U.S. patent application number 11/505663 was filed with the patent office on 2006-12-07 for antidepressant arylpiperazine derivatives of heterocycle-fused benzodioxans.
This patent application is currently assigned to Wyeth. Invention is credited to Susan Christman Croce, Deborah Ann Evrard, Amedeo A. Failli, Gary Paul Stack, Aranapakam Madumbai Venkatesan, Dahui Zhou.
Application Number | 20060276481 11/505663 |
Document ID | / |
Family ID | 31997900 |
Filed Date | 2006-12-07 |
United States Patent
Application |
20060276481 |
Kind Code |
A1 |
Evrard; Deborah Ann ; et
al. |
December 7, 2006 |
Antidepressant arylpiperazine derivatives of heterocycle-fused
benzodioxans
Abstract
Compounds of the formula I: ##STR1## 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: |
Evrard; Deborah Ann;
(Hamilton Square, NJ) ; Zhou; Dahui; (East
Brunswick, NJ) ; Stack; Gary Paul; (Ambler, PA)
; Venkatesan; Aranapakam Madumbai; (Regopark, NY)
; Failli; Amedeo A.; (Princeton Junction, NJ) ;
Croce; Susan Christman; (Lambertville, NJ) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE - 46TH FLOOR
PHILADELPHIA
PA
19103
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
31997900 |
Appl. No.: |
11/505663 |
Filed: |
August 16, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10659537 |
Sep 10, 2003 |
|
|
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11505663 |
Aug 16, 2006 |
|
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60410082 |
Sep 12, 2002 |
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Current U.S.
Class: |
514/253.03 ;
544/361 |
Current CPC
Class: |
A61P 3/04 20180101; C07D
491/04 20130101; A61P 13/02 20180101; A61P 25/06 20180101; A61P
15/00 20180101; A61P 25/04 20180101; A61P 15/08 20180101; A61P 9/14
20180101; A61P 43/00 20180101; A61P 25/14 20180101; A61P 25/00
20180101; A61P 25/24 20180101; A61P 17/14 20180101; A61P 25/32
20180101; A61P 25/36 20180101; Y02P 20/582 20151101; A61P 25/22
20180101 |
Class at
Publication: |
514/253.03 ;
544/361 |
International
Class: |
A61K 31/496 20060101
A61K031/496; C07D 491/02 20060101 C07D491/02 |
Claims
1. 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, obesity, eating disorders, vasomotor
flushing, cocaine and alcohol addiction, and sexual dysfunction,
comprising the step of: providing to said subject a therapeutically
effective amount of
(2S)-2-{[4-(dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]methyl}-8-methyl--
2,3-dihydro[1,4]dioxino[2,3-f]quinoline, or a pharmaceutically
acceptable salt thereof.
2. The method according to claim 1, wherein said condition is
depression.
3. The method according to claim 1, wherein said condition is
selected from the group consisting of obsessive-compulsive
disorder, panic attacks, generalized anxiety disorder, and social
anxiety disorder.
4. A method of treating a subject suffering from cocaine addiction,
comprising the step of: providing to said subject a therapeutically
effective amount of a compound of formula I ##STR32## wherein
R.sup.1 is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6
carbon atoms, trifluoromethyl, alkyl of 1 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, or alkanesulfonamido of 1 to 6 carbon atoms; the
group X--Y is --N.dbd.C(R.sup.2)--C(R.sup.3).dbd.N--,
--N.dbd.C(R.sup.2)--C(R.sup.4).dbd.CH--,
--N.dbd.C(R.sup.2)--N.dbd.CH--, --N.dbd.C(R.sup.2)--O--, or
--NH--C(R.sup.5).dbd.CH--; R.sup.2 and R.sup.3 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;
R.sup.4 is hydrogen or alkyl of 1 to 6 carbon atoms; R.sup.5 is
hydrogen, halo, trifluoromethyl, pentafluoroethyl or alkyl of 1 to
6 carbon atoms; Ar is phenyl, naphthyl, indolyl, indazolyl,
thienyl, pyridinyl, pyrimidinyl, quinolinyl, benzofuranyl,
benzothienyl, benzoisothiazolyl, or benzisoxazolyl, each optionally
substituted with one to three substituents independently selected
from hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6
carbon atoms, trifluoromethyl, alkyl of 1 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, or alkanesulfonamido of 1 to 6 carbon atoms;
and, n is 1 or 2; or a pharmaceutically acceptable salt
thereof.
5. The method according to claim 4, wherein R.sup.1 is hydrogen,
halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or
alkoxy of 1 to 6 carbon atoms.
6. The method according to claim 4, wherein R.sup.1 is hydrogen,
halo or alkoxy of 1 to 6 carbon atoms.
7. The method according to claim 4, wherein R.sup.1 is
hydrogen.
8. The method according to claim 4, wherein Ar is phenyl,
quinolinyl, benzofuranyl, benzothienyl, or indolyl, each optionally
substituted.
9. The method according to claim 4, wherein X--Y is
--N.dbd.C(R.sup.2)--C(R.sup.4).dbd.CH-- and R.sup.4 is hydrogen or
alkyl of 1 to 3 carbon atoms.
10. The method according to claim 4, wherein R.sup.2 and R.sup.3
when present are independently selected from the group consisting
of hydrogen, amino, and alkyl of 1 to 6 carbon atoms.
11. The method according to claim 4, wherein R.sup.5 is hydrogen,
trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon
atoms.
12. The method according to claim 4, wherein R.sup.5 is hydrogen,
trifluoromethyl or alkyl of 1 to 3 carbon atoms.
13. The method according to claim 4, wherein said compound is
selected from the group consisting:
(2S)-2-{[4-(3-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,-
4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,-
4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr-
o[1,4]dioxine[2,3-f]quinoline;
(2S)-2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1-
,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1-
,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1-
,4]dioxino[2,3-f]quinoline;
(2S)-8-methyl-2-[4-(3-trifluoromethyl-phenyl)piperazin-1-ylmethyl]-2,3-di-
hydro[1,4]dioxino[2,3-f]quinoline;
(2S)-8-methyl-2-[4-(3-fluorophenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]-
dioxino[2,3-f]quinoline;
(2S)-2-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr-
o[1,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(3,4-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr-
o[1,4]dioxino[2,3-f]quinoline;
(2S)-8-methyl-2-[(4-quinolin-2-ylpiperazin-1-yl)methyl]-2,3-dihydro[1,4]d-
ioxino[2,3-f]quinoline;
((2S)-8-methyl-2-{4-(6-nitroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline;
(2S)-8-methyl-2-{4-(6-chloroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline;
2-(4-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}p-
iperazin-1-yl}quinoline-6-carbonitrile;
(2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,-
3-dihydro[1,4]dioxino[2,3-f]quinoline;
((2S)-2-{[4-(7-methoxy-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl--
2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
(2S)-8-methyl-2-{[(2S)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline;
2-((3R)-3-methyl-4-{[(2S))-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoli-
n-2-yl]methyl}piperazin-1-yl]quinoline-6-carbonitrile;
(2S)-8-methyl-2-{[(2R)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline;
(2S)-8-methyl-2-{[4-(2-naphthyl)piperazin-1-yl]methyl}-2,3-dihydro[1,4]di-
oxino[2,3-f]quinoline;
(2S)-2-[4-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-piperazi-
n-1-yl]-quinoline-6-carboxylic acid amide;
(2S)-2-[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin--
1-yl]-quinoline-6-carbonitrile;
(2S)-2-[4-(8-Ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-pi-
perazin-1-yl]-quinoline-6-carbonitrile;
(2S)-2-[4-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthale-
n-8-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile;
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-di-
hydro[1,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-meth-
yl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-2,3-dihydro--
[1,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,-
3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}--
1,4-diazepan-1-yl)quinoline-6-carbonitrile;
(2S)-2-{[4-(6-Trifluoromethoxy-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-
-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,3-dihy-
dro-[1,4]dioxino[2,3-f]quinoline;
(2S)-2-{[4-(6-Bromo-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline;
8-Methyl-2-(4-quinolin-2-yl-[1,4]diazepan-1-ylmethyl)-2,3-dihydro-[1,4]di-
oxino[2,3-f]quinoline; and,
8-Methyl-2-[4-(4-methyl-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline, and pharmaceutically acceptable
salts thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/659,537, filed Sep. 10, 2003 (now allowed), which claims the
benefit of U.S. Application Ser. No. 60/410,082, filed Sep. 12,
2002, the entire disclosures of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] This invention relates to antidepressant arylpiperazine
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 ILLUSTRATIVE EMBODIMENTS
[0010] In accordance with this invention, there is provided a group
of novel compounds of the Formula I: ##STR2## wherein [0011]
R.sup.1 is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6
carbon atoms, trifluoromethyl, alkyl of 1 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, or alkanesulfonamido of 1 to 6 carbon atoms;
[0012] the group X--Y is --N.dbd.C(R.sup.2)--C(R.sup.3).dbd.N--,
--N.dbd.C(R.sup.2)--C(R.sup.4).dbd.CH--,
--N.dbd.C(R.sup.2)--N.dbd.CH--, --N.dbd.C(R.sup.2)--O--, or
--NH--C(R.sup.5).dbd.CH--; [0013] R.sup.2 and R.sup.3 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.4 is hydrogen or alkyl of 1 to 6 carbon
atoms; [0015] R.sup.5 is hydrogen, halo, trifluoromethyl,
pentafluoroethyl, or alkyl of 1 to 6 carbon atoms; [0016] Ar is
phenyl, naphthyl, indolyl, indazolyl, thienyl, pyridinyl,
pyrimidinyl, quinolinyl, benzofuranyl, benzothienyl,
benzoisothiazolyl, or benzisoxazolyl, each optionally substituted
with one to three substituents independently selected from hydroxy,
halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms,
trifluoromethyl, alkyl of 1 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,
or alkanesulfonamido of 1 to 6 carbon atoms; [0017] n is 1 or 2; or
pharmaceutically acceptable salts thereof.
[0018] 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.
[0019] R.sup.4 is preferably hydrogen or alkyl of 1 to 3 carbon
atoms.
[0020] R.sup.2 and R.sup.3 are preferably independently selected
from hydrogen, amino or alkyl of 1 to 6 carbon atoms. More
preferably, R.sup.2 and R.sup.3 are independently hydrogen or alkyl
of 1 to 3 carbon atoms.
[0021] R.sup.5 is preferably hydrogen, trifluoromethyl,
pentafluoroethyl or alkyl of 1 to 6 carbon atoms. More preferably,
R.sup.5 is hydrogen, trifluoromethyl or alkyl of 1 to 3 carbon
atoms.
[0022] Ar is preferably phenyl, quinolinyl, benzofuranyl,
benzothienyl, or indolyl, each optionally substituted with one to
three substituents independently selected from hydroxy, halo,
cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms,
trifluoromethyl, alkyl of 1 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,
or alkanesulfonamido of 1 to 6 carbon atoms.
[0023] 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.
[0024] Where a single stereoisomer is preferred, it may, in some
embodiments be provided substantially free of the corresponding
enantiomer or diastereomers. Thus, a single stereoisomer
substantially free of the corresponding enantiomer or diastereomers
refers to a compound which is isolated or separated via separation
techniques or prepared free of the corresponding enantiomer or
diastereomers. "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 or
diastereomeric 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).
