20180101; A61P 25/18 20180101; A61P 3/04
20180101 |
Class at
Publication: |
514/250 ; 546/90;
514/291; 544/345; 546/271.7; 514/338 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; C07D 491/056 20060101 C07D491/056; A61K 31/436
20060101 A61K031/436; C07D 498/04 20060101 C07D498/04; A61K 31/454
20060101 A61K031/454; A61P 25/24 20060101 A61P025/24 |
Claims
1. A compound of Formula I: ##STR00026## wherein R.sup.1, R.sup.2
and R.sup.3 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; X and Y, taken together, form R.sup.4 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; the dotted line
represents an optional double bond; Z is oxygen or sulfur; Q is
carbon or nitrogen; and n is 0 or 1; or a pharmaceutically
acceptable salt thereof.
2. A compound according to claim 1, wherein Q is carbon and Z is
S.
3-6. (canceled)
7. A compound according to claim 1, wherein R.sup.1 is hydrogen,
halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or
alkoxy of 1 to 6 carbon atoms.
8. A compound according to claim 1, wherein R.sup.1 is hydrogen,
halo or alkoxy of 1 to 6 carbon atoms.
9. A compound according to claim 1, wherein R.sup.1 is
hydrogen.
10. A compound according to claim 1, wherein R.sup.2 and R.sup.3
are independently selected from hydrogen, hydroxy, halo, cyano,
carboxamido, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6
carbon atoms.
11. A compound according to claim 1, wherein R.sup.2 and R.sup.3
are independently selected from hydrogen, cyano or halogen.
12-15. (canceled)
16. A compound according to claim 1, wherein n is 0 and the dotted
line represents a double bond.
17-24. (canceled)
25. A compound according to claim 1, wherein said compound is
8-(4-benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-7,-
8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazole or a pharmaceutically
acceptable salt thereof.
26-30. (canceled)
31. A compound according to claim 1, wherein said compound is the S
enantiomer, substantially free of the R enantiomer of said
compound.
32. A method of 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, anorexia nervosa, bulimia nervosa,
vasomotor flushing, cocaine and alcohol addiction, and premature
ejaculation, comprising the step of: administering to said subject
suffering from said condition, a therapeutically effective amount
of a compound according to claim 1 or a pharmaceutically acceptable
salt thereof.
33. A method according to claim 32, wherein the condition is
depression.
34. A method according to claim 32, wherein the condition is
selected from the group consisting of obsessive compulsive
disorder, panic attacks, generalized anxiety disorder, and social
anxiety disorder.
35. A pharmaceutical composition, comprising: an effective amount
of a compound according to claim 1 or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier or
excipient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Application Ser.
No. 60/410,033, filed Sep. 12, 2002, the disclosure of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to antidepressant piperidine
derivatives of heterocycle-fused benzodioxans, to processes for
preparing them, methods of using them and to pharmaceutical
compositions containing them.
BACKGROUND OF THE INVENTION
[0003] Major depression is a serious health problem affecting more
than 5% of the population, with a lifetime prevalence of
15-20%.
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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,
5HT.sub.1A 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.
[0008] A 5HT.sub.1A 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.
[0009] Thus, it is highly desirable to provide improved compounds
which both inhibit serotonin reuptake and which are antagonists of
the 5HT.sub.1A receptor.
DESCRIPTION OF THE INVENTION
[0010] In accordance with this invention, there is provided a group
of novel compounds of Formula I:
##STR00002##
wherein [0011] R.sup.1, R.sup.2 and R.sup.3 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; [0012] X and Y 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, or X and Y,
taken together, form --N.dbd.C(R.sup.4)--C(R.sup.5).dbd.N--,
--N.dbd.C(R.sup.4)--C(R.sup.6).dbd.CH--,
--N.dbd.C(R.sup.4)--N.dbd.CH--, N.dbd.C(R.sup.4)--O--,
--NH--C(R.sup.7).dbd.N-- or --NH--C(R.sup.8).dbd.CH--; [0013]
R.sup.4 and R.sup.5 are, independently, 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; [0014] R.sup.6 is hydrogen
or alkyl of 1 to 6 carbon atoms; [0015] R.sup.7 is hydrogen, halo,
trifluoromethyl, pentafluoroethyl, amino, mono- or di-alkylamino in
which each alkyl group has 1 to 6 carbon atoms or alkyl of 1 to 6
carbon atoms; [0016] R.sup.8 is hydrogen, halo, trifluoromethyl,
pentafluoroethyl or alkyl of 1 to 6 carbon atoms; [0017] the dotted
line represents an optional double bond; [0018] Z is oxygen or
sulfur;
[0019] Q is carbon or nitrogen; [0020] n is 0 or 1; [0021] or a
pharmaceutically acceptable salt thereof.
[0022] R.sup.1 is preferably hydrogen, halo, cyano,
trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6
carbon atoms. More preferably, R.sup.1 is hydrogen, halo or alkoxy
of 1 to 6 carbon atoms. In still more preferred embodiments of the
present invention, R.sup.1 is hydrogen.
[0023] R.sup.2 and R.sup.3 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 R.sup.2 and R.sup.3
are preferably independently selected from hydrogen, cyano or
halogen.
[0024] R.sup.4 and R.sup.5 are preferably independently hydrogen,
amino or alkyl of 1 to 6 carbon atoms. More preferably, R.sup.4 and
R.sup.5 are independently hydrogen or alkyl of 1 to 3 carbon
atoms.
[0025] R.sup.7 and R.sup.8 are preferably independently selected
from hydrogen, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6
carbon atoms. More preferably, R.sup.7 and R.sup.8 are
independently hydrogen, trifluoromethyl or alkyl of 1 to 3 carbon
atoms.
[0026] R.sup.6 is preferably hydrogen or alkyl of 1 to 3 carbon
atoms, Z is preferably sulfur, Q is preferably carbon, n is
preferably 0 and the dotted line represents a double bond.
[0027] In other preferred embodiments of the invention is provided
compounds of Formula Ia.
##STR00003##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.6 are as
described above.
[0028] In still other preferred embodiments of the invention is
provided compounds of Formula Ib.
##STR00004##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.8 are as described
above.
[0029] This invention relates to both the R and S stereoisomers of
the benzodioxan methylamines 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
preferred. For certain of the compounds of the invention (i.e., X
and Y form an imidazole), tautomeric forms may exist. This
application thus encompasses all tautomeric forms of compounds of
the present invention.
[0030] 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 al., 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, Ind. 1972).
[0031] "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.
[0032] "Alkanamido," as used herein, refers to the group
R--C(.dbd.O)--NH-- where R is an alkyl group of 1 to 5 carbon
atoms.
[0033] "Alkanoyl," as used herein, refers to the group
R--C(.dbd.O)-- where R is an alkyl group of 1 to 5 carbon
atoms.
[0034] "Alkanoyloxy," as used herein, refers to the group
R--C(.dbd.O)--O-- where R is an alkyl group of 1 to 5 carbon
atoms.
[0035] "Alkanesulfonamido," as used herein, refers to the group
R--S(O).sub.2--NH-- where R is an alkyl group of 1 to 6 carbon
atoms.
[0036] "Alkanesulfonyl," as used herein, refers to the group
R--S(O).sub.2-- where R is an alkyl group of 1 to 6 carbon
atoms.
[0037] "Alkoxy," as used herein, refers to the group R--O-- where R
is an alkyl group of 1 to 6 carbon atoms.
[0038] "Carboxamido," as used herein, refers to the group
NH.sub.2--C(.dbd.O)--.
[0039] "Carboalkoxy," as used herein, refers to the group
R--O--C(.dbd.O)-- where R is an alkyl group of 1 to 5 carbon
atoms.
[0040] "Halogen" (or "halo"), as used herein, refers to chlorine,
bromine, fluorine and iodine.
[0041] 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.