[0025] "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.
[0026] "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.
[0027] "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.
[0028] "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.
[0029] "Alkoxy," as used herein, refers to the group R--O-- where R
is an alkyl group of 1 to 6 carbon atoms.
[0030] "Carboxamido," as used herein, refers to the group
NH.sub.2--C(.dbd.O)--.
[0031] "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.
[0032] "Halogen" (or "halo"), as used herein, refers to chlorine,
bromine, fluorine and iodine.
[0033] 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.
[0034] Specific examples of compounds of Formula I are: [0035]
(2S)-2-{[4-(3-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,-
4]dioxino[2,3-f]quinoline; [0036]
(2S)-2-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,-
4]dioxino[2,3-f]quinoline; [0037]
(2S)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr-
o[1,4]dioxine[2,3-f]quinoline; [0038]
(2S)-2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1-
,4]dioxino[2,3-f]quinoline; [0039]
(2S)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1-
,4]dioxino[2,3-f]quinoline; [0040]
(2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1-
,4]dioxino[2,3-f]quinoline; [0041]
(2S)-2-{[4-(dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]methyl}-8-methyl--
2,3-dihydro[1,4]dioxino[2,3-f]quinoline; [0042]
(2S)-8-methyl-2-[4-(3-trifluoromethyl-phenyl)piperazin-1-ylmethyl]-2,3-di-
hydro[1,4]dioxine[2,3-f]quinoline; [0043]
(2S)-8-methyl-2-[4-(3-fluorophenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]-
dioxine[2,3-f]quinoline; [0044]
(2S)-2-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr-
o[1,4]dioxino[2,3-f]quinoline; [0045]
(2S)-2-{[4-(3,4-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydr-
o[1,4]dioxino[2,3-f]quinoline; [0046]
(2S)-8-methyl-2-[(4-quinolin-2-ylpiperazin-1-yl)methyl]-2,3-dihydro[1,4]d-
ioxino[2,3-f]quinoline; [0047]
(2S)-8-methyl-2-{4-(6-nitroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihyd-
ro[1,4]dioxino[2,3-f]quinoline; [0048]
(2S)-8-methyl-2-{4-(6-chloroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline; [0049]
2-(4-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}p-
iperazin-1-yl}quinoline-6-carbonitrile; [0050]
(2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinoline; [0051]
(2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,-
3-dihydro[1,4]dioxino[2,3-f]quinoline; [0052]
(2S)-2-{[4-(7-methoxy-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2-
,3-dihydro[1,4]dioxino[2,3-f]quinoline; [0053]
(2S)-8-methyl-2-{[(2S)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline; [0054]
2-((3R)-3-methyl-4-{[(2S))-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoli-
n-2-yl]methyl}piperazin-1-yl]quinoline-6-carbonitrile; [0055]
(2S)-8-methyl-2-{[(2R)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline; [0056]
(2S)-8-methyl-2-{[4-(2-naphthyl)piperazin-1-yl]methyl}-2,3-dihydro[1,4]di-
oxino[2,3-f]quinoline; [0057]
(2S)-2-[4-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-piperazi-
n-1-yl]-quinoline-6-carboxylic acid amide; [0058]
(2S)-2-[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin--
1-yl]-quinoline-6-carbonitrile; [0059]
(2S)-2-[4-(8-Ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-pi-
perazin-1-yl]-quinoline-6-carbonitrile; [0060]
(2S)-2-[4-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthale-
n-8-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile; [0061]
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline; [0062]
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline; [0063]
(2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-di-
hydro[1,4]dioxino[2,3-f]quinoline; [0064]
(2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-meth-
yl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline; [0065]
2-[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-2,3-dihydro--
[1,4]dioxino[2,3-f]quinoline; [0066]
(2S)-2-{[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,-
3-dihydro[1,4]dioxino[2,3-f]quinoline; [0067]
2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}--
1,4-diazepan-1-yl)quinoline-6-carbonitrile; [0068]
(2S)-2-{[4-(6-Trifluoromethoxy-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-
-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline; [0069]
2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,3-dihy-
dro-[1,4]dioxino[2,3-f]quinoline; [0070]
(2S)-2-{[4-(6-Bromo-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline; [0071]
8-Methyl-2-(4-quinolin-2-yl-[1,4]diazepan-1-ylmethyl)-2,3-dihydro-[1,4]di-
oxino[2,3-f]quinoline; and [0072]
8-Methyl-2-[4-(4-methyl-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline; and pharmaceutically acceptable
salts thereof.
[0073] 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 arylpiperazine is combined with a suitably substituted
benzodioxanmethyl sulfonate (e.g., R is 4-methylphenyl or
4-bromopheneyl) or halide in a solvent such as dimethyl sulfoxide
and heated to a temperature of 50-100.degree. C. for several hours
as illustrated below. ##STR3##
[0074] The arylpiperazines appropriate to the chemistry of Scheme 1
are known in the literature or may be prepared by those skilled in
the art.
[0075] The
2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethyltosylates in which
R.sup.2 is hydrogen (R is 4-methylphenyl) appropriate to the
chemistry in Scheme 1 can be prepared as illustrated in Scheme 2
below. Specifically, the appropriately substituted nitroguaiacol
(2) is alkylated with allyl bromide in the presence of a suitable
base such as sodium hydride to produce (3) and then demethylated by
a reagent such as sodium hydroxide. The resulting
4-nitro-2-allyloxyphenol (4) is then alkylated with glycidyl
tosylate or an epihalohydrin in the presence of a base such as
sodium hydride to produce (5) and heated in a high boiling solvent
such as mesitylene or xylene to effect both rearrangement of the
allyl group and cyclization to the dioxan ring. The resulting
primary alcohol (6) is converted to the tosylate by reaction with
p-toluenesulfonyl chloride in the presence of a tertiary amine 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 to produce (7). Allylic oxidation 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-methyl-tosylate (8).
##STR4##
[0076] The
2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethyltosylates in which
R.sup.2 is alkyl may be prepared from the nitro olefin described
above in the manner described in Scheme 3. The rearranged olefin
(7) is treated sequentially with ozone and a tertiary amine or with
osmium tetroxide and sodium periodate to give the
o-nitrobenzaldehyde (9). Condensation with the appropriate
triphenyl phosphoranylidene ketone under Wittig conditions gives
the o-nitrostyryl ketone (10), which upon reduction by iron in
acetic acid, cyclizes to the corresponding
2,3-dihydro-1,4-dioxino[2,3-f]-quinoline-2-methyltosylate (11).
Replacement of the tosylate with the appropriately substituted
arylpiperazine as above gives the title compounds of the invention.
##STR5##
[0077] Substitution of trimethyl phosphonoacetate for the
triphenylphosphoranylidene 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.2 is hydroxy. Alkylation of this hydroxy derivative by a
suitable alkyl halide or tosylate in the presence of base gives the
compounds of the invention in which R.sup.2 is alkoxy. 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.2 is halo. Substitution of diethyl
cyanomethylphosphonate for the triphenyl-phosphoranylidene 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.2 is amino.
[0078] The o-nitrobenzaldehyde (9) used in the Wittig chemistry
described in Scheme 3 may be alternatively prepared as shown in
Scheme 4. The appropriate mono-allylated catechol (12) is
elaborated with glycidyl tosylate as described above to produce
(13) and rearranged in refluxing mesitylene. Cyclization to the
benzodioxan methanol is effected by treatment with sodium
bicarbonate in ethanol and the alcohol (14) is converted to the
tosylate. After rearrangement of the double bond by treatment with
catalytic bis-acetonitrile palladium chloride in refluxing
methylene chloride to produce 15 and cleavage with ozone or osmium
tetroxide/sodium periodate as described above, the resulting
aldehyde (16) is regioselectively nitrated with a combination of
nitric acid and tin (IV) chloride to produce (9). ##STR6##
[0079] 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]quinoline may be
alternatively prepared by a variation of the Skraup quinoline
synthesis according to Scheme 5. The appropriately substituted
benzodioxan methyltosylate (17) is nitrated under standard
conditions with nitric acid in a solvent such as dichloroethane and
the resulting nitro compound (18) reduced by treatment with
hydrogen in the presence of a catalyst such as platinum on sulfide
carbon. Treatment of the resulting aniline (19) 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 (20). Replacement of the
tosylate with the appropriately substituted arylpiperazine as above
gives the title compounds of the invention. ##STR7##
[0080] The
2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of the
invention are prepared as illustrated below (Scheme 6). The
o-nitrobenzaldehyde (9) described above is converted to the oxime
(21) 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 (22) 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 may be
isolated by column chromatography. Replacement of the tosylate or
halide with the appropriately substituted arylpiperazine in some
high boiling solvent such as dimethyl sulfoxide gives the title
compounds of the invention. ##STR8##
[0081] 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 7 below. The nitro
olefin (7) 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 (23) is then
converted to the aldehyde (24) 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 (22) or
halide is effected by treatment of the amido aldehyde (24) with
ammonia and replacement of the tosylate or halide with the
appropriately substituted piperazine in some high boiling solvent
such as dimethyl sulfoxide as described above gives the title
compounds of the invention. ##STR9##
[0082] The
2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-ylmethylamines of the
invention are prepared as illustrated in Scheme 8 below. The
o-nitrobenzaldehyde (9) described above is oxidized to the
o-nitrobenzoic acid (25) by a suitable oxidant such as chromium
trioxide (Jones' oxidation) or sodium chlorite and the acid
converted to the o-nitroaniline (26) with diphenylphosphoryl azide
(DPPA) in the presence of a tertiary base such as
diisopropylethylamine. Reduction of the resulting nitroaniline to
the diamine (27) 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 (28).
Replacement of the tosylate with the appropriately substituted
arylpiperazine in some high boiling solvent such as dimethyl
sulfoxide gives the title compounds of the invention. ##STR10##
[0083] The
7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethylamines of
the invention are prepared as illustrated in Scheme 9 below. The
o-amidobenzaldehyde (24) described in Scheme 7 is converted to the
phenol (29) 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 (30) 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 with the appropriately substituted
arylpiperazine in some high boiling solvent such as dimethyl
sulfoxide gives the title compounds of the invention. ##STR11##
[0084] Alternatively (Scheme 10), the nitro olefin (7) may be
reduced with tin (II) chloride as described in Scheme 7 above and
protected with a suitable protecting group such as carbobenzoxy
(Cbz) before the olefin is cleaved to the aldehyde (32) by
treatment with osmium tetroxide/sodium periodate and the aldehyde
converted to a phenol (33) by the Baeyer-Villager procedure.
Deprotection by treatment with hydrogen over palladium on carbon
gives the o-aminophenol, (34) which is cyclized to the
7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (30) 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.2 is amino. Treatment of the o-aminophenol
with carbonyl diimidazole gives the oxazolone that leads to
compounds of the invention in which R.sup.2 is halo via treatment
with an inorganic anhydride such as phosphoryl chloride or bromide.
Replacement of the tosylate with the appropriately substituted
arylpiperazine as above gives the title compounds of the invention.
##STR12##
[0085] Compounds of the invention in which R.sup.1 is hydrogen and
R.sup.2 is alkyl are most conveniently prepared according to Scheme
11 below. The appropriate 2',3',4'-trihydroxyacylphenone (35) 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 (36).
Following conversion of the ketone to the oxime (37) by reaction
with hydroxylamine hydrochloride and sodium acetate, cyclization to
the oxazole (38) 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 (39) by treatment with
p-toluenesulfonyl chloride in pyridine and combined with the
appropriate arylpiperazine as described above to give the title
compounds of the invention. ##STR13##
[0086] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the
invention are prepared as illustrated in Scheme 12 below.
Specifically, the primary alcohol (6) from the Claisen
rearrangement described in Scheme 2 is converted to the tosylate
(40) 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 (41) 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 (42) in which R.sup.5 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.5 is alkyl or trifluoromethyl.
Replacement of the tosylate with the appropriately substituted
arylpiperazine in some high boiling solvent such as dimethyl
sulfoxide gives the title compounds of the invention. ##STR14##
[0087] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the
invention may alternatively be prepared following procedure (Scheme
13). The o-nitrobenzaldehyde (9) is condensed with the appropriate
nitroalkane in the presence of a suitable base catalyst to yield
the corresponding o,.beta.-dinitrostyrene (43). Reduction of both
nitro groups with hydrogen over palladium on carbon is accompanied
by cyclization to form the indole (44). Replacement of the tosylate
with the appropriately substituted arylpiperazine as above gives
the title compounds of the invention. ##STR15##
[0088] In yet another method, compounds of the present invention
may be prepared in accordance with Scheme 14. The synthesis of
compound I is comprised of steps that begin with halogenation of 45
where R' is alkyl of 1-6 carbon atoms, with reagents such as
N-halosuccinimide in acetonitrile to give 46 (where Hal is halogen
such as Br, Cl or I). Deprotection of 46 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 47. Free base 47 may be obtained by neutralization
with an Amberlyst A-21 resin slurry in polar solvents such as
ethanol or methanol. Alkylation of 47, either as the free base or
as the salt, with benzyl or substituted benzyl protected glycidyl
ethers ##STR16## 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 dimethyl
sulfoxide, dimethyl formamide, or dimethyl acetamide in the
presence of bases such as sodium carbonate, potassium carbonate, or
triethylamine gives 48. The compound 48 is 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 a 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
49. Deprotection of 49 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 50. The hydroxyl moiety of
50 can be activated with an aryl- or alkyl-sulfonyl 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 51 where R''' is sulfonate such as p-toluenesulfonate,
methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2- or
4-bromobenzenesulfonate. The final coupling of 51 with
arylpiperazines appropriate to the invention, in the presence of
bases such as diisopropyl ethylamine, potassium carbonate, or
sodium carbonate in polar solvents such as THF, dioxane, DMSO, DMF,
or DMA affords compounds of Formula I. ##STR17## ##STR18##
[0089] 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 Plate.RTM. counter to quantify 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
.sup.3H-serotonin uptake inhibition.
[0090] High affinity for the serotonin 5HT.sub.1A receptor was
established by testing the claimed compound's ability to displace
[.sup.3H] 8-OH-DPAT (dipropylamino-tetralin) from the 5HT.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 5HT.sub.1A receptors. The 5HT.sub.1A
affinities for the compounds of the invention are reported below as
K.sub.i's.
[0091] Antagonist activity at 5HT.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
5HT.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-OH-DPAT. The test
compound's maximum inhibitory effect is represented as the
I.sub.max, while its potency is defined by the IC.sub.50.
[0092] The results of the three standard experimental test
procedures described in the preceding three paragraphs were as
follows: TABLE-US-00001 5-HT 5HT.sub.1A Transporter Receptor
Affinity Affinity 5HT.sub.1A Function Compound K.sub.i (nM) K.sub.i
(nM) IC.sub.50 (nM) (I.sub.max) Example 1 15.7 15.9 4564 (100)
Example 2 565 22.9 632 (26) Example 3 76 1055? nd Example 4 34%@1
.mu.M 95%@1 .mu.M 994 (87) Example 5 35.5 80%@1 .mu.M 1715 (84)
Example 6 0%@1 .mu.M 81% A1 .mu.M 3938 (37) Example 7 1.20 91%@1
.mu.M 557 (71) Example 8 21.6 31.4 3107 (100) Example 9 Example 10
88.5 82.5 403 (98) Example 11 85.5 18.2 345 (84) Example 12 48.0
47.3 3002 (100) Example 13 0.25 20.0 326 (70) Example 14 0.65 214
74.7 (58) Example 15 13.5 3.70 82.5 (87) Example 16 266 28.5 ND
Example 17 74.0 718 ND Example 18 16.0 40.3 ND Example 19 123 167
3000 (90) Example 20 688 2.85 82.8 (92) Example 21 32.8 5.53 867
(83.5) Example 22 19.8 53.2 4539 (76) Example 23 56% @ 1 .mu.M 7.21
129 (71) Example 24 310 7.27 57 (58) Example 25 67 4.74 EC.sub.50 =
1135(E.sub.max = 67) Example 26 407 25.1 EC.sub.50 = 700 (E.sub.max
= 64) Example 27 101 17.15 2412 (82) Example 29 200 1.26 1325 (100)
Example 33 7.30 1.75 316 (92) Example 34 1.09 2.04
[0093] 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 pain (including, but not limited to migraine,
chronic back pain, phantom limb pain, neuropathic pain such as
diabetic neuropathy, and post herpetic neuropathy) and related
illnesses. Moreover, the compounds of this invention have potent
affinity for and antagonist activity at brain 5HT.sub.1A serotonin
receptors. Recent clinical trials employing drug mixtures (e.g.,
fluoxetine and pindolol) have demonstrated a more rapid onset of
antidepressant efficacy for a treatment combining SSRI activity and
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.
[0094] 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.
[0095] 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.
[0096] 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, methylcellulose, sodium carboxymethyl
cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange
resins.
[0097] 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.
[0098] 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.
[0099] 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.
[0100] 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.
[0101] "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.
[0102] The present invention includes prodrugs of compounds of
Formula I and Ia. 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).
[0103] The following examples illustrate the production of
representative compounds of this invention.
Intermediate 1
5-Bromo-6-Methoxy-2-Methylquinoline
[0104] 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 g, 1.12 mol) over
a period of 30 minutes while maintaining the same temperature. The
resulted brown slurry was warmed to ambient temperature and stirred
for an additional 6 hours. The reaction was then quenched by a 10%
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 hour 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).
[0105] Elemental Analysis for: C.sub.11H.sub.10NOBr
[0106] Calc'd: C, 52.40; H, 3.97; N, 5.56 Found: C, 52.13; H, 3.94;
N, 5.61
Intermediate 2
5-Bromo-2-Methyl-6-Quinolinol Hydrobromide
[0107] A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12
mol) in 48% HBr (135 mL) was heated to reflux for 7 hours then
cooled to 5.degree. C. in 1 hour to give a brown and thick slurry.
The slurry was stirred at 0-5.degree. C. for 1 hour then filtered,
washed with EtOAc (2.times.50 mL) and dried in a vacuum oven to
give 34.9 g (92%) 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);
.sup.13C NMR (DMSO) .delta. 155.7, 152.0, 142.8, 133.3, 128.9,
126.4, 123.3, 121.2, 103.3, 24.1.
Intermediate 3
5-Bromo-2-Methyl-6-Quinolinol
[0108] 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 hours. 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 4
(2S)-1-(Benzyloxy)-3-[(5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanol
[0109] 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); [.alpha.].sub.D=+6.2.degree. (c=1, CH.sub.3OH).
[0110] Elemental Analysis for: C.sub.20H.sub.20BrNO.sub.3
[0111] Calc'd: C, 59.66; H, 4.97; N, 3.48
[0112] Found: C, 59.43; H, 4.97; N, 3.55
Intermediate 5
(2S)-2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline
[0113] A solution of
(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol
(10 g, 24.9 mmol), potassium phosphate tribasic (11.4 g, 50 mmol),
Pd(OAc).sub.2 (280 mg, 1.25 mmol) and racemic BINAP (1.55 g, 2.49
mmol) in toluene (50 mL) was heated in a 100-102.degree. C. oil
bath for 3 d. The solution was cooled to room temperature then
EtOAc (50 mL) and water (50 mL) were added. The reaction mixture
was filtered through a bed of celite. The two layers were
separated. The aqueous layer was extracted with EtOAc (30 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo to give 8 g (100%) of the crude product
as a brown syrup. The crude product can be carried through the
debenzylation step before purification. A sample of the crude
mixture was purified on SiO.sub.2, eluted with (3:1) hexane:EtOAc
gave the title compound as a yellow oil which solidified upon
standing: R.sub.f=0.5 (EtOAc); .sup.1H NMR (DMSO) .delta. 8.24 (d,
J=8.6 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.27-7.38 (m, 7H);
[.alpha.].sub.D=+7.9.degree. (c=1.2, CHCl.sub.3).
[0114] Elemental Analysis for: C.sub.20H.sub.19NO.sub.3
[0115] Calc'd: C, 74.68; H, 5.91; N, 4.36
[0116] Found: C, 74.48; H, 6.03; N, 4.14
Intermediate 6
[(2S)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol
[0117] 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 hours then cooled and filtered. The catalyst
was rinsed with methanol and the filtrate was concentrated in vacuo
to afford 0.113 g (98%) of the title alcohol as an off-white solid:
.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 7
[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl
4-Bromobenzenesulfonate
[0118] 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 hours. The reaction mixture was cooled to room temperature then
water (20 mL) was added. After 30 minutes, the two layers were
separated. The organic layer was extracted with 8% 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 hour 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
Intermediate 8
[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl
4-Methylbenzenesulfonate
[0119] A solution of
[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol
(0.13 g, 0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) and
triethylamine (0.65 mL, 4.7 mmol) in CH.sub.2Cl.sub.2 (8 mL) was
stirred at room temperature for 18 hours. CHCl.sub.3 (30 mL) and
H.sub.2O (30 mL) were added. The two layers were separated. The
aqueous layer was extracted with CHCl.sub.3 (20 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. Purification on SiO.sub.2, eluting with
(1:1) hexane:EtOAc gave 0.19 g (88%) of the title compound as a
brown syrup: mp 115-117.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 8.12 (d, J=8.6 Hz, 1H), 7.76 (m, 2H), 7.51 (d, J=9 Hz, 1H),
7.20-7.60 (m, 4H), 4.5-4.6 (m, 1H), 4.2-4.4 (m, 3H), 4.1-4.2 (m,
1H), 2.70 (s, 3H), 2.39 (s, 3H);
[0120] .sup.13C NMR (DMSO) .delta. 156.9, 145.4, 143.6, 137.9,
134.7, 132.2, 130.4, 128.7, 128.0, 121.8, 121.6, 121.3, 121.3,
118.3, 70.9, 68.6, 64.1, 60.1, 24.9, 21.4, 21.1, 14.4.