[0042] Specific examples of compounds of Formula I are: [0043]
2-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-8-methyl-2,-
3-dihydro-[1,4]dioxino[2,3-f]quinoline; [0044]
2-(4-Benzo[b]thiophen-2-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-8-methyl-2,-
3-dihydro-[1,4]dioxino[2,3-f]quinoline; [0045]
2-[4-(5-Fluoro-benzo[b]thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]--
8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; [0046]
2-[4-(7-Methoxy-benzofuran-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8-met-
hyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; [0047]
2-[4-(5-Fluoro-benzo[b]thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]--
2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; [0048]
2-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2,3-dihydro-
-[1,4]dioxino[2,3-f]quinoline; [0049]
2-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2,3-dihydro-
-7H-[1,4]dioxino[2,3-e]indole; [0050]
2-[4-(5-Fluoro-benzo[b]thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]--
2,3-dihydro-7H-[1,4]dioxino[2,3-e]indole; [0051]
8-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-7,-
8-dihydro-[1,4]dioxino[2,3-g][1,3]benzoxazole; [0052]
2-(4-Benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-8-methyl-2,-
3-dihydro-[1,4]dioxino[2,3-f]quinoline; [0053]
2-(4-Benzofuran-2-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-8-methyl-2,3-dihy-
dro-[1,4]dioxino[2,3-f]quinoline; [0054]
2-(4-Benzofuran-2-yl-piperidin-1-ylmethyl)-8-methyl-2,3-dihydro-[1,4]diox-
ino[2,3-f]quinoline; [0055]
2-[4-(5-Chloro-benzo[b]thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]--
8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; [0056]
2-(4-Benzoxazol-2-yl-piperidin-1-ylmethyl)-8-methyl-2,3-dihydro-[1,4]diox-
ino[2,3-f]quinoline;
[0057] 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. Specifically (Scheme 1), the appropriately
substituted piperidine (2) is combined with a suitably substituted
benzodioxan methyltosylate or bromide (1) in a solvent such as
dimethyl sulfoxide and heated to a temperature of 70-100.degree. C.
for several hours as illustrated below. Alternatively, the
appropriately substituted piperidine may be acylated with a
suitably substituted benzodioxan carboxylic acid chloride, and the
resulting amide reduced to the amine with a suitable reducing agent
such as lithium aluminum hydride or borane/THF. The piperidine may
also be combined with a suitably substituted benzodioxan
carboxaldehyde in the presence of a reducing agent such as sodium
cyanoborohydride.
##STR00005##
[0058] Alternatively (Scheme 2), an appropriately substituted
pyridine (3) may be alkylated with a suitably substituted
benzodioxan methyltosylate or bromide (1) by heating the mixture in
a high-boiling polar solvent such as dimethyl sulfoxide to produce
the pyridinium ion (4). The pyridinium ion may be reduced to the
tetrahydropyridine by treatment with a suitable reducing agent such
as sodium borohydride in ethanol or directly to the piperidine by
treatment with hydrogen over a suitable catalyst such as palladium
on carbon.
##STR00006##
[0059] The benzodioxan methyltosylates and halides (1) are known
compounds or they may be prepared from the appropriately
substituted salicylaldehydes by the method (a) described in Scheme
3 below. The salicylaldehyde (5) is alkylated with an epihalohydrin
or glycidyl arylsulfonate in the presence of a suitable base. The
aldehyde moiety is then converted to a phenol by a Baeyer-Villager
procedure and cyclization to the benzodioxan methanol (7) effected
by treatment with a base such as potassium carbonate. The alcohol
is elaborated to a tosylate (1) by treatment with p-toluenesulfonyl
chloride and a tertiary amine base or to a bromide by treatment.
Alternatively (b), the substituted salicylaldehyde (8) may be
protected with a suitable protecting group such as benzyl and the
aldehyde (9) converted to a phenol (10) as described above.
Following elaboration of the phenol to the glycidyl ether (11) by
treatment with an epihalohydrin or glycidyl arylsulfonate,
deprotection and cyclization are effected in a single step via a
transfer hydrogenation in the presence of sodium bicarbonate. The
bromide or tosylate is prepared as described above. Or the
benzodioxan methylbromide may be prepared from a suitably
substituted guaiacol (12) by procedure (c) shown above. The guiacol
is alkylated with a glycidyl arylsulfonate or an epihalohydrin as
described above. The methyl ether (13) is then cleaved by treatment
with 48% HBr; this also converts the epoxide to a bromohydrin (14).
Cyclization directly to the benzodioxan methylbromide (1) is
effected by the Mitsonobu procedure.
##STR00007## ##STR00008##
[0060] The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines
of the invention in which R.sup.4 is H are alternatively prepared
as illustrated in Scheme 4 below. Specifically, the appropriately
substituted nitroguaiacol (15) 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 (17) 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 (19) 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 20
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 (21) or
halide. Replacement of the tosylate or halide with the
appropriately substituted piperidine in some high boiling solvent
such as dimethyl sulfoxide gives the title compounds of the
invention.
##STR00009##
[0061] The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines
of the invention in which R.sup.4 is alkyl may be prepared from the
nitro olefin described above in the following manner (Scheme 5).
The rearranged olefin (20) is treated sequentially with ozone and a
tertiary amine or with osmium tetroxide and sodium periodate to
give the o-nitrobenzaldehyde (22). Condensation with the
appropriate triphenylphosphorylidene ketone under Wittig conditions
gives the o-nitrocinnamyl ketone (23), which upon reduction by iron
in acetic acid, cyclizes to the corresponding
2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyltosylate (24).
Replacement of the tosylate with the appropriately substituted
piperidine 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
R.sup.4 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 R.sup.4 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
R.sup.4 is amino.
##STR00010##
[0062] Compounds of the invention in which R.sup.1 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 6 below. The appropriately
substituted benzodioxan methyltosylate (25) is nitrated under
standard conditions with nitric acid in a solvent such as
dichloroethane and the resulting nitro compound (26) reduced by
treatment with hydrogen in the presence of a catalyst such as
platinum on sulfide carbon. Treatment of the resulting aniline (27)
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 (28). Replacement of the
tosylate with the appropriately substituted piperidine as above
gives the title compounds of the invention.
##STR00011##
[0063] The
2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of the
invention are prepared as illustrated below (Scheme 7). The
o-nitrobenzaldehyde (22) described above is converted to the oxime
(29) 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 (30) 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 piperidine in
some high boiling solvent such as dimethyl sulfoxide gives the
title compounds of the invention.
##STR00012##
[0064] 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 8 below. The nitro
olefin (20) 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 (31) is then
converted to the aldehyde (32) 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 (30) or
halide is effected by treatment of the amido aldehyde (32) with
ammonia and replacement of the tosylate or halide with the
appropriately substituted piperidine in some high boiling solvent
such as dimethyl sulfoxide as described above gives the title
compounds of the invention.
##STR00013##
[0065] The
2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-ylmethylamines of the
invention are prepared as illustrated in Scheme 9 below. The
o-nitrobenzaldehyde (22) described above is oxidized to the
o-nitrobenzoic acid (33) by a suitable oxidant such as chromium
trioxide (Jones' oxidation) or sodium chlorite and the acid
converted to the o-nitroaniline (34) with diphenylphosphoryl azide
(DPPA) in the presence of a tertiary base such as
diisopropylethylamine. Reduction of the resulting nitroaniline to
the diamine (35) 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 (36) or
halide. Replacement of the tosylate or halide with the
appropriately substituted piperidine in some high boiling solvent
such as dimethyl sulfoxide gives the title compounds of the
invention.
##STR00014##
[0066] The o-nitrobenzaldehyde (22) used in the chemistry described
above may be alternatively prepared as shown in scheme 10 below.
The appropriate mono-allylated catechol (37) is elaborated with
glycidyl tosylate as described above and rearranged in refluxing
mesitylene. Cyclization to the benzodioxan methanol (39) is
effected by treatment with sodium bicarbonate in ethanol and the
alcohol is converted to the tosylate (40) 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 (41) is regioselectively nitrated with a combination of
nitric acid and tin (IV) chloride.
##STR00015##
[0067] 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 (31) described in Scheme B is cleaved to the
corresponding o-amidobenzaldehyde (32) by treatment with catalytic
osmium tetroxide in the presence of sodium periodate. The aldehyde
is converted to the phenol (42) 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
(43) 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 piperidine in some high boiling
solvent such as dimethyl sulfoxide gives the title compounds of the
invention.
##STR00016##
[0068] Alternatively (Scheme 12), the nitro olefin (20) may be
reduced with tin (II) chloride as described in Scheme 8 above and
protected with a suitable protecting group such as carbobenzoxy
(Cbz) before the olefin is cleaved to the aldehyde (45) by
treatment with osmium tetroxide/sodium periodate and the aldehyde
converted to a phenol (46) by the Baeyer-Villager procedure.
Deprotection by treatment with hydrogen over palladium on carbon
gives the o-aminophenol, (47) which is cyclized to the
7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (43) 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 R.sup.4 is amino. Treatment of the o-aminophenol
with carbonyl diimidazole gives the oxazolone that leads to
compounds of the invention in which R.sup.4 is halo via treatment
with an inorganic anhydride such as phosphoryl chloride or bromide.
Replacement of the tosylate with the appropriately substituted
piperidine as above gives the title compounds of the invention.
##STR00017##
[0069] Compounds of the invention in which R.sup.1 is hydrogen and
R.sup.4 is alkyl are most conveniently prepared according to scheme
13 below. The appropriate 2',3',4'-trihydroxyacylphenone (48) 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 (49).
Following conversion of the ketone to the oxime (50) by reaction
with hydroxylamine hydrochloride and sodium acetate, cyclization to
the oxazole (51) 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 (52) by treatment with
p-toluenesulfonyl chloride in pyridine and combined with the
appropriate piperidine as described above to give the title
compounds of the invention.
##STR00018##
[0070] The
7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenes of the
invention are prepared as illustrated in Scheme 14 below. The
diamine 35 described in Scheme 9 is cyclized by treatment at reflux
with the appropriate carboxylic acid to give the imidazole (53).