EXAMPLE 1
(2S)-2-{[4-(3-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4-
]dioxino[2,3-f]quinoline
[0121] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (647 mg, 1.44 mmol),
3-chlorophenyl-piperazine hydrochloride (1.0 g, 4.3 mmol) and
diisopropylethylamine (0.75 mL, 4.3 mmol) in anhydrous DMSO (6 mL)
were heated at 50.degree. C. overnight. The cooled reaction mixture
was diluted with saturated aqueous sodium bicarbonate (10 mL) and
extracted with ethyl acetate (3.times.10 mL). The combined organic
layers were washed with brine (3.times.30 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (5% MeOH/CH.sub.2Cl) afforded 280 mg
(68%) of the desired product as a beige solid: mp 110-112.degree.
C.; MS (ESI) m/z nnn [M+H].sup.+.
[0122] Elemental Analysis for:
C.sub.23H.sub.24ClN.sub.3O.sub.2.0.2H.sub.2O
[0123] Calc'd: C, 66.81; H, 5.95; N, 10.16
[0124] Found: C, 66.68; H, 6.02; N, 10.20
EXAMPLE 2
(2S)-2-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4-
]dioxino[2,3-f]quinoline
[0125] To a mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (577 mg, 1.28 mmol) and
4-chlorophenylpiperazine dihydrochloride (1.03 g, 3.81 mmol) in
anhydrous DMSO (10 mL) was added N,N-diisopropylethylamine (1.33
mL, 3.81 mmol). The reaction mixture was heated at 75.degree. C.
overnight. The cooled reaction mixture was diluted with saturated
aqueous sodium bicarbonate solution (50 mL) and extracted with
ethyl acetate (3.times.50 mL). The combined organic layers were
dried over MgSO.sub.4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (50% hexanes/EtOAc) afforded 260 mg
(15%) of the title compound as a tan solid: MS EI m/z 410.09
[M+H].sup.+.
[0126] Elemental Analysis for:
C.sub.23H.sub.24ClN.sub.3O.sub.2.0.67H.sub.2O.0.13
C.sub.4H.sub.8O.sub.2
[0127] Calc'd: C, 65.18; H, 6.13; N, 9.69
[0128] Found: C, 65.56; H, 6.09; N, 9.29
EXAMPLE 3
(2S)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro-
[1,4]dioxine[2,3-f]quinoline
[0129]
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-methylbenzene-sulfonate (0.41 g, 1.1 mmole) and
1-(3,4-dichlorophenyl)-piperazine (0.26 g, 1.1 mmole) were combined
in 3 mL of DMSO. This solution was stirred at 100.degree. C. under
nitrogen for 5.5 hours. The reaction was cooled to room
temperature. The solvent was evaporated at reduced pressure. The
residue was partitioned between ethyl acetate and saturated aqueous
sodium bicarbonate. The organic phase was washed twice with water,
dried over magnesium sulfate and concentrated in vacuum to give
0.61 g of oil. The crude residue was column chromatographed on
silica gel using a gradient of ethyl acetate and hexane to give
0.17 g of the title compound as a yellow oil. This was dissolved in
EtOH and fumaric acid (0.05 g, 0.4 mmole) was added. Filtration
gave 0.100 g of the title compound as a tan solid: mp
140-144.degree. C.; MS (ESI) m/z 444 [M+H].sup.+.
[0130] Elemental Analysis for:
C.sub.23H.sub.23Cl.sub.2N.sub.3O.sub.2.0.5
C.sub.4H.sub.4O.sub.4.0.75H.sub.2O
[0131] Calc'd: C, 58.20; H, 5.18; N, 8.14
[0132] Found: C, 58.35; H, 5.01; N, 7.75
EXAMPLE 4
(2S)-2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,-
4]dioxino[2,3-f]quinoline
[0133] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (783 mg, 1.74 mmol) and 2-methoxyphenyl
piperazine (1.0 g, 5.22 mmol) in anhydrous DMSO (10 mL) were heated
at 70.degree. C. overnight. The reaction was quenched with the
addition of saturated aqueous sodium bicarbonate (50 mL) and
extracted with EtOAc (3.times.50 mL). The combined organic layers
were dried over MgSO.sub.4, filtered, and concentrated in vacuo.
Flash chromatography on silica gel (50% EtOAc/hexanes) afforded 420
mg (60%) of the desire product as a white foam: mp 44-47.degree.
C.; MS (ESI) m/z 406 [M+H].sup.+.
[0134] Elemental Analysis for:
C.sub.24H.sub.27N.sub.3O.sub.3.0.22H.sub.2O.0.06
C.sub.4H.sub.8O.sub.2
[0135] Calc'd: C, 70.20; H, 6.79; N, 10.13
[0136] Found: C, 70.51; H, 6.87; N, 9.73
EXAMPLE 5
(2S)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-8-methyl-2,3-dihydro[1,-
4]dioxino[2,3-f]quinoline
[0137] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (702 mg, 1.56 mmol) and 3-methoxyphenyl
piperazine (890 mg, 4.63 mmol) in anhydrous DMSO (10 mL) were
heated at 65.degree. C. overnight. The cooled reaction mixture was
diluted with saturated aqueous sodium bicarbonate (50 mL) and
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Flash chromatography on silica gel (50% EtOAc/hexanes)
afforded 560 mg (88%) of the desired product as a white solid: mp
90-91.degree. C.; MS (ESI) m/z 406 [M+H].sup.+.
[0138] Elemental Analysis for:
C.sub.24H.sub.27N.sub.3O.sub.3.0.72H.sub.2O
[0139] Calc'd: C, 68.89; H, 6.85; N, 10.04
[0140] Found: C, 68.51; H, 6.79; N, 9.87
EXAMPLE 6
(2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,-
4]dioxino[2,3-f]quinoline
[0141] This compound was prepared as described for Example 5, using
4-methoxyphenyl piperazine (880 mg, 4.58 mmol) and 742 mg (1.65
mmol) of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzene-sulfonate, to afford 560 mg (84%) of the title
compound as a white solid: mp 164-165.degree. C.; MS (ESI) m/z 406
[M+H].sup.+.
[0142] Elemental Analysis for: C.sub.24H.sub.27N.sub.3O.sub.3
[0143] Calc'd: C, 71.09; H, 6.71; N, 10.36
[0144] Found: C, 70.87; H, 6.81; N, 10.29
EXAMPLE 7
(2S)-2-([4-(dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]methyl)-8-methyl-2-
,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0145] This compound was prepared as described for Example 5, using
1-(2,3-dihydro-1,4-benzodioxan-5-yl)-piperazine (710 mg, 3.22 mmol)
and 534 mg (1.19 mmol) of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromo-benzenesulfonate, to afford 480 mg (93%) of the title
compound as a yellow oil. The fumarate salt was generated using 0.9
eq of fumaric acid to yield 302 mg of a beige solid: mp
154-155.degree. C.; MS (ESI) m/z 434.16 [M+H].sup.+.
[0146] Elemental Analysis for: C.sub.25H.sub.27N.sub.3O.sub.4.0.5
C.sub.4H.sub.4O.sub.4.0.72H.sub.2O
[0147] Calc'd: C, 64.28; H, 6.08; N, 8.33
[0148] Found: C, 63.89; H, 5.97; N, 8.06
EXAMPLE 8
(2S)-8-methyl-2-[4-(3-trifluoromethyl-phenyl)piperazin-1-ylmethyl]-2,3-dih-
ydro[1,4]dioxine[2,3-f]quinoline
[0149] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (652 mg, 1.45 mmol) and
3-trifluoromethylpiperazine (0.82 mL, 4.34 mmol) in anhydrous DMSO
(5 mL) were heated at 50.degree. C. for 2 days. The cooled reaction
mixture was diluted with saturated aqueous sodium bicarbonate (10
mL) and extracted with ethyl acetate (3.times.10 mL). The combined
organic layers was washed with brine (3.times.30 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (70% EtOAc/hexanes) afforded 580 mg
(90%) of the title compound as a white solid: mp 123-124.degree.
C.; MS EI m/z 444.13 [M+H].sup.+.
[0150] Elemental Analysis for:
C.sub.24H.sub.24F.sub.3N.sub.3O.sub.2
[0151] Calc'd: C, 65.00; H, 5.45; N, 9.48
[0152] Found: C, 64.99; H, 5.52; N, 9.39
EXAMPLE 9
(2S)-8-methyl-2-[4-(3-fluorophenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]d-
ioxine[2,3-f]quinoline
[0153] This compound was prepared as described for Example 8, using
1-(3-fluorophenyl)-piperazine (1.35 g, 7.49 mmol), and 1.12 g (2.5
mmol) of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzene-sulfonate in 10 mL of DMSO, to afford 0.95 g (97%)
of the title compound as an orange-brown solid: mp 133-135.degree.
C.; MS (ESI) m/z 394 [M+H].sup.+.
[0154] Elemental Analysis for: C.sub.23H.sub.24FN.sub.3O.sub.2
[0155] Calc'd: C, 70.21; H, 6.15; N, 10.68
[0156] Found: C, 70.24; H, 6.24; N, 10.65
EXAMPLE 10
(2S)-2-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinoline
[0157] A mixture of 1-(2,3-dimethylphenyl)-piperazine (1.13 g, 5.94
mmol) and
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzene-sulfonate (871 mg, 1.93 mmol) in anhydrous DMSO (10
mL) was heated overnight at 70.degree. C. The reaction was diluted
with saturated aqueous sodium bicarbonate (50 mL) and extracted
with EtOAc (3.times.50 mL). The combined organic layers were dried
over MgSO.sub.4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (50% EtOAc/hexanes) afforded 700 mg
(90%) of the title compound as a white solid: mp 112-113.degree.
C.; MS (ESI) m/z 404 [M+H].sup.+.
[0158] Elemental Analysis for: C.sub.25H.sub.2N.sub.3O.sub.2
[0159] Calc'd: C, 74.41; H, 7.24; N, 10.41
[0160] Found: C, 73.98; H, 7.15; N, 10.34
EXAMPLE 11
(2S)-2-{[4-(3,4-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinoline
[0161] This compound was prepared as described for Example 10,
using 1-(3,4-dimethylphenyl)-piperazine (1.01 g, 5.33 mmol), and
804 mg (1.79 mmol) of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methy- l
4-bromobenzene-sulfonate, to afford 404 mg (68%) of the title
compound as a white foam: mp 118-120.degree. C.; MS (ESI) m/z 404
[M+H].sup.+.
[0162] Elemental Analysis for: C.sub.25H.sub.29N.sub.3O.sub.2
[0163] Calc'd: C, 74.41; H, 7.24; N, 10.41
[0164] Found: C, 74.19; H, 7.05, N, 10.29
EXAMPLE 12
(2S)-8-methyl-2-[(4-quinolin-2-ylpiperazin-1-yl)methyl]-2,3-dihydro[1,4]di-
oxino[2,3-f]quinoline
[0165] A solution of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (0.34 g, 0.75 mmol),
2-(1-piperazinyl)quinoline (0.46 g, 1.38 mmole), and 0.34 mL of
triethylamine (0.34 mL, 2.4 mmol) in dimethyl sulfoxide (30 mL) was
heated under nitrogen at 90.degree. C. for 12 hours. The cooled
reaction mixture was poured into water (100 ml) and extracted with
methylene chloride (3.times.100 ml). The organic layer was washed
with water (3.times.150 ml), dried over anhydrous sodium sulfate,
filtered and the solvent was removed under vacuum. Flash
chromatography on silica gel (Jan. 44, 1955 methanol/ethyl
acetate/hexanes) afforded 0.15 g (21%) of a light brown oil. The
oil was dissolved in ethyl acetate and made into its hydrochloride
salt using excess ethereal hydrochloric acid, to give 0.07 g of an
orange-brown solid: mp 237-243.degree. C.
[0166] Elemental Analysis for:
C.sub.26H.sub.26FN.sub.4O.sub.2.0.50H.sub.2O.4.0 HCl
[0167] Calc'd: C, 53.72; H, 5.37; N, 9.64
[0168] Found: C, 54.04; H, 5.82; N, 9.84
EXAMPLE 13
(2S)-8-methyl-2-{4-(6-nitroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihydr-
o[1,4]dioxino[2,3-f]quinoline
[0169] A solution of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (0.44 g, 0.97 mmol),
6-nitro-2-piperazin-1-yl-quinoline (0.3 g, 1.2 mmol) and
triethylamine (0.2 ml, 1.9 mmol) in dimethylsulfoxide (40 ml) was
heated at 90.degree. C. under nitrogen for 12 hours. The reaction
mixture was poured into water (100 ml) and extracted with methylene
chloride (3.times.100 ml). The organic layer was washed with water
(3.times.150 ml), dried over anhydrous sodium sulfate, filtered and
the solvent was removed under vacuum. The crude oil was column
chromatographed on silica gel (2.5% methanol-ethyl acetate). The
product-containing fractions were concentrated under vacuum to give
0.22 g (48%) of the title compound as a orange foam. The hydrogen
chloride salt was prepared in ethyl acetate and collected as a
yellow solid: mp: 200.degree. C. (dec).
[0170] Elemental Analysis for:
C.sub.26H.sub.25N.sub.5O.sub.4.2.75HCl
[0171] Calc'd: C, 54.62; H, 4.89; N, 12.25
[0172] Found: C, 54.97; H, 4.91; N, 12.38
EXAMPLE 14
(2S)-8-methyl-2-{4-(6-chloroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihyd-
ro[1,4]dioxino[2,3-f]quinoline
[0173] This compound was prepared by the same method as for Example
13, using 6-chloro-2-piperazin-1-yl-quinoline (0.60 g, 2.42 mmole),
0.55 g (1.2 mmol) of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzene-sulfonate, and 0.34 mL (2.4 mmol) of triethylamine
in dimethyl sulfoxide (36 mL), to afford 0.38 g (69%) of a light
yellows oil after chromatography. The oil was dissolved in ethyl
acetate and made into its hydrochloride salt using hydrochloric
acid in ether in excess to give 0.08 g of orange crystals: m.p.
209-218.degree. C.
[0174] Elemental Analysis for:
C.sub.26H.sub.25ClN.sub.4O.sub.2.0.50H.sub.2O.4.0 HCl.0.05
C.sub.4H.sub.8O.sub.2
[0175] Calc'd: C, 47.30; H, 5.36; N, 8.42
[0176] Found: C, 47.67; H, 5.43; N, 8.93
EXAMPLE 15
2-(4-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}pi-
perazin-1-yl}quinoline-6-carbonitrile
[0177] This compound was prepared by the same method as for Example
13, using 6-cyano-2-piperazin-1-yl-quinoline (0.30 g, 1.26 mmole),
0.28 g (0.63 mmol) of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzene-sulfonate, and 0.18 mL (1.3 mmol) of triethylamine
in dimethyl sulfoxide (36 mL), to afford 0.38 g (%) of a colorless
oil after chromatography. The oil was dissolved in ethyl acetate
and made into its hydrochloride salt using excess ethereal
hydrochloric acid to give 0.04 g of a grayish powder: m.p.
213-241.degree. C.
[0178] Elemental Analysis for: C.sub.27H.sub.25N.sub.5O.sub.2.3.0
HCl.0.25H.sub.2O.0.30 C.sub.4H.sub.8O.sub.2
[0179] Calc'd: C, 57.23; H, 5.26; N, 11.83
[0180] Found: C, 57.11; H, 5.66; N, 11.66
EXAMPLE 16
(2S)-2-{[4-(7-methoxy-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,-
3-dihydro[1,4]dioxino[2,3-f]quinoline
[0181] Step 1: To a stirred solution of TiCl.sub.4 (1 M solution in
CH.sub.2Cl.sub.2, 32 ml) and 7-methoxy-benzofuran-3-one (5.0 g,
30.5 mmol) in methylene chloride (200 ml) at -10.degree. C.,
ethyl-1-piperazine carboxylate (18.96 g, 120 mmol) was slowly
added. After the addition, the reaction mixture was warmed to room
temperature and slowly refluxed for 24 hrs. After cooling to room
temperature, the reaction was quenched with 2 N aqueous HCl. The
organic layer was separated and the aqueous layer was extracted
with chloroform. The combined organic layers were washed well with
water and dried over anhydrous MgSO.sub.4, then filtered and
concentrated. The brown residue was triturated with diethyl ether
and the separated brown solid was filtered and air-dried. The
product was pure enough and taken to next step without further
purification. Yield: 8.3 g, (90%); Mp 121.degree. C.; MS (ESI) m/z
305 [M+H].sup.+.
[0182] Step 2:
4-(7-Methoxy-benzofuran-3-yl)-piperazine-1-carboxylic acid ethyl
ester obtained in step 1, (7.0 g, 23 mmol) was dissolved in 95%
ethanol and 3 N aqueous NaOH (25 ml) was added. The reaction
mixture was refluxed for 24 hrs. At the end, the reaction mixture
was concentrated and extracted with chloroform. The combined
organic layers were washed well with brine, then were dried over
anhydrous MgSO.sub.4, filtered and concentrated. The brown oil was
pure enough to take on to the next step without purification.
Yield: 5.0 g (93%); MS (ESI) m/z 233 [M+H].sup.+.
[0183] Step 3: A mixture of
1-(7-methoxy-benzofuran-3-yl)-piperazine obtained from the step 2
(232 mg, 1 mmol) and
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-methylbenzenesulfonate (385 mg, 1 mmol) and diisopropyl ethyl
amine (5 ml, excess) was heated at 120.degree. C. for 24 hrs. At
the end, the reaction mixture was poured into water and extracted
with chloroform. The combined organic layers were washed well with
water, then were dried over anhydrous MgSO.sub.4, filtered and
concentrated. Flash chromatography on SiO.sub.2 (50% ethyl
acetate/hexane the 90% ethyl acetate/hexane afforded 89 mg (20%) of
the title compound as a yellow spongy solid: mp 56.degree. C.; MS
(ESI), m/z 446 [M+H]; .sup.1H NMR (CDCl.sub.3): .delta. 8.27 (d,
1H), 7.64 (d, 1H), 7.3-7.1 (m, 5H), 6.9 (d, 1H), 4.55-4.40 (m, 2H),
4.1-4.2 (m, 1H), 4.0 (s, 3H), 3.5 (t, 1H), 3.2-3.2 (m, 4H), 2.9-2.7
(m, 5H), 2.7 (s, 3H).
EXAMPLE 17
(2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline
[0184] Step 1: Following the procedure outlined in Example 16, Step
1, 4-(5-fluoro-benzofuran-3-yl)-piperazine-1-carboxylic acid ethyl
ester was prepared from 5-fluoro-benzofuran-3-one (3.0 g 19.7
mmol), TiCl.sub.4 (1 M solution in CH.sub.2Cl.sub.2, 7.0 ml) and
ethyl-1-piperazine carboxylate (3.9 g, 25 mmol). Yield: 3.5 g (60%)
of a brown oil: MS (ESI) m/z 293 [M+H].sup.+.
[0185] Step 2: Following the procedure outlined in Example 16, Step
2, 1-(5-fluoro-benzofuran-3-yl)-piperazine was prepared from
4-(5-fluoro-benzofuran-3-yl)-piperazine-1-carboxylic acid ethyl
ester (3.0 g 10.2 mmol) and 3 N aqueous NaOH (25 ml). Yield: 800 mg
(35%) of a brown oil: MS (ESI) m/z 221 [M+H].sup.+.
[0186] Step 3: Following the procedure outlined in Example 16, Step
3,
(2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,-
3-dihydro[1,4]dioxino-[2,3-f]quinoline was prepared starting from
1-(5-fluoro-benzofuran-3-yl)-piperazine (220 mg, 1 mmol) and
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-methylbenzenesulfonate (385 mg, 1 mmol). The product was purified
by silica gel column chromatography (80% ethyl acetate/hexane). The
HCl salt was prepared by dissolving the free base in 10% methanolic
HCl, to afford a green solid. Yield: 160 mg (36%); MS (ESI) m/z 434
[M+H].sup.+; .sup.1H NMR (d.sub.6-DMSO): .delta. 11.97 (bs, 1H),
9.3 (bs, 1H), 8.0-8.5 (m, 7H), 7.2 (t, 1H), 5.2 (bs, 1H), 4.6-3-0
(complex multiplet, 12H), 2.9 (s, 3H).
EXAMPLE 18
(2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro[-
1,4]dioxino[2,3-f]quinoline
[0187] Step 1: Following the procedure outlined in Example 16, Step
1, 4-(benzofuran-3-yl)-piperazine-1-carboxylic acid ethyl ester was
prepared starting from benzofuran-3-one (10.0 g 74.6 mmol),
TiCl.sub.4 (1 M solution in CH.sub.2Cl.sub.2, 60 ml) and
ethyl-1-piperazine carboxylate (48 g, 303 mmol). Yield: 16 g (78%)
of a brown oil; MS (ESI) m/z 275 [M+H].sup.+.
[0188] Step 2: Following the procedure outlined in Example 16, Step
2, 1-(benzofuran-3-yl)-piperazine was prepared starting from
4-(benzofuran-3-yl)-piperazine-1-carboxylic acid ethyl ester (15.0
g, 54.7 mmol) and 3 N aqueous NaOH (50 ml). Yield: 6.0 g (54%) of a
brown oil: MS (ESI) m/z 203 [M+H].sup.+.
[0189] Step 3: Following the procedure outlined in Example 16, Step
3,
(2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinoline was prepared starting from
1-(benzofuran-3-yl)-piperazine (404 mg, 2 mmol) and
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-methylbenzenesulfonate (770 mg, 2 mmol). The product was purified
by silica gel chromatography (60% ethyl acetate/hexane). Yield: 150
mg (18%); MS (ESI) m/z 416 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3):
.delta. 8.3 (d, 1H), 7.2-7.9 (m, 8H), 4.5-4.7 (m, 2H), 4.1 (m, 1H),
3.3-2.7 (m, 10H), 2.6 (s, 3H).
EXAMPLE 19
(2S)-8-methyl-2-{[(2S)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3--
dihydro[1,4]dioxino[2,3-f]quinoline
[0190] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (0.165 g, 0.367 mmol) and
(S)-2-(3-methyl-piperazin-1-yl)-quinoline (250 mg, 1.10 mmol) in
anhydrous dimethylsulfoxide (4 mL) was heated at 50.degree. C.
overnight. The cooled reaction was diluted with saturated aqueous
sodium bicarbonate (20 mL) and extracted with ethyl acetate
(3.times.20 mL). The combined organic layers were washed with brine
(30 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography on silica gel (2/2/96
methanol/2 M ammonia in methanol/methylene chloride) afforded 100
mg (62%) of the title compound as an off-white solid: mp
141-144.degree. C.; MS (ES) m/z 441 [M+H].sup.+;
[.alpha.].sub.D-36.5.degree. (c 1.0, DMSO).