Refluxing the diamine dihydrochloride in higher boiling carboxylic
acids occasionally causes replacement of a tosylate group with a
chloride. Replacement of the tosylate or halide with the
appropriately substituted piperidine in some high boiling solvent
such as dimethyl sulfoxide gives the
7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenes of the
invention in which R.sup.7 is hydrogen, perfluoroalkyl or alkyl.
Treatment of the diamine described above with cyanogen bromide or
chloride or a suitably substituted carbamoyl chloride leads to
compounds of the invention in which R.sup.7 is amino. Treatment of
the diamine with carbonyl diimidazole gives the imidazolone which
leads to compounds of the invention in which R.sup.7 is halo via
treatment with an inorganic anhydride such as phosphoryl chloride
or bromide. Replacement of the tosylate with the appropriately
substituted piperidine as above gives the title compounds of the
invention.
##STR00019##
[0071] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the
invention are prepared as illustrated in Scheme 15 below.
Specifically, the primary alcohol (19) from the Claisen
rearrangement described in Scheme 4 is converted to the tosylate
(54) 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
cleaved to the aldehyde (55) by treatment with ozone at low
temperature, followed by work-up with a tertiary base such as
diisopropylethylamine or triethylamine, or by treatment with
catalytic osmium tetroxide and sodium periodate. Reduction of the
nitro group with hydrogen over platinum oxide leads directly to
formation of the indole (56) in which R.sup.8 is hydrogen.
Alternatively, the aldehyde may be treated with an appropriate
alkyl Grignard reagent or with trifluoromethyl trimethylsilane in
the presence of cesium fluoride, then oxidized to a ketone with a
suitable oxidant such as pyridinium chlorochromate (PCC) or the
Swern reagent and reduced with hydrogen over platinum oxide to give
the indoles in which R.sup.8 is alkyl or trifluoromethyl.
Replacement of the tosylate or halide with the appropriately
substituted piperidine in some high boiling solvent such as
dimethyl sulfoxide gives the title compounds of the invention.
##STR00020##
[0072] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the
invention may alternatively be prepared from nitroaldehyde 21 by
the following procedure (Scheme 16). The o-nitrobenzaldehyde (22)
is condensed with the appropriate nitroalkane in the presence of a
suitable base catalyst to yield the corresponding
o,.beta.-dinitrostyrene (57). Reduction of both nitro groups with
hydrogen over palladium on carbon is accompanied by cyclization to
form the indole (58). Replacement of the tosylate with the
appropriately substituted piperidine as above gives the title
compounds of the invention.
##STR00021##
[0073] 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.
[0074] In yet another method, the heterocycle-fused benzodioxans of
the present invention may be prepared in accordance with Scheme 17.
The synthesis of compound I is comprised of steps that begin with
halogenation of 59 where R' is alkyl of 1-6 carbon atoms, with
reagents such as N-halosuccinimide in acetonitrile to give 60
(where Hal is halogen such as Br, Cl or I). Deprotecting 60 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 HCl gives the salt 61. Free base 61 may be
obtained by neutralization with an Amberlyst A-21 resin slurry in
polar solvents such as ethanol or methanol.
[0075] Alkylation of 61, either as the free base or as the salt,
with benzyl or substituted benzyl protected glycidyl ethers (
##STR00022##
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 62. 62 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 t-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
63.
##STR00023##
[0076] Deprotection of quinoline 63 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 HCl
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 64. The hydroxyl moiety of 64 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 65 where R''' is a sulfonate such as p-toluenesulfonate,
methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2- or
4-bromobenzenesulfonate. The final coupling of 65 with piperidines
appropriate to the invention, in the presence of bases such as
Hunia's base (diisopropylethylamine), potassium carbonate, or
sodium carbonate in polar solvents such as THF, dioxane, DMSO, DMF,
or DMA affords the compounds of the invention 1.
[0077] The phenols, 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 appropriately substituted
piperidines and tetrahydropyridines are known compounds or can
readily be prepared by one schooled in the art, for example as
illustrated in Scheme 18 below for
4-(7-methoxybenzofuran-3-yl)-1,2,3,6-tetrahydropyridine. The
appropriately substituted benzofuranone (66) is converted to the
triflate (67) by treatment with triflic anhydride and a tertiary
base such as triethylamine. Conversion to the dioxaborolane (68) is
effected by treatment with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane
in the presence of a tertiary base and a suitable palladium
catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium
(II) chloride. The dioxaborolane (68) is coupled with the
appropriately protected azaheterocyclic triflate under Suzuki
conditions involving a palladium catalyst such as
tetrakis(triphenylphospine)palladium(0) to give (69), which
following deprotection affords the substituted tetrahydropyridine
(70) suitable for production of certain of the compounds of the
invention. Reduction of the double bond in 70 by hydrogenation over
a catalyst such as palladium on carbon gives the substituted
piperidine, which is needed for the production of still other
compounds of the invention.
##STR00024##
[0078] The substituted pyridines appropriate to Scheme 2 are known
compounds or may be readily prepared by one schooled in the art by
the method illustrated for 4-benzo[b]thiophen-7-yl-pyridine in
Scheme 19 below. The suitably substituted bromobenzothiophene or
bromobenzofuran (71) may be coupled with pyridine-4-boronic acid
under Suzuki conditions involving a palladium catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride to
give intermediates (72) useful for the production of the compounds
of the invention.
##STR00025##
[0079] 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 .sup.3H-paroxetine from male rat
frontal cortical membranes was determined using a Tom Tech
filtration device to separate bound from free .sup.3H-paroxetine
and a Wallac 1205 Beta Plates counter to quantitate bound
radioactivity. K.sub.i'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 .sup.3H-paroxetine binding in rat frontal cortex and
3H-serotonin uptake inhibition.
[0080] High affinity for the serotonin 5-HT.sub.1A receptor was
established by testing the claimed compound's ability to displace
[.sup.3H] 8-OHDPAT (dipropylaminotetralin) from the 5-HT.sub.1A
serotonin receptor following a modification of the procedure of
Hall et al., J. Neurochem. 44, 1685 (1985) which utilizes CHO cells
stably transfected with human 5-HT.sub.1A receptors. The
5-HT.sub.1A affinities for the compounds of the invention are
reported below as K.sub.i's.
[0081] Antagonist activity at 5-HT.sub.1A receptors was established
by using a .sup.35S-GTP.gamma.S 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
.sup.35S-GTP.gamma.S to membranes containing cloned human
5-HT.sub.1A 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
I.sub.max, while its potency is defined by the IC.sub.50.
[0082] The results of the three standard experimental test
procedures described in the preceding three paragraphs were as
follows:
TABLE-US-00001 5-HT Transporter 5-HT.sub.1A Affinity Receptor
Affinity 5-HT.sub.1A Function Compound KI (nM) KI (nM) IC.sub.50
(nM) (I.sub.max) Example 1 9.25 4.89 498.5 (100) Example 2 78.00
21.59 Example 3 18.50 15.88 436.6 (87.4) Example 4 70.00 2.66 167.3
(91.0) Example 5 35.00 23.43 1000.0 (30.0) Example 6 8.50 14.53
145.5 (100) Example 7 2.48 4.74 25.8 (100) Example 8 33.00 3.45
146.9 (100) Example 9 13.00 20.20 1978.0 (50.0) Example 10 10.00
34.87 391.9 (40.5) Example 11 213.00 15.71 15530.0 (70.0) Example
12 109.00 8.67 589.6 (100) Example 13 94.00 134.90 2516.0 (100)
Example 14 17.00 19.75 166.8 (100)
[0083] Like the antidepressants fluoxetine, paroxetine and
sertraline, the compounds of this invention have the ability to
potently block the reuptake of the brain neurotransmitter
serotonin. They are thus useful for the treatment of diseases
commonly treated by the administration of serotonin selective
reuptake inhibitor (SSRI) antidepressants, such as 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
pre-menstrual syndrome), attention deficit disorder (with and
without hyperactivity), obsessive compulsive disorders (including
but not limited to trichotillomania), obsessive compulsive spectrum
disorders (including but not limited to autism), social anxiety
disorder, generalized anxiety disorder, obesity, eating disorders
such as anorexia nervosa and 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 related illnesses. Moreover, the compounds of
this invention have potent affinity for and antagonist activity at
brain 5HT.sub.1A serotonin receptors. Recent clinical trials
employing drug mixtures (eg, fluoxetine and pindolol) have
demonstrated a more rapid onset of antidepressant efficacy for a
treatment combining SSRI activity and 5HT.sub.1A antagonism (Blier
and Bergeron, 1995; F. Artigas et al., 1996; M. B. Tome et al.,
1997). The compounds of the invention are thus exceedingly
interesting and useful for treating depressive illnesses.
[0084] 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.
[0085] 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.
[0086] 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.
[0087] 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 solubilizers, 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] The present invention includes prodrugs of compounds of
Formula I, Ia 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, et 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).
[0093] The following examples illustrate the production of
representative compounds of this invention.