[0191] Elemental Analysis for:
C.sub.27H.sub.28N.sub.4O.sub.2.0.2H.sub.2O
[0192] Calc'd: C, 73.02; H, 6.45; N, 12.61
[0193] Found: C, 72.91; H, 6.74; N, 12.52
EXAMPLE 20
2-((3R)-3-methyl-4-{[(2S))-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-
-2-yl]methyl}piperazin-1-yl]quinoline-6-carbonitrile
[0194] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (476 mg, 1.06 mmol) and
(R)-2-(3-methyl-piperazin-1-yl)-quinoline-6-carbonitrile (800 mg,
3.17 mmol) in anhydrous dimethylsulfoxide (11 mL) was heated at
50.degree. C. overnight. The cooled reaction was diluted with
saturated aqueous sodium bicarbonate (50 mL) and extracted with
ethyl acetate (3.times.50 mL). The combined organic layers were
washed with brine (70 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography on silica
gel (90/5/5 ethyl acetate/hexane/triethylamine) afforded 330 mg
(67%) of the title compound as light yellow stable foam: MS (ES)
m/z 466 [M+H].sup.+; [.alpha.].sub.D-34.0.degree. (c 1.0,
DMSO).
[0195] Elemental Analysis for:
C.sub.28H.sub.27N.sub.5O.sub.2.0.4H.sub.2O
[0196] Calc'd: C, 71.14; H, 5.93; N, 14.81
[0197] Found: C, 71.00; H, 5.79; N, 14.59
EXAMPLE 21
(2S)-8-methyl-4-{[(2R)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3--
dihydro[1,4]dioxino[2,3-f]quinoline
[0198] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (238 mg, 0.528 mmol) and
(R)-2-(3-methyl-piperazin-1-yl)-quinoline (350 mg, 1.58 mmol) in
anhydrous dimethylsulfoxide (6 mL) was heated at 50.degree. C.
overnight. The cooled reaction was diluted with saturated aqueous
sodium bicarbonate (30 mL) and extracted with ethyl acetate
(3.times.30 mL). The combined organic layers were washed with brine
(50 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography on silica gel (Feb. 2,
1996 methanol/2 M ammonia in methanol/methylene chloride) afforded
110 mg (47%) of the title compound as an off-white solid: mp
78-82.degree. C.; MS (ES) m/z 441 [M+H].sup.+;
[.alpha.].sub.D-33.00 (c 1.0, DMSO)
[0199] Elemental Analysis for:
C.sub.27H.sub.28N.sub.4O.sub.2.0.3H.sub.2O Calc'd: C, 72.72; H,
6.46; N, 12.56
[0200] Found: C, 72.77; H, 6.40; N, 12.29
EXAMPLE 22
(2S)-8-methyl-2-{[4-(2-naphthyl)piperazin-1-yl]methyl}-2,3-dihydro[1,4]dio-
xino[2,3-f]quinoline
[0201] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl
4-bromobenzenesulfonate (2.73 g, 6.06 mmol) and
1-naphthalen-2-yl-piperazine (3.86 g, 18.2 mmol) in anhydrous
dimethylsulfoxide (60 mL) was heated at 50.degree. C. overnight.
The cooled reaction was diluted with saturated aqueous sodium
bicarbonate (200 mL) and extracted with ethyl acetate (3.times.200
mL). The combined organic layers were washed with brine (300 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography on silica gel (Feb. 2, 1995
methanol/ammonium hydroxide/methylene chloride) did not provide
clean product. Re-chromatography on silica gel (90/5/5 ethyl
acetate/hexane/triethylamine) afforded 1.80 g (69%) of the title
compound as a beige solid: mg 134-137.degree. C.; MS (ES) m/z 426
[M+H].sup.+.
[0202] Elemental Analysis for:
C.sub.27H.sub.27N.sub.3O.sub.2.0.1H.sub.2O
[0203] Calc'd: C, 75.89; H, 6.42; N, 9.83
[0204] Found: C, 75.69; H, 6.68; N, 9.96
Intermediate
2-piperazin-1-yl-quinoline-6-carboxylic acid amide
[0205] To a 0.degree. C. solution of
6-cyano-2-piperazin-1-yl-quinoline (0.82 g, 3.5 mmol) and potassium
carbonate (0.17 g, 12.1 mmol) in dimethyl sulfoxide (10 ml) was
added hydrogen peroxide (30%, 1.3 ml). The mixture was stirred at
0.degree. C. for 4 hours, then was quenched with saturated sodium
hydrogen sulfite/sodium bicarbonate solution. The mixture was
extracted with dichloromethane. The solvent was removed under
vacuum. The mixture was adsorbed onto silica gel and chromatograph
on silica gel (20/2/78 methanol/ammonium hydroxide/ethyl acetate).
The product-containing fractions were concentrated under vacuum to
give 0.67 g of a light yellow oil. The oil was dissolved in ethyl
acetate and treated with excess ethereal hydrochloric acid to give
the hydrochloride salt as an off-white solid: mp 295-298.degree.
C.
[0206] Elemental Analysis for: C.sub.14H.sub.16N.sub.4O.1.5
HCl.0.25H.sub.2O
[0207] Calc'd: C, 53.30; H, 5.75; N, 17.76
[0208] Found: C, 53.09; H, 5.67; N, 18.00
EXAMPLE 23
(2S)-2-[4-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-piperazin-
-1-yl]-quinoline-6-carboxylic acid amide
[0209] A solution of (2R)-4-bromobenzenesulfonic acid
2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.56 g,
1.2 mmol) and triethylamine (0.26 ml, 1.9 mmol) in 20 ml of
dimethyl sulfoxide was heated under nitrogen at 90.degree. C. for
18 hours. The mixture was quenched with 1 N aqueous sodium
hydroxide and extracted with ethyl acetate. The organic layer was
washed with water. The solvent was removed under vacuum. The
mixture was then adsorbed onto silica get and chromatographed on
silica gel (Oct. 1, 1989 methanol/ammonium hydroxide ethyl
acetate). The product-containing fractions were concentrated under
vacuum to give 0.25 g of a colorless oil. The oil was dissolved in
ethyl acetate and treated with excess ethereal hydrochloric acid to
give 0.25 g of the hydrochloride salt as a yellow solid: m.p.
decomposed at 290.degree. C.
[0210] Elemental Analysis for: C.sub.27H.sub.27N.sub.5O.sub.3.2
HCl.H.sub.2O
[0211] Calc'd: C, 57.86; H, 5.58; N, 12.50
[0212] Found: C, 57.64; H, 5.60; N, 12.14
EXAMPLE 24
(2S)-2-[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin-1-
-yl]-quinoline-6-carbonitrile
[0213] A solution of (2R)-toluene-4-sulfonic acid
2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.49 g,
1.4 mmol), 6-cyano-2-piperazin-1-yl-quinoline (0.32 g, 1.6 mmol)
and triethylamine (0.28 ml, 2.0 mmol) in 20 ml of dimethyl
sulfoxide was heated under nitrogen at 90.degree. C. for 18 hours.
The mixture was quenched with 1 N aqueous sodium hydroxide and
extracted with methylene chloride. The organic layer was washed
with water. The solvent was removed under vacuum. The mixture was
adsorbed onto silica get and chromatographed on silica gel (Feb.
54, 1944 methanol/ethyl acetate/hexane). The product-containing,
fractions were concentrated under vacuum to give 0.33 g of a
colorless oil. The oil was dissolved in ethyl acetate and treated
with excess ethereal hydrochloric acid to give 0.24 g of the
hydrochloride sat as a yellow solid: mp decomposed at 205.degree.
C.
[0214] Elemental Analysis for: C.sub.26H.sub.23N.sub.5O.sub.2.3
HCl.2H.sub.2O
[0215] Calc'd: C, 53.57; H, 5.19; N, 12.01
[0216] Found: C, 53.29; H, 5.13; N, 11.72
EXAMPLE 25
(2S)-2-[4-(8-Ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-pip-
erazin-1-yl]-quinoline-6-carbonitrile
[0217] A solution of (2R)-toluene-4-sulfonic acid
8-ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester
(0.4 g, 1.0 mmol), 6-cyano-2-piperazin-1-yl-quinoline (0.24 g, 1.0
mmol) and triethylamine (0.218 ml, 1.5 mmol) in 20 ml of dimethyl
sulfoxide was heated under nitrogen at 90.degree. C. for 18 hours.
The mixture was quenched with 1 N aqueous sodium hydroxide and
extracted with methylene chloride. The organic layer was washed
with water. The solvent was removed under vacuum. The mixture was
adsorbed onto silica get and chromatographed on silica gel (Feb.
54, 1944 methanol/ethyl acetate/hexane. The product-containing
fractions were concentrated under vacuum to give 0.11 g of a clear
oil. The oil was dissolved in ethyl acetate and treated with excess
ethereal hydrochloric acid to give 0.12 g of the hydrochloric acid
salt as a yellow solid: m.p. decomposed at 184.degree. C.
[0218] Elemental Analysis for: C.sub.28H.sub.27N.sub.5O.sub.2.3
HCl.2H.sub.2O.0.5 C.sub.4H.sub.8O.sub.2
[0219] Calc'd: C, 55.01; H, 5.85; N, 10.69
[0220] Found: C, 55.16; H, 5.45; N, 10.77
EXAMPLE 26
(2S)-2-[4-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-
-8-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile
[0221] A solution of (2R)-toluene-4-sulfonic acid
2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethy-
l ester (0.5 g, 1.3 mmol), 6-cyano-2-piperazin-1-yl-quinoline (0.31
g, 1.3 mmol) and triethylamine (0.28 ml, 2.0 mmol) in 20 ml of
dimethyl sulfoxide was heated under nitrogen at 90.degree. C. for
18 hours. The mixture was quenched with 1 N aqueous sodium
hydroxide and extracted with methylene chloride. The organic layer
was washed with water. The solvent was removed under vacuum. The
mixture was adsorbed onto silica get and chromatographed on silica
gel (Feb. 54, 1944 methanol/ethyl acetate/hexane). The
product-containing fractions were concentrated under vacuum to give
0.34 g of a clear oil. The oil was dissolved in ethyl acetate and
treated with excess ethereal hydrochloric acid to give 0.26 g of
the hydrochloride salt as a white powder: m.p. decomposed at
227.degree. C.
[0222] Elemental Analysis for: C.sub.25H.sub.23N.sub.5O.sub.3.2
HCl.2H.sub.2O
[0223] Calc'd: C, 54.55; H, 5.31; N, 12.72
[0224] Found: C, 54.70; H, 5.01; N, 12.58
EXAMPLE 27
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihyd-
ro[1,4]dioxino[2,3-f]quinoline
[0225] The title compound was prepared as per either general Scheme
I or II. ##STR19##
Step A. 6-Bromo-2-Chloroquinoline
[0226] A suspension of 6-bromo-3,4-dihydro-2-1H-quinolin-2-one
(4.068 g, 18 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(4.92 g, 21.6 mmol) in toluene (60 mL) is treated dropwise with
phosphorous oxychloride (8.5 mL, 90 mmol). After heating for 2
hours at 92.degree. C. the mixture is cooled, quenched with ice
water, basified with 50% aqueous sodium hydroxide and extracted
with ethyl acetate. The extracts are dried over anhydrous magnesium
sulfate and evaporated. The residue is flash chromatographed on
silica gel Merck-60 using a gradient of ethyl acetate (10-25%) in
hexane to provide the title compound (4.27 g).