INTERMEDIATE 1
3-Allyloxy-4-methoxynitrobenzene
[0094] 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.degree. C. for two hours,
after which time much of the dark color had discharged and tlc (1:1
CH.sub.2Cl.sub.2/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.degree. C.
INTERMEDIATE 2
2-Allyloxy-4-nitrophenol
[0095] To one liter of dimethyl sulfoxide was added 750 mL of 2 N
aqueous sodium hydroxide and the mixture was heated to 65.degree.
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.degree. 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 HCl. 73 Grams of crude but homogeneous (by tlc 1:1
CH.sub.2Cl.sub.2/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.degree. 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 CH.sub.2Cl.sub.2/hexane gave an additional 12 g of the title
compound as a yellow solid. Elution with 2% MeOH in CHCl.sub.3 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-Allyloxy-4-nitrophenoxymethyl)-oxirane
[0096] 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.degree. 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 HCl, 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 tlc with 1:1 hexane/methylene chloride)
(R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64.degree.
C.).
[0097] Elemental Analysis for: C.sub.12H.sub.13NO.sub.5
[0098] Calc'd: C, 57.37; H, 5.21; N, 5.58
[0099] Found: C, 57.50; H, 5.21; N, 5.43
INTERMEDIATE 4
(8-Allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol
[0100] (R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80
mmoles) prepared as above was heated at 155.degree. 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.degree.
C.). The yield based on recovered starting material is 75%.
[0101] Elemental Analysis for: C.sub.12H.sub.13NO.sub.5
[0102] Calc'd: C, 57.37; H, 5.21; N, 5.58
[0103] Found: C, 57.26; H, 5.20; N, 5.35
INTERMEDIATE 5
Toluene-4-sulfonic acid
8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester
[0104] 9.55 g (38.0 mmole) 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 mmole) of
p-toluenesulfonyl chloride was added and the mixture stirred at
room temperature under nitrogen overnight. Water was then added to
quench the excess tosyi chloride and the solvent was removed in
vacuum and replaced with methylene chloride. This solution was
washed with 2 N HCl, 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.degree. C.) upon
standing.
[0105] Elemental Analysis for: C.sub.19H.sub.19NO.sub.7S
[0106] Calc'd: C, 56.29; H, 4.72; N, 3.45
[0107] Found: C, 56.13; H, 4.58; N, 3.44
INTERMEDIATE 6
{7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl
4-methylbenzenesulfonate
[0108] To a solution of 10.0 g (24.0 mmole) 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
eluant 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.degree. C.) by evaporation of a pure E isomer-containing
fraction.
[0109] Elemental Analysis for: C.sub.19H.sub.19NO.sub.7S
[0110] Calc'd: C, 56.29; H, 4.72; N, 3.45
[0111] Found: C, 56.12; H, 4.64; N, 3.39
INTERMEDIATE 7
{7-Nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl
4-methylbenzenesulfonate
[0112]
{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methy-
l 4-methyl benzenesulfonate (6.15 g, 15.2 mmole) was dissolved in
180 mL of dioxane. Selenium dioxide (4.20 g, 37.9 mmole) 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.degree. C.).
[0113] Elemental Analysis for: C.sub.19H.sub.17NO.sub.8S
[0114] Calc'd: C, 54.41; H, 4.09; N, 3.34
[0115] Found: C, 54.10; H, 3.85; N, 3.31
INTERMEDIATE 8
2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl
4-methylbenzenesulfonate
[0116] To a solution of
{(2R)-7-nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methy-
l 4-methylbenzenesulfonate (3.50 g, 8.35 mmole) in 200 mL of acetic
acid/ethanol (1:1) was added 2.35 g (42.1 mmole) 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. .sup.1H-NMR (CDCl.sub.3): doublet 8.8
.delta. (1H); doublet 8.2 .delta. (1H); doublet 7.8 .delta. (2H);
doublet 7.6 .delta. (1H); multiplet 7.35 .delta. (1H); multiplet
7.25 .delta. (3H); multiplet 4.6 .delta. (1H); multiplet 4.3-4.4
.delta. (3H); multiplet 4.2 .delta. (1H); singlet 2.4 .delta.
(3H).
INTERMEDIATE 9
(8-Formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl
4-methylbenzenesulfonate
[0117]
{(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methy-
l 4-methyl benzenesulfonate (10.5 g, 25.9 mmole) dissolved in 400
mL of methylene chloride was treated with excess ozone at
-78.degree. C. Diisopropylethylamine (11.5 mL, 66.0 mmole) 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 HCl (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. .sup.1H-NMR (CDCl.sub.3):
doublet 7.8 .delta. (2H); doublet 7.62 .delta. (1H); doublet 7.4
.delta. (2H); doublet 7.0 .delta. (1H); multiplet 4.4-4.6 .delta.
(2H); multiplet 4.2 .delta. (3H); singlet 2.4 .delta. (3H).
INTERMEDIATE 10
{7-Nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl
4-methylbenzenesulfonate
[0118] To a solution of 3.00 g (7.37 mmole) of
[(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl
4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g
(9.10 mmole) 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.
.sup.1H-NMR (CDCl.sub.3): doublet 7.8 .delta. (2H); doublet 7.6
.delta. (1H); doublet 7.5 .delta. (2H); doublet 7.4 .delta. (2H);
doublet 6.95 .delta. (1H); doublet 6.6 .delta. (1H); multiplet 4.5
.delta. (1H); doublet of doublets 4.0 .delta. (1H); multiplet 4.2
.delta. (3H); singlet 2.45 .delta. (3H); singlet 2.4 .delta.
(3H).
INTERMEDIATE 11
(8-Methyl-2,3-dihydro[1,4]dioxino[2,3-]quinolin-2-yl)methyl
4-methylbenzenesulfonate
[0119] To a solution of
{(2R)-7-nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}me-
thyl 4-methylbenzenesulfonate (3.40 g, 7.83 mmole) in 200 mL of
acetic acid/ethanol (3:2) was added 2.25 g (40.2 mmole) 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. .sup.1H-NMR (CDCl.sub.3): doublet 8.1
.delta. (1H); doublet 7.6 .delta. (2H); doublet 7.45 .delta. (1H);
multiplet 7.2 .delta. (4H); multiplet 4.6 .delta. (1H); multiplet
4.3 .delta. (3H); multiplet 4.1 .delta. (1H); singlet 2.5 .delta.
(3H); singlet 2.4 .delta. (3H).
INTERMEDIATE 12
[7-Nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl
4-methylbenzenesulfonate
[0120] A solution of 4.2 g (10 mmole) of toluene-4-sulfonic acid
(2R)-8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester
in 400 mL of methylene chloride was cooled in a dry ice/isopropanol
bath and saturated with ozone. It was then purged with oxygen and
2.6 g (20 mmole) of diisopropylethylamine added. The mixture was
allowed to come to room temperature and stirred under nitrogen for
24 hours. It was then washed with 300 mL portions of 2 N HCl (aq),
water and saturated brine, dried over magnesium sulfate, filtered
and concentrated in vacuum to give 3.8 g of the (R)-enantiomer of
the title compound as a white solid one-quarter hydrate, m.p.
116-120.degree. C.
[0121] Elemental Analysis for:
C.sub.18H.sub.17NO.sub.8S.0.25H.sub.2O
[0122] Calc'd: C, 52.49; H, 4.28; N, 3.40
[0123] Found: C, 52.33; H, 3.92; N, 3.36
INTERMEDIATE 13
2,3-Dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl
4-methylbenzenesulfonate
[0124] A mixture of 3.75 g (9.2 mmole) of
[(2R)-7-nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl
4-methylbenzenesulfonate and 3.0 g of platinum oxide in 50 mL of
ethyl acetate was treated with 45 psi of hydrogen on a Parr
hydrogenation apparatus for 6 hours. The mixture was then filtered
through celite and concentrated in vacuum. The residue was column
chromatographed on silica gel with first 10% hexane/methylene
chloride, then 1% methanol/methylene chloride and finally 2%
methanol/methylene chloride to give 1.50 g of the (R)-enantiomer of
the title compound as a white solid one-quarter hydrate, m.p.
145.degree. C.
[0125] Elemental Analysis for:
C.sub.18H.sub.17NO.sub.5S.0.25H.sub.2O
[0126] Calc'd: C, 59.41; H, 4.85; N, 3.85
[0127] Found: C, 59.41; H, 4.57; N, 3.72
INTERMEDIATE 14
1-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanon-
e
[0128] To a solution of 2',3',4'-trihydroxyacetophenone (10.6 g,
63.0 mmole) in DMF (75 mL) was added potassium carbonate (17.4 g,
126 mmole). After 5 minutes (R)-glycidyl tosylate (9.67 g, 42.3
mmole) was added, then the heterogeneous mixture was heated to
70.degree. 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.times.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).sup.-.
[0129] Elemental Analysis for:
C.sub.11H.sub.12O.sub.5.0.10H.sub.2O
[0130] Calc'd: C, 58.46; H, 5.44
[0131] Found: C, 58.02; H, 5.09
INTERMEDIATE 15
1-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanon-
e oxime
[0132] A solution of hydroxylamine hydrochloride (2.38 g, 34.2
mmole) 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-e-
thanone (1.92 g, 8.57 mmole) 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 HCl (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.degree. C. MS (ESI) m/z 240
(M+H).sup.+.
[0133] Elemental Analysis for:
C.sub.11H.sub.13NO.sub.5.0.35H.sub.2O
[0134] Calc'd: C, 53.81; H, 5.62; N, 5.71
[0135] Found: C, 53.51; H, 5.30; N, 5.58
INTERMEDIATE 16
[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]-benzoxazol-8-yl]methanol
[0136] 3.03 g (12.6 mmole) of
1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-e-
thanone 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 mmole) in 1:3
N,N-dimethylacetamide/acetonitrile (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.degree. C. MS (ESI) m/z 222
(M+H).sup.+.
[0137] Elemental Analysis for:
C.sub.11H.sub.11NO.sub.4.0.20H.sub.2O
[0138] Calc'd: C, 58.77; H, 5.11; N, 6.23
[0139] Found: C, 58.93; H, 4.91; N, 6.14
INTERMEDIATE 17
[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl
4-methylbenzenesulfonate
[0140] To a solution of
[(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methano-
l (1.80 g, 8.14 mmole) in methylene chloride (100 mL) was added
p-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was
cooled in an ice bath and a solution of diisopropylethylamine (3.55
mL, 20.4 mmole) in methylene chloride (20 mL) was then added
dropwise, followed by 4-dimethylaminopyridine (0.65 g, 5.30 mmole).
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
HCl (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.degree. C. MS (ESI) m/z 376
(M+H).sup.+.
[0141] Elemental Analysis for:
C.sub.18H.sub.17NO.sub.6S.0.20H.sub.2O
[0142] Calc'd: C, 57.04; H, 4.63; N, 3.70
[0143] Found: C, 56.75; H, 4.62; N, 3.51
INTERMEDIATE 18
5-Bromo-6-methoxy-2-methylquinoline
[0144] A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol)
in acetonitrile (1.77 L) was cooled to 0-3.degree. C. followed by
portion-wise addition of N-bromo-succinimide (200 n, 1.12 mol) over
a period of 30 mm while maintaining the same temperature. The
resulted brown slurry was warmed to ambient temperature and stirred
for an additional 6 h. The reaction was then quenched by a 10%
NaHSO.sub.3 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 h then filtered, washed with water (2.times.1 L) and dried in a
vacuum oven to give 253 g (98.6%) of the title compound as a brown
solid. R.sub.f=0.39 (3:7) EtOAc:heptane; .sup.1H NMR (DMSO) .delta.
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);
[0145] Elemental Analysis for: C.sub.11H.sub.10NOBr
[0146] Calc'd: C, 52.40; H, 3.97; N, 5.56
[0147] Found: C, 52.13; H, 3.94; N, 5.61
INTERMEDIATE 19
5-Bromo-2-methyl-6-quinolinol
[0148] 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 h then cooled
to 5.degree. C. in 1 h to give a brown and thick slurry. The slurry
was stirred at 0-5.degree. C. for 1 h then filtered, washed with
EtOAc (2.times.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.
.sup.1H NMR (DMSO) .delta. 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.sub.f=0.36 (1:1) EtOAc:heptane; .sup.1H
NMR (DMSO) .delta. 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-(Benzyloxy)-3-[(5-bromo-2-methyl-6-quinolinyl)oxy]-2-propanol
[0149] 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.degree. 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.sub.f=0.35 (EtOAc); .sup.1H NMR (DMSO) .delta. 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=8.7 Hz, 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.degree. (c=1,
CH.sub.3OH);
[0150] Elemental Analysis for: C.sub.20H.sub.20BrNO.sub.3
[0151] Calc'd: C, 59.66; H, 4.97N, 3.48
[0152] Found: C, 59.43; H, 4.97; N, 3.55
INTERMEDIATE 21
(2S)-2-[(Benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0153] To a mixture of
(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxy]-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.degree. C. over 20 min. The reaction mixture was kept at
35.degree. C. for 30 minutes then heated to 110.degree. C. slowly.
After 30 minutes, the reaction was cooled to 60.degree. C.,
additional NaH (10.9 g, 0.45 mol) was added. This was warmed to
110.degree. C. 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.times.50 mL) and water (50 mL). The two layers were
separated. The organic layer was extracted with water (100 mL),
NH.sub.4OH (100 mL), 25% NaCl (100 mL) and concentrated in vacuo to
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
[(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methanol
[0154] 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 N.sub.2 for 18 h 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.
[0155] .sup.1H NMR (CD.sub.3OD) .delta. 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
[(2R)-8-Methyl-2,3-Dihydro[1,4]-Dioxino[2,3-f]quinolin-2-yl]Methyl
4-Bromobenzenesulfonate
[0156] A solution of
[(2S)-8-methyl-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.degree. C. for
6 h. The reaction mixture was cooled to room temperature then water
(20 mL) was added. After 30 min, the two layers were separated. The
organic layer was extracted with 8% NaHCO.sub.3 (20 mL) and
H.sub.2O (20 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The solid obtained was dissolved in
isopropyl alcohol (50 mL) and toluene (10 mL) at 80.degree. C.,
cooled to room temperature over 1 h then filtered, washed with
(5:1) IPA: toluene (2.times.5 mL) and dried in a vacuum oven to
give 5.99 g (76.9%) of the title compound as an off-white solid.
.sup.13C NMR (CDCl.sub.3) .delta. 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
EXAMPLE 1
2-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-8-methyl-2,3-
-dihydro-[1,4]dioxino[2,3-f]quinoline
[0157] To a mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-toluenesulfonate (0.87 g, 2.3 mmol) and
4-benzo[b]thiophen-3-yl-1,2,3,6-tetrahydro-pyridine (0.48 g, 2.2
mmol) was added 3 mL of dimethylsulfoxide. The mixture was stirred
at 97.degree. C. for 18 hours. The solvent was evaporated under
reduced pressure. The residue was partitioned between 500 mL each
of methylene chloride and saturated aqueous sodium bicarbonate. The
methylene chloride layer was washed once with 500 mL of water and
dried over anhydrous magnesium sulfate. Filtration and
concentration in vacuum gave 0.91 g of oil. This was
chromatographed on silica gel with a gradient of ethyl acetate and
hexane. The product fractions were collected to give 0.059 g of the
free base as pure, yellow oil. This was dissolved in ethanol and
heated. Oxalic acid dihydrate (0.0125 g, 0.0991 mmol) in ethanol
was added. After the mixture had cooled, filtration gave 0.0619 g
of the S enantiomer of the title compound as an orange oxalate
salt, m.p. 129-133.degree. C.
[0158] Elemental Analysis for:
C.sub.26H.sub.24N.sub.2O.sub.2S.C.sub.2H.sub.2O.sub.4.2/3H.sub.2O
[0159] Calc'd: C, 63.38; H, 5.19; N, 5.28
[0160] Found: C, 63.48; H, 4.97; N, 5.08
EXAMPLE 2
2-(4-Benzo[b]thiophen-2-yl-3,6-dihydro-2H-Pyridin-1-yl
methyl)-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0161] To a mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-toluenesulfonate (0.638 g, 1.66 mmol) and
4-benzo[b]thiophen-2-yl-1,2,3,6-tetrahydro-pyridine (0.46 g, 2.1
mmol) was added 12 mL of dimethylsulfoxide. The mixture was stirred
at 90.degree. C. for 18 hours. The solvent was evaporated under
reduced pressure. The residue was partitioned between 500 mL each
of methylene chloride and saturated aqueous sodium bicarbonate. The
methylene chloride layer was washed with water twice and dried over
anhydrous magnesium sulfate. Evaporation of the solvent gave 0.98 g
of oil. This was chromatographed on silica gel with a gradient of
ethyl acetate and hexane. The product fractions were collected and
concentrated in vacuum to give 0.39 g of the title compound as
nearly pure, light yellow oil. This was triturated with ethanol to
give 0.2563 g of the S enantiomer of the title compound as a light
yellow solid, m.p. 174-176.degree. C.
[0162] Elemental Analysis for:
C.sub.26H.sub.24N.sub.2O.sub.2S.1/4H.sub.2O
[0163] Calc'd: C, 72.11; H, 5.70; N, 6.47
[0164] Found: C, 72.01; H, 5.42; N, 6.32
EXAMPLE 3
2-[4-(5-Fluoro-benzo[b]thiophen-3-yl)-3,6-dihydro-2H-Pyridin-1-ylmethyl]-8-
-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0165] To a solution of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-toluenesulfonate (0.50 g, 1.1 mmol),
4-(5-fluoro-benzo[b]thiophen-3-yl)-1,2,3,6-tetrahydropyridine (0.35
g, 1.5 mmol), 21 mL of THF and 21 mL of DMF was added NaHCO.sub.3
(0.45 g, 5.4 mmol. The mixture was stirred at reflux for 18 hours.