[0227] MS[(+)APCl, m/z]: 242.1 [M+H].sup.+
[0228] Anal. Calcd. For C.sub.9H.sub.5BrClN: C, 44.58; H, 2.08; N,
5.78. Found: C, 44.46; H, 2.04; N, 5.78
Step B. 6-Bromo-2-piperazin-1-yl-quinoline
[0229] To a solution of 6-bromo-2-chloroquinoline of Step A (1.25
g, 5.15 mmol) in N,N-dimethylformamide (35 mL) is added piperazine
(4.43 g, 51.4 mmol) and the mixture is heated at 110.degree. C.
under nitrogen for 3 hours. After cooling, it is diluted with
saturated aqueous sodium bicarbonate and extracted with ethyl
acetate. The extracts are dried over anhydrous magnesium sulfate
and evaporated to dryness.
[0230] The residue is flash chromatographed on silica gel Merck-60
using a gradient of methanol (0-15%) in dichloromethane containing
0.2% ammonium hydroxide to provide the title compound as an
off-white solid (1.3 g), m.p. 129-130.degree. C.
[0231] MS [(+)ES, m/z]: 292.1 [M+H].sup.+
[0232] Anal. Calcd for C.sub.13H.sub.14BrN.sub.3: C, 53.44; H,
4.83; N, 14.38. Found: C, 53.17; H, 4.81; N, 14.41
Step C.
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2-
,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0233] To a solution of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4
bromobenzene sulfonate (2.31 g, 5.13 mmol) in dimethylsulfoxide
(123 mL) is added the 6-bromo-2-piperazin-1-yl-quinoline of Step B
(1.5 g, 5.13 mmol) and the mixture is heated at 75.degree. C. under
nitrogen overnight. The mixture is poured into saturated aqueous
sodium bicarbonate and extracted with ethyl acetate. The extracts
are dried over anhydrous magnesium sulfate and evaporated to
dryness. The residue is flash chromatographed on silica gel
Merck-60 using a gradient of methanol (0.5-2%) in ethyl
acetate-hexane (55:45) to provide the title compound as an
off-white solid (1.02 g), m.p. 153-154.degree. C.
[0234] MS [(+)ES, m/z]: 505.1 (M+H].sup.+
[0235] Anal. Calcd. For C.sub.26H.sub.25BrN.sub.4O.sub.2: C, 61.79;
H, 4.99; N, 11.09. Found: C, 62.24; H, 4.72; N, 10.71
EXAMPLE 28
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihyd-
ro[1,4]dioxino[2,3-f]quinoline
[0236] ##STR20##
Step A.sup.1.
(2S)-4-(8-Methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-pipe-
razine 1 carboxylic acid tert-butyl ester
[0237] To a suspension of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromo-
benzene sulfonate (0.783 g, 1.74 mmol) is added N-Boc-piperazine
(0.972 g, 5.22 mmol) in dimethylsulfoxide (10 mL), The mixture is
heated at 75.degree. C. under nitrogen for 4 hours, cooled, poured
into saturated aqueous sodium bicarbonate and extracted with ethyl
acetate. The extracts are dried over anhydrous magnesium sulfate
and evaporated to dryness. The residue is flash chromatographed on
silica gel Merck-60 using a gradient of ethyl acetate (20-50%) in
hexane to provide the title compound as a colorless glass (0.635
g).
[0238] MS [(+)ES, m/z]: 400.2 {M+H].sup.+
Step B.sup.1.
8-Methyl-2-piperazin-1-ylmethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0239] To an ice-cold solution of
(2S)-4-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-pipe-
razine 1 carboxylic acid tert-butyl ester of Step A' (0.550 g, 1.37
mmol) in ethyl acetate (8 mL) is added dropwise 1 M hydrochloric
acid in diethyl ether (15 mL). The mixture is allowed to come to
room temperature, diluted with methanol (10-15 mL) and warmed at
35.degree. C. until the reaction is complete by TLC. The solvents
are removed in vacuo and the residue is slurried in diethyl ether.
The solid is collected and dried in vacuo. The free base is
prepared by basifying an aqueous solution of the hydrochloride salt
with concentrated aqueous sodium hydroxide, followed by extraction
with dichloromethane. The title compound is obtained as a thick oil
(quantitative yield).
[0240] MS [(+)ES, m/z]: 300.1 [M+H].sup.+
Step C.sup.1.
(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihy-
dro[1,4]dioxino[2,3-f]quinoline
[0241] A mixture of
8-methyl-2-piperazin-1-ylmethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
of Step B' (0.493 g, 1.64 mmol) and 6-bromo-2-chloroquinoline of
Example 1, Step A (0.507 g) is heated at 95.degree. C. under
nitrogen for 6 hours, followed by heating at 105.degree. C. for 4
hours. The mixture is cooled, poured into saturated aqueous sodium
bicarbonate and extracted with ethyl acetate. The extracts are
dried over anhydrous magnesium sulfate and evaporated to dryness.
The residue is flash chromatographed on silica Merck-60 using a
gradient of methanol (0.5-2%) in dichloromethane-hexane (45:55), to
provide the title compound (0.147 g) identical to the compound of
Example 27, Step C.
EXAMPLE 29
[0242] The compound of Step B' of Scheme 2 can be alternatively,
prepared in one step according to the following procedure
##STR21##
8-Methyl-2-piperazin-1-ylmethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0243] A mixture of
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromo-
benzene sulfonate (1.35 g, 3 mmol) and piperazine (2.58 g, 30 mmol)
in dimethylsulfoxide (16 mL) is heated at 75.degree. C. under
nitrogen for 1 hour, cooled and poured into saturated aqueous
sodium bicarbonate. The mixture is extracted with ethyl acetate and
the extracts are dried over anhydrous magnesium sulfate and
evaporated to dryness. The residue is flash chromatographed on
silica gel Merck-60 using a gradient of methanol (5-25%) in
dichloromethane containing 0.2% ammonium hydroxide to provide the
title compound as an off-white oil (0.736 g), identical to the
compound of example 1B, step B'.
EXAMPLE 30
(2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-dih-
ydro[1,4]dioxino[2,3-f]quinoline
[0244] The title compound was prepared according to Scheme III.
##STR22##
Step A. 6-Methoxyquinoline 1-oxide
[0245] A solution of 6-methoxyquinoline (11.21 g, 70 mmol) in
glacial acetic acid is treated dropwise with 30% hydrogen peroxide
(15 mL) and then heated at 82.degree. C. for 19 hours. The reaction
mixture is cooled, poured onto ice and carefully basified with
concentrated ammonium hydroxide. The precipitate is collected,
washed with hexane and dried in vacuo to provide the title compound
(quantitative yield), which is used as such in the next step.
[0246] MS [(+)ES, m/z]: 176.1 [M+H].sup.+
Step B. 6-Methoxy-1H-quinolin-2-one
[0247] The crude 6-methoxyquinoline 1-oxide of Step A (70 mmol) is
suspended in acetic anhydride (70 mL) and heated at 75.degree. C.
under nitrogen for 18 hours. The mixture is poured onto ice and
carefully basified with ammonium hydroxide. The precipitate is
collected, washed with hexane and dried. The solid is suspended in
dichloromethane, filtered and dried to provide the title compound
(5.136 g). Additional material (1.79 g) is obtained by flash
chromatography of the mother liquors on silica gel Marck-60 using a
gradient of methanol (1-5%) in hexane-ethyl acetate (1:1).
[0248] MS [(+)ES, m/z]: 176.1 [M+H].sup.+
Step C. 2-Chloro-6-methoxy-quinoline
[0249] A suspension of 6-methoxy-1H-quinolin-2-one of Step B (5.136
g, 29.2 mmol) in toluene (100 mL) is treated with phosphorous
oxychloride 913.8 mL) and heated at 95.degree. C. under nitrogen
for 2 hours. The crude mixture is poured into ice water and
basified with 50% aqueous sodium hydroxide. The solution is
extracted with ethyl acetate, the extracts are dried over anhydrous
magnesium sulfate and evaporated to dryness. The residue is
pre-absorbed on silica gel Merck-60 and flash chromatographed using
a gradient of ethyl acetate (10-20%) in hexane to provide the title
compound (5.25 g) as a white crystalline solid, m.p.
105-107.degree. C.
[0250] MS [(+)ES, m/z]: 194.04 [M+H].sup.+
Step D. 6-Methoxy-2-piperazin-1-yl-quinoline
[0251] To a solution of 2-chloro-6-methoxy-quinoline of Step C (2.5
g, 12.91 mmol) in N,N-dimethylformamide (50 mL) is added piperazine
(12 g) and the mixture is heated at 110.degree. C. under nitrogen
for 6 hours. The solution is diluted with saturated aqueous sodium
bicarbonate and extracted with ethyl acetate. The extracts are
dried over anhydrous magnesium sulfate and evaporated to dryness.
The residue is flash chromatographed on silica gel Merck-60 using a
gradient of methanol (4-10%) in dichloromethane containing 0.2%
ammonium hydroxide to provide the title compound (1.6 g) as an
off-white solid, m.p. 95-97.degree. C.
[0252] MS [(+)ES, m/z]: 244.1 [M+H].sup.+
Step E.
(2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-
-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0253] A mixture of 6-methoxy-2-piperazin-1-yl-quinoline of Step D
(1.05 g, 4.31 mmol) in dimethylsulfoxide (15 mL) and
[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromo-
benzene sulfonate (1.62 g) is heated at 80.degree. C. under
nitrogen for 3 hours and at 90.degree. C. for 1 additional hour.
The solution is poured into saturated aqueous sodium bicarbonate
and extracted with ethyl acetate. The extracts are dried over
anhydrous magnesium sulfate and evaporated to dryness. The residue
is flash chromatographed on silica gel Merck-60 using a gradient of
methanol (0.5-3%) in dichloromethane-hexane (1:1) containing 0.1%
ammonium hydroxide to provide the title compound (0.790 g). The
pure material is charcoalized (in ethyl acetate), filtered,
evaporated and induced to crystallize from hexane by sonication.
The off-white solid melts at 158-160.degree. C.
[0254] Calcd for C.sub.27H.sub.28N.sub.4O.sub.3 0.3H.sub.2O: C,
70.20; H, 6.24; N, 12.13. Found; C, 70.47; H, 6.95; N, 12.09
[0255] MS[(+)ES, m/z]: 457.1 [M+H].sup.+
EXAMPLE 31
(2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methy-
l-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0256] The compound may be prepared according to Scheme IV.