The solvent was removed in vacuum and the residue partitioned
between 500 mL each of methylene chloride and water. The methylene
chloride layer was washed with water 3 times and dried over
anhydrous magnesium sulfate. Filtration and concentration in vacuum
gave 0.62 g of dark oil. This was chromatographed on silica gel
with a gradient of ethyl acetate and hexane to give 0.12 g of the
free base as a pure light yellow oil. The oil was dissolved in
ethanol and added to a solution of oxalic acid dihydrate (0.0400 g,
0.317 mmol) in ethanol. Filtration gave 0.0871 g of the S
enantiomer of the title compound as a yellow oxalate, m.p.
197-201.degree. C.
[0166] Elemental Analysis for:
C.sub.26H.sub.23FN.sub.2O.sub.2S.C.sub.2H.sub.2O.sub.4.2H.sub.2O
[0167] Calc'd: C, 58.73; H, 5.10; N, 4.89
[0168] Found: C, 58.78; H, 4.46; N, 4.63
INTERMEDIATE 24
Trifluoro-methanesulfonic acid 7-methoxy-benzofuran-3-yl ester
[0169] To a cold solution (-20.degree. C.) of 3.3 g (20 mmol)
7-methoxy-benzofuranone in 30 mL methylene chloride was added 8.3
mL (6.0 mmol) of triethylamine. To the cold mixture, a solution of
8.5 g (30 mmol) of triflic anhydride in 20 ml of methylene chloride
was added dropwise. The temperature was kept at -20.degree. C. or 1
hour. The reaction was then quenched with 100 mL of saturated
aqueous sodium bicarbonate and extracted with methylene chloride
(2.times.150 mL). The combined organic extracts were dried over
magnesium sulfate and concentrated in vacuum to give 5.6 g of the
desired product. MS (ES) m/z (relative intensity): 265 (M+H,
100);
INTERMEDIATE 25
2-(7-Methoxybenzo[b]furan-3-yl0-4,4,5,5-tetramethyl-[1,2]oxaborolane
[0170] To a mixture of trifluoro-methanesulfonic acid
7-methoxy-benzofuran-3-yl ester (0.660 g, 2.23 mmol)) in
triethylamine (1 ml) was added first 3.75 mL (3.75 mmol) of 1 N
pinacoleborane in THF followed by 0.10 g of
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
chloride/methylene chloride 1:1 complex. The reaction was heated at
150.degree. C. for 3 minutes in the microwave. The solvent was
removed under vacuum. The residue was taken up in 300 mL of water
and extracted with ether (2.times.200 mL). The combined organic
extracts were dried over magnesium sulfate, filtered and the
solvent removed in vacuum. The residue was filtered through 50 mL
of silica gel using 10% ethyl acetate/hexane to give 0.350 g of the
title compound. .sup.1H NMR (300 MHz, CDCl.sub.3); .delta. 1.36 (s,
12H), 4.01 (s, 3H), 6.81 (d, 1H), 7.18 (t, 1H), 7.52 (d, 1H), 7.95
(s, 1H).
INTERMEDIATE 26
4-(7-Methoxy-benzofuran-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester
[0171] To a solution of
2-(7-methoxybenzo[b]furan-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane
(1.10 g, 4.0 mmol) in dimethoxyethane (1 mL) was added CsCO.sub.3
(0.650 g, 2.0 mmol), H.sub.2O (1 mL),
4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (0.480 g, 1.45 mmol), LiCl (0.10 g, 2.4 mmol)
and tetrakis(triphenylphosphine)palladium (0) (0.06 g, 0.05 mmol).
The reaction was heated in the microwave for 5 min at 150.degree.
C. The solvent was removed in vacuum, the residue taken up in 300
mL of methylene chloride, washed with 200 mL portions of saturated
aqueous sodium carbonate and 1 N NH.sub.4OH (aq), dried over
anhydrous sodium sulfate, filtered and concentrated in vacuum. The
residue was filtered through 150 mL of silica gel with 15% ethyl
acetate/hexane as eluant to give 0.50 g of the title compound.
.sup.1H NMR (300 MHz, CDCl.sub.3); .delta. 1.5 (s, 9H), 2.51 (t,
2H), 3.66 (t, 2H), 4.04 (s, 3H), 4.12 (dd, 2H), 6.24 (br s, 1H),
6.91 (d, 1H), 7.17 (t, 1H), 7.39 (d, 1H), 7.59 (s, 1H), MS (ES) m/z
(relative intensity): 330 (M+H, 100).
INTERMEDIATE 27
4-(7-Methoxy-benzofuran-3-yl)-1,2,3,6-tetrahydro-pyridine
[0172] To a solution of
4-(7-methoxy-benzofuran-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (0.50 g, 1.5 mmol) in methylene chloride (10
mL), was added dropwise a solution of TFA (1 mL) in methylene
chloride (5 mL). The reaction was stirred at room temperature for
one hour, then was diluted with 250 mL of methylene chloride,
washed with 1 N NaOH (100 mL) and with saturated brine, dried over
magnesium sulfate, filtered and concentrated in vacuum to give 0.30
g of the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3); .delta.
2.5 (t, 2H), 3.19 (t, 2H), 3.64 (dd, 2H), 4.01 (s, 3H), 6.30 (br s,
1H), 7.10 (d, 1H), 7.21 (t, 1H), 7.52 (d, 1H), 7.64 (s, 1H); MS
(ES) m/z (relative intensity): 230 (M+H, 100).
EXAMPLE 4
2-[4-(7-Methoxy-benzofuran-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8-meth-
yl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0173] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate ester (0.173 g, 0.38 mmol),
4-(7-methoxybenzofuran-3-yl)-1,2,3,6-tetrahydropyridine (0.10 g,
0.44 mmol) and potassium carbonate (0.145 g, 1.0 mmol) in 2 mL of
N,N-dimethylformamide was stirred under nitrogen at room
temperature for 2 days and then at 60.degree. C. for 6 hours. Water
was added and the resulting precipitate was filtered, dried and
column chromatographed on 100 mL of silica gel using first 50%
ethyl acetate in hexane and then 75% ethyl acetate/hexane as
eluant. Combination and concentration of the product fractions gave
0.015 g of the S enantiomer of the title compound as a yellow
solid.
[0174] MS (ESI) m/z 443 (M+H).sup.+.
EXAMPLE 5
2-[4-(5-Fluoro-benzo[b]thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2-
,3-dihydro-[1.4]dioxino[2,3-f]quinoline
[0175] To a solution
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-toluenesulfonate (0.51 g, 1.4 mmol),
4-(5-fluoro-benzo[b]thiophen-3-yl)-1,2,3,6-tetrahydro-pyridine
(0.39 g, 1.7 mmol), 24 mL of THF and 24 mL of DMF was added
NaHCO.sub.3 (0.50 g, 5.9 mmol). The mixture was stirred and heated
at reflux for 18 hours. The solvents were evaporated in vacuum and
the residue was partitioned between 500 mL portions of ethyl
acetate and water. The ethyl acetate layer was washed with water
and dried over anhydrous magnesium sulfate. Filtration and
concentration in vacuum gave 0.731 g of oil. This was
chromatographed on silica gel with a gradient of ethyl acetate and
hexane. Only the fractions clean enough to use were combined. They
were concentrated to give 0.13 g of the free base as an oil. This
was dissolved in ethanol. A solution of oxalic acid dihydrate
(0.0410 g, 0.325 mmol) in ethanol was added. Filtration gave 0.11 g
of the S enantiomer of the title compound as a light yellow
oxalate, m.p. 183-185.degree. C.
[0176] Elemental Analysis for:
C.sub.25H.sub.21FN.sub.2O.sub.2S.C.sub.2H.sub.2O.sub.4.H.sub.2O
[0177] Calc'd: C, 59.99; H, 4.66; N, 5.18
[0178] Found: C, 60.05; H, 4.39; N, 4.97
EXAMPLE 6
2-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2,3-dihydro--
[1,4]dioxino[2,3-f]quinoline
[0179] To a solution of
[(2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
toluenesulfonate (0.43 g, 1.2 mmol),
4-benzo[b]thiophen-3-yl-1,2,3,6-tetrahydro-pyridine (0.31 g, 1.4
mmol), 21 mL of THF and 21 mL of DMF was added NaHCO.sub.3 (0.43 g;
5.1 mmol). The mixture was stirred and heated at 60.degree. C. for
2 days and then allowed to stand at room temperature for one day.
The solvent was evaporated in vacuum. The residue was partitioned
between 500 mL each of ethyl acetate and water. The ethyl acetate
layer was washed with water four times and then dried over
anhydrous magnesium sulfate. Filtration and concentration in vacuum
gave 0.24 g of oil. This was chromatographed on silica gel with a
gradient of ethyl acetate and hexane to give 0.06 g of the free
base as an oil. This was dissolved in ethanol and added to a
solution of oxalic acid dihydrate (0.021 g, 0.17 mmol) in ethanol.
Filtration gave 0.042 g of the S-enantiomer of the title compound
as a yellow oxalate, m.p. 178-180.degree. C.
[0180] Elemental Analysis for:
C.sub.25H.sub.22N.sub.2O.sub.2S.C.sub.2H.sub.2O.sub.4.1.6H.sub.2O
[0181] Calc'd: C, 60.80; H, 5.14; N, 5.25
[0182] Found: C, 60.59; H, 4.79; N, 5.00
EXAMPLE 7
2-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-yl
methyl)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indole
[0183] To a solution of
[(2R)-7,8-dihydro-3H-6,9-dioxa-3-aza-cyclopenta[a]naphthalen-8-yl]methyl
toluene-4-sulfonate (0.6 g, 2 mmol),
4-benzo[b]thiophen-3-yl-1,2,3,6-tetrahydro-pyridine (0.04 g, 0.2
mmol), 30 mL of THF and 25 mL of DMF was added NaHCO.sub.3 (0.6 g,
7 mmol). The mixture was stirred and heated at 70.degree. C. for 1
day and then allowed to stand at room temperature for 3 days. The
solvent was evaporated in vacuum. The residue was partitioned
between 500 mL each of ethyl acetate and water. The ethyl acetate
layer was washed with water four times and dried over anhydrous
magnesium sulfate. Filtration and concentration in vacuum gave 0.86
g of oil. This was chromatographed on silica gel with a gradient of
ethyl acetate and hexane to give 0.25 g of the free base as a very
light tan oil. This was dissolved in ethanol. A solution of oxalic
acid dihydrate (0.0851 g, 0.675 mmol) in ethanol was added.
Filtration gave 0.1436 g of the S enantiomer of the title compound
as a light cream color amorphous oxalate.
[0184] Elemental Analysis for:
C.sub.24H.sub.22N.sub.2O.sub.2S.C.sub.2H.sub.2O.sub.4
[0185] Calc'd: C, 63.36; H, 4.91; N, 5.68
[0186] Found: C; 63.22; H, 4.86; N. 5.50
EXAMPLE 8
2-[4-(5-Fluorobenzo[b]thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,-
3-dihydro-7H-[1,4]dioxino[2,3-e]indole
[0187] To a mixture of
[(2R)-7,8-dihydro-3H-6,9-dioxa-3-aza-cyclopenta[a]naphthalen-8-yl]methyl
4-toluenesulfonate (0.67 g, 1.9 mmol),
4-(5-fluoro-benzo[b]thiophen-3-yl)-1,2,3,6-tetrahydro-pyridine
(0.48 g, 2.1 mmol) and Na.sub.2CO.sub.3 (0.80 g, 7.5 mmol) was
added 21 mL of dimethylsulfoxide. The mixture was stirred heated at
70.degree. C. for 18 hours. TLC on silica gel showed much tosylate
was unreacted. Stirring and heating at 80.degree. C. was continued
for 18 hours. The solvent was evaporated at reduced pressure. The
residue was partitioned between 500 mL portions of ethyl acetate
and water. The ethyl acetate layer was washed five times with water
and dried over anhydrous magnesium sulfate. Filtration and
concentration in vacuum gave 0.86 g of dark oil. This was
chromatographed on silica gel with 40% ethyl acetate in hexane to
give 0.29 g of the free base as a light tan oil. This was dissolved
in ethanol and added to a solution of oxalic acid dihydrate (0.0978
g, 0.776). Filtration gave 0.1049 g of the S enantiomer of the
title compound as a light gray amorphous oxalate.
[0188] Elemental Analysis for:
C.sub.24H.sub.21FN.sub.2O.sub.2S.C.sub.2H.sub.2O.sub.4.0.2H.sub.2O
[0189] Calc'd: C, 60.74; H, 4.59; N, 5.45
[0190] Found: C, 60.72; H, 4.34; N, 5.26
EXAMPLE 9
8-(4-Benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-7,8-
-dihydro-[1,4]dioxino[2,3-q][1,3[-benzoxazole
[0191] To a mixture of
[(2R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta
[a]naphthalen-8-yl]methyl 4-toluenesulfonate (0.3081 g, 0.8207
mmol) and 4-benzo[b]thiophen-3-yl-1,2,3,6-tetrahydro-pyridine (0.54
g, 2.5 mmol) was added 10 mL of dimethylsulfoxide. The solution was
stirred and heated at 85.degree. C. for 4.5 hours. The solvent was
evaporated under reduced pressure. The residue was partitioned
between 500 mL each of ethyl acetate and saturated aqueous sodium
bicarbonate. The ethyl acetate layer was washed four times with
water. Drying over magnesium sulfate, filtration and evaporation of
the solvent gave 0.55 g of oil. This was eluted from silica gel
with a gradient of hexane and ethyl acetate to give 0.09 g of the
free base as an oil. This was dissolved in EtOH and added to a
solution of oxalic acid dihydrate 0.0304 g, 0.241 mmol) in ethanol.
Filtration gave 0.0948 g of the S enantiomer of the title compound
as a fine white oxalate, m.p. 126-129.degree. C.
[0192] Elemental Analysis for:
C.sub.24H.sub.22N.sub.2O.sub.3S.C.sub.2H.sub.2O.sub.4.0.5H.sub.2O
[0193] Calc'd: C, 60.34; H, 4.87; N, 5.41
[0194] Found: C, 60.36; H, 4.99; N, 5.26
INTERMEDIATE 28
4-Benzo[b]thiophen-7-yl-pyridine
[0195] To 7-bromo-benzo[b]thiophene (5.28 g, 24.7 mmol) was added
pyridine-4-boronic acid (2.734 g, 22.24 mmol), K.sub.3PO.sub.4
(12.0 g, 56.5 mmol), 37.5 mL of 1,4-dioxane and 3.8 mL of water.
The mixture was placed under vacuum for several minutes and flushed
with nitrogen. This was repeated 5 times. Pd(dppf)Cl.sub.2.
CH.sub.2Cl.sub.2 (0.909 g, 1.11 mmol), PdCl.sub.2 (0.1994 g, 1.124
mmol) and 1,1''-bis(diphenylphosphino)ferrocene (0.6234 g, 1.124
mmol) were purged in the same way using high vacuum. The catalyst
was added to the reaction flask, which was purged again 3 times.
The mixture was stirred at 80.degree. C. under nitrogen. After 1
day TLC showed much starting material remained. Additional
K.sub.3PO.sub.4 (2.3 g, 10.8 mmol) was added after purging.
Stirring at 80.degree. C. under nitrogen was continued for 12 to 14
hours and then at room temperature till the next day. The mixture
was partitioned between water and ethyl acetate, filtered through
Celite and the layers separated. The organic layer was concentrated
in vacuum. The residue was redissolved in ethyl acetate, washed
with water and dried over magnesium sulfate. Concentration in
vacuum gave 6.06 g of dark oil. This was eluted from silica gel
with a gradient of hexane and ethyl acetate to give 2.43 g of the
title compound as a tan oil that crystallizes slowly. (m.p.
71-72.degree. C.).
[0196] Elemental Analysis for: Cl.sub.3HgNS.1/3H.sub.2O
[0197] Calc'd: C, 71.86; H, 4.48; N, 6.45
[0198] Found: C, 71.93; H, 4.37; N, 5.66
INTERMEDIATE 25
S-4-Benzo[b]thiophen-7-yl-1-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quino-
lin-2-ylmethyl)-pyridinium 4-bromo-benzenesulfonate
[0199] To a mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (1.00 g, 2.22 mmol) and
4-benzo[b]thiophen-7-yl-pyridine (0.58 g, 2.7 mmol) was added 4 mL
of benzene. The mixture was stirred at 75.degree. C. for 18 hours,
after which time most of the solvent had evaporated. TLC on silica
gel showed much of the starting material remained. The reaction
mixture stood at room temperature and open to the atmosphere for
several days. The residual tar was triturated with acetone at
52.degree. C. to give a solid. The solid was broken up and the
volume was reduced by evaporation to approximately 20 mL.
Filtration gave 0.6581 g of the title compound as a gray solid,
(dec.>175.degree. C.).
[0200] Elemental Analysis for:
C.sub.32H.sub.25BrN.sub.2O.sub.5S.sub.2.2H.sub.2O
[0201] Calc'd: C, 55.09; H, 3.61; N, 4.02
[0202] Found: C, 55.13; H, 3.88; N, 3.77
EXAMPLE 10
2-(4-Benzo[b]thiophen-7-VE-3,6-dihydro-2H-pyridin-1-ylmethyl)-8-methyl-2,3-
-dihydro-[1,4]dioxino[2,3-f]quinoline
[0203] To a stirring suspension of
S-4-benzo[b]thiophen-7-yl-1-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quin-
olin-2-ylmethyl)-pyridinium 4-bromo-benzenesulfonate ((0.5060 g,
0.7648 mmol) in 4.5 mL of EtOH cooled in an ice-bath was added
sodium borohydride (0.045 g, 1.2 mmol). This was stirred until it
had warmed almost to room temperature. TLC on silica gel showed
product and maybe some starting material. A slight excess of sodium
borohydride was added to the mixture stirring at 0.degree. C. The
reaction was allowed to stir and warm to room temperature
overnight. The solvent was evaporated at reduced pressure. The
residue was partitioned between ethyl acetate and water. The ethyl
acetate layer was washed with water twice and dried over anhydrous
magnesium sulfate. Filtration and concentration in vacuum gave 0.31
g of oil. This was chromatographed on silica gel with a gradient of
ethyl acetate and hexane to give 0.1307 g of the free base as an
oil. This was dissolved in EtOH and added to a solution of oxalic
acid dihydrate (0.0426 g, 0.338 mmol) in ethanol. Filtration gave
0.1237 g of the S enantiomer of the title compound as a white solid
oxalate, m.p. 183-185.degree. C.
[0204] Elemental Analysis for:
C.sub.26H.sub.24N.sub.2O.sub.2S.fwdarw.C.sub.2H.sub.2O.sub.4.1/3H.sub.2O
[0205] Calc'd: C, 64.11; H, 5.12; N, 5.34
[0206] Found: C, 64.01; H, 5.05; N, 5.28
EXAMPLE 11
2-(4-Benzofuran-2-yl-3,6-dihydro-2H-pyridin-1-ylmethyl)-8-methyl-2,3-dihyd-
ro-[1,4]dioxino[2,3-f]quinoline
[0207] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate ester (0.18 g, 0.40 mmol),
4-benzofuran-2-yl-1,2,3,6-tetrahydropyridine (0.15 g, 0.75 mmol)
and potassium carbonate (0.21 g, 1.5 mmol) in 3 mL of
N,N-dimethylformamide was stirred under nitrogen at 60.degree. C.
for 24 hours. The mixture was partitioned between 250 mL each of
water and ethyl acetate. The organic fraction was dried over
magnesium sulfate, filtered and concentrated in vacuum. The residue
was column chromatographed on 50 mL of silica gel using first 25%
ethyl acetate in hexane and then 50% ethyl acetate in hexane as
eluant. Combination and concentration of the product fractions gave
0.025 g of the S enantiomer of the title compound as a pale yellow
solid, m.p. 149-150.degree. C.
[0208] Elemental Analysis for:
C.sub.26H.sub.24N.sub.2O.sub.3.0.5H.sub.2O
[0209] Calc'd: C, 74.09; H, 5.98; N, 6.65
[0210] Found: C, 73.96: H, 5.89; N. 6.43
EXAMPLE 12
2-(4-Benzofuran-2-yl-piperidin-1-ylmethyl)-8-methyl-2,3-dihydro-[1,4]dioxi-
no[2.3-f]quinoline
[0211] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate ester (0.18 g, 0.40 mmol),
4-benzofuran-2-yl-piperidine (0.103 g, 0.51 mmol) and potassium
carbonate (0.21 g, 1.5 mmol) in 3 mL of N,N-dimethylformamide was
stirred under nitrogen at room temperature for 3 days and then at
60.degree. C. for 6 hours. The mixture was partitioned between 250
mL each of water and ethyl acetate. The organic fraction was dried
over magnesium sulfate, filtered and concentrated in vacuum. The
residue was column chromatographed on 50 mL of silica gel using
first 25% ethyl acetate in hexane and then 50% ethyl acetate in
hexane as eluant. Combination and concentration of the product
fractions gave 0.060 g of the S enantiomer of the title compound as
a pale yellow solid, m.p. 103-104.degree. C.
[0212] Elemental Analysis for:
C.sub.26H.sub.26N.sub.2O.sub.3.0.25H.sub.2O
[0213] Calc'd: C, 74.53; H, 6.37; N, 6.69
[0214] Found: C, 74.52; H, 6.49; N, 6.63
INTERMEDIATE 26
4-(5-Chloro-benzo[b]thiophen-3-yl)-pyridine
[0215] To 3-bromo-5-chloro-benzo[b]thiophene (9.80 g, 39.6 mmol)
was added pyridine-4-boronic acid (4.445 g, 36.2 mmol),
K.sub.3PO.sub.4 (19.5 g, 91.9 mmol), 61 mL of 1,4-dioxane and 6 mL
of water. The mixture was placed under house vacuum for several
minutes and flushed with nitrogen. This was repeated 5 times.
Pd(dppf)Cl.sub.2. CH.sub.2Cl.sub.2 (2.71 g, 3.31 mmol), PdCl.sub.2
(0.0563 g, 0.318 mmol) and 1,1''-bis(diphenylphosphino)ferrocene
(0.1747 g, 0.3151 mmol) were purged in the same way. The catalyst
was added to the reaction flask which was purged with nitrogen 3
more times. The mixture was stirred (stir bar) at 80.degree. C. for
22 hours. TLC showed little change. The mixture was mechanically
stirred at 80.degree. C. for 4 hours. The mixture was partitioned
between water and ethyl acetate, filtered through Celite and the
layers were separated. The organic layer was evaporated. The
residue was dissolved in ethyl acetate, washed with water twice.
Saturated brine was added the second time to separate the layers
more quickly. The organic solution was dried over magnesium
sulfate. Filtration and concentration in vacuum gave 11.35 g of
black oil. This was eluted from silica gel with a gradient of
hexane and ethyl acetate to give 3.86 g of recovered starting
material and 4.28 g of the title compound as light brown crystals,
m.p. 90-91.degree. C.
[0216] Elemental Analysis for: C.sub.13H.sub.8CINS
[0217] Calc'd: C, 63.54; H, 3.28; N, 5.70
[0218] Found, C, 63.19; H, 3.26; N, 5.46
EXAMPLE 13
2-[4-(5-Chlorobenzo[b]thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8--
methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0219] To a mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate ester (0.92 g, 2.0 mmol) and
4-(5-chloro-benzo[b]thiophen-3-yl)-pyridine (0.50 g, 2.0 mmol) was
added 8 mL of acetone. The mixture was refluxed for 4 hours,
stirred at room temperature overnight and refluxed for 5 hours
more. The solvent slowly evaporated and was replenished as needed.
After standing at room temperature overnight some crystals had
formed. To this was added 15 mL of methylethylketone. The mixture
was refluxed overnight. TLC on silical gel showed starting material
and no obvious product. The solvent was evaporated. The residue was
stirred at 130.degree. C. overnight. The thick mixture had
solidified. It was broken up and crushed. To this was added 12 mL
of ethanol. This heterogeneous mixture was stirred in an ice-bath.
Sodium borohydride (0.12 g, 3.2 mmol) was added initially. A slight
excess was added to insure consumption of the pyridinium salt. The
reaction was allowed to stir and warm to room temperature
overnight. The solvent was evaporated at reduced pressure. The
residue was partitioned between ethyl acetate and water. The ethyl
acetate layer was washed with water 3 times and dried over
anhydrous magnesium sulfate. Filtration and concentration in vacuum
gave 0.84 g of dark oil. This was chromatographed on silica gel
with a gradient of ethyl acetate and hexane to give 0.29 g of the
free base as an oil. This was dissolved in ethanol and added to a
solution of oxalic acid dihydrate (0.0811 g, 0.643 mmol) in
ethanol. Filtration gave 0.2659 g of the S enantiomer of the title
compound as white oxalate, m.p. 203-207.degree. C.
[0220] Elemental Analysis for:
C.sub.26H.sub.23ClN.sub.2O.sub.2S.fwdarw.C.sub.2H.sub.2O.sub.4.2/3H.sub.2-
O
[0221] Calc'd: C, 59.52; H, 4.70; N, 4.96
[0222] Found: C, 59.59; H, 4.40; N, 4.74
EXAMPLE 14
2-(4-Benzoxazol-2-yl-piperidin-1-ylmethyl)-8-methyl-2,3-dihydro-[1,4]dioxi-
no[2,3-f]quinoline
[0223] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate ester (0.18 g, 0.40 mmol),
2-piperidin-4-yl-benzoxazole (0.121 g, 0.59 mmol) and potassium
carbonate (0.21 g, 1.5 mmol) in 3 mL of N,N-dimethylformamide was
stirred under nitrogen at room temperature for 3 days and then at
60.degree. C. for 6 hours. The mixture was partitioned between 250
mL each of water and ethyl acetate. The organic traction was dried
over magnesium sulfate, filtered and concentrated in vacuum. The
residue was column chromatographed on 50 mL of silica gel using
first 50% ethyl acetate in hexane and then 75% ethyl acetate/hexane
as eluant. Combination and concentration of the product fractions
gave 0.040 g of the S enantiomer of the title compound as a dark
beige solid, m.p. 128-130.degree. C.
[0224] Elemental Analysis for:
C.sub.25H.sub.25N.sub.3O.sub.3.0.25H.sub.2O
[0225] Calc'd: C, 71.49; H, 6.12; N, 10.00
[0226] Found: C, 71.60; H, 6.06; N, 10.19
[0227] 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.
[0228] The disclosures of each patent, patent application, and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0229] 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.
* * * * *