##STR23##
Step A. 6-Trifluoromethoxy-quinoline
[0257] A mechanically stirred mixture of 4-trifluoromethoxyaniline
(8.85 g, 50 mmol), iron(II) sulfate heptahydrate (3 g),
3-nitrobenzene sulfonate sodium salt (16.85 g), boric acid (5 g)
and glycerol (125 mL) is cooled in an ice bath and treated dropwise
with concentrated sulfuric acid (30 mL). The mixture is then heated
to 150.degree. C. for 2 hours, cooled, poured onto ice and
carefully basified with 50% aqueous sodium hydroxide. The mixture
is repeatedly extracted with diethyl ether, the combined extracts
are washed with brine, dried over anhydrous magnesium sulfate and
evaporated to dryness (bath temperature below 32.degree. C.). The
residue is flash chromatographed on silica gel Merck-60 using
dichloromethane to provide the title compound as a pale yellow oil,
which is used as such in the next step.
[0258] MS [(+)ES, m/z]: 214.0 [M+H].sup.+
Step B. 6-Trifluoromethoxy-quinoline 1-oxide
[0259] To a solution of the crude 6-trifluoromethoxy-quinoline of
Step A (obtained from 50 mmol of 4-trifluoromethoxy aniline) in
glacial acetic acid (54 mL) is added dropwise 30% hydrogen peroxide
(8 mL). The mixture is heated at 82.degree. C. under nitrogen for
16 hours, cooled, carefully basified with concentrated ammonium
hydroxide and extracted with ethyl acetate. The extracts are washed
with brine, dried over anhydrous magnesium sulfate and evaporated
to dryness. The residue is twice azeotroped with benzene, and then
flash chromatographed on silica gel Merck-60 using dichloromethane
followed by a gradient of methanol (0.5-2%) in dichloromethane to
provide the title compound as a pale brown oil that solidifies upon
standing. The pale brown crystals (4.8 g) melt at 68-70.degree.
C.
[0260] MS [(+)ES, m/z]: 230.0 [M+H].sup.+
Step C. 6-Trifluoromethoxy-1H-quinolin-2-one
[0261] A solution of 6-trifluoromethoxy-quinoline 1-oxide of Step B
(4.58 g, 20 mmol) in acetic anhydride (20 mL) is heated at
135.degree. C. under nitrogen for 4 hours. The mixture is poured
onto ice, carefully basified with sodium carbonate and extracted
with ethyl acetate. The extracts are washed with brine, dried over
anhydrous magnesium sulfate and evaporated to dryness. The residue
is flash chromatographed on silica Merck-60 using a gradient of
methanol (0-3%) in hexane-ethyl acetate (1:1). The appropriate
fractions are combined and evaporated. The residue is triturated
with diethyl ether. The insoluble is collected, washed with hexane
and dried to provide the title compound as a pale brown crystalline
solid (1.086 g), m.p. 215-217.degree. C.
[0262] MS [(+)ES, m/z]: 230.0 [M+H].sup.+
Step D. 2-Chloro-6-trifluoromethoxy-quinoline
[0263] The title compound may be prepared in a manner analogous to
Example 3, Step C from the 6-trifluoromethoxy-1H-quinolin-2-one of
Step C and phosphorous oxychloride.
Step E. 2-piperazin-1-yl-6-trifluoromethoxy-quinoline
[0264] The title compound is being prepared in a manner analogous
to Example 3, Step D from the 2-chloro-6-trifluoromethoxy-quinoline
of Step D and piperazine.
Step F.
(2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-
-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0265] The title compound may be prepared in a manner analogous to
Example 3, Step E from the
2-piperazin-1-yl-6-trifluoromethoxy-quinoline of Step E and
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromob-
enzene sulfonate in dimethylsulfoxide.
EXAMPLE 32
2-[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-2,3-dihydro-[-
1,4]dioxino[2,3-f]quinoline
[0266] The compound may be prepared according to Scheme V.
##STR24##
Step A. 6-Fluoroquinoline
[0267] A mechanically stirred mixture of 4-fluoro aniline (31 g,
279 mmol), iron(II) sulfate heptahydrate (9.4 g), nitrobenzene
(19.6 g), boric acid (17 g), and glycerol (102 g) is cooled to ice
bath temperature and treated dropwise with concentrated sulfuric
acid (45 mL). The mixture is heated at 156.degree. C. for 20 hours,
then cooled in an ice bath and carefully basified with 50% aqueous
sodium hydroxide. The mixture is repeatedly extracted with diethyl
ether and then with dichloromethane. The combined extracts are
washed with brine, dried over anhydrous magnesium sulfate,
filtered, and evaporated to dryness (bath temperature below
30.degree. C.). The residue is flash chromatographed on silica gel
Merck-60 using a gradient of methanol (0-2%) in dichloromethane to
provide the title compound as an oil (33 g), which is used without
further purification.
Step B. 6-Fluoroquinoline 1-oxide
[0268] The 6-fluoroquinoline from Step A (6.0 g, 40.8 mmol) in
glacial acetic acid (60 mL) is treated dropwise with hydrogen
peroxide (14 mL) and heated with an oil bath to 78.degree. C.
overnight. The reaction mixture is concentrated at reduced pressure
and the concentrate basified with solid sodium carbonate and
extracted with dichloromethane. The extracts are dried over
anhydrous magnesium sulfate, filtered, and concentrated to a light
yellow solid (6.0 g). The residue is flash chromatographed on
silica gel Merck-60 using a gradient of methanol (5-10%) in
dichloromethane to provide the title compound as a white solid
(0.99 g), m.p. 105-106.degree. C.
[0269] MS [(+) ES, m/z]: 164.0 [M+H].sup.+;
[0270] Anal. Calcd for C.sub.9H.sub.6FNO: C, 66.26; H, 3.71; N,
8.59. Found: C, 66.09; H, 3.36; N, 8.65.
Step C. 6-Fluoroquinolin-2(1H)-one
[0271] A solution of 6-fluoroquinoline 1-oxide from Step B (5.0 g,
30.65 mmol) in acetic anhydride (30 mL) is heated at 110.degree. C.
for 6.5 hours. The reaction is allowed to stand at room temperature
overnight. The solid (1.1 g) is collected and recrystallized from
anhydrous ethanol (75 mL). The reddish crystals are collected by
filtration and dried under high vacuum to give the title compound
(0.653 g), m.p. dec. 269-270.degree. C.
[0272] MS [(-)ES, m/z}: 162.0 (M-H].sup.-
Step D. 2-Chloro-6-fluoroquinoline
[0273] A mixture of 6-fluoroquinolin-2(1H)-one from Step C (0.971
g, 6 mmol), phosphorous oxychloride (2.83 mL, 30 mmol), and toluene
(20 mL) is heated at 95.degree. C. for 2 hours. The reaction is
cooled in an ice bath and basified with 50% aqueous sodium
hydroxide. The mixture is extracted with ethyl acetate and the
extracts are dried over anhydrous magnesium sulfate, filtered, and
concentrated to an orange solid (1.01 g). The residue is flash
chromatographed on silica gel Merck-60 with 5% ethyl acetate in
hexane to provide the title compound as a light pink solid, m.p.
99-101.degree. C.
[0274] MS [EI, m/z]: 181 [M].sup.+
[0275] Anal. Calcd for C.sub.9H.sub.5ClFN: C, 59.53; H, 2.78; N,
7.71. Found: C, 59.56; H, 2.79; N, 7.59.
Step E. 4-(6-Fluoroquinolin-2-yl)piperazine-1-carbaldehyde
[0276] A solution of 2-chloro-6-fluoroquinoline from Step D (0.8 g,
4.4 mmol) and piperazine (3.79 g, 44 mmol) in N,N-dimethylformamide
(20 mL) is heated at 110.degree. C. for 2 hours. The reaction is
then basified with saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The extracts are dried over anhydrous
magnesium sulfate, filtered, and concentrated to give a tan oil.
The oil is flash chromatographed on silica gel Merck-60 with a
gradient of methanolic ammonia (5-10%) in ethyl acetate to provide
the title compound (0.330 g) as an off-white solid, m.p.
110-111.degree. C.
[0277] MS [(+) ES, m/z]: 260.1 [M+H].sup.+
Step F. 6-Fluoro-2-piperazin-1-yl-quinoline
[0278] The title compound may be prepared by treatment of
4-(6-fluoroquinolin-2-yl)piperazine-1-carbaldehyde of Step E with
4M sulfuric acid.
Step G.
(2S)-2-{[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-
-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0279] The title compound is being prepared in a manner analogous
to Example 3, Step E from the 6-fluoro-2-piperazin-1-yl-quinoline
of Step F and
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-br-
omobenzene sulfonate in dimethylsulfoxide.
EXAMPLE 33
(2S)-2-{[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-
-dihydro[1,4]dioxino[2,3-f]quinoline
[0280] The title compound was prepared according to Scheme VI.
##STR25##
Step A. 2-[1,4-Diazepan-2-yl-6-methoxy-quinoline
[0281] To a solution of 2-chloro-6-methoxy-quinoline (2.5 g, 12.91
mmol) in N,N-dimethylformamide (50 mL) is added homopiperazine
(7.76 g, 77.46 mmol) and the mixture is heated at 110.degree. C.
under nitrogen for 6 hours. The solution is poured into saturated
aqueous sodium bicarbonate and extracted with ethyl acetate. The
extracts are dried over anhydrous magnesium sulfate and evaporated
to dryness. The residue is flash chromatographed on silica gel
Merck-60 using a gradient of methanol (2-10%) in dichloromethane
containing 0.1% ammonium hydroxide to provide the title compound as
a pale yellow syrup (1.54 g).
[0282] MS [(+)ES, m/z]: 258.2 [M+H].sup.+.
Step B.
(2S)-2-[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-met-
hyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0283] A mixture of 2-[1,4-diazepan-2-yl-6-methoxy-quinoline of
Step A (1.45 g, 5.66 mmol) and
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromob-
enzene sulfonate (3.1 g) in dimethylsulfoxide (15 mL) is heated at
75.degree. C. under nitrogen for 9 hours. The reaction mixture is
diluted with saturated aqueous sodium bicarbonate and extracted
with ethyl acetate. The extracts are dried over anhydrous magnesium
sulfate and evaporated to dryness. The residue is flash
chromatographed on silica gel Merck-60 using a gradient of methanol
(0.4-1.5%) in hexane-dichloromethane (1:1) containing 0.1% ammonium
hydroxide to provide the title compound as a foam (0.800 g). The
latter is dissolved in ethyl acetate, treated with charcoal,
filtered, and treated with excess 1 M hydrochloric acid in diethyl
ether. The mixture is evaporated and the residue triturated with
cold diethyl ether. The insoluble is collected, washed with diethyl
ether, and dried in vacuo to provide the hydrochloride salt of the
title compound as a yellow solid, m.p. dec. around 238.degree.
C.
[0284] Anal. Calcd for
C.sub.28H.sub.30N.sub.4O.sub.3.3HCl.2H.sub.2O: C, 54.60; H, 6.05;
N, 9.10. Found: C, 54.27; H, 5.68; N, 8.70.
[0285] MS[(+)ES, m/z]: 471.2 [M+H].sup.+
EXAMPLE 34
2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}-1-
,4-diazepan-1-yl)quinoline-6-carbonitrile
[0286] The title compound was prepared according to Scheme VII.
##STR26## Step A. 2-(1,4-Diazepan-1-yl)quinoline-6-carbonitrile
[0287] A solution of 2-chloroquinoline-6-carbonitrile (2.0 g, 10.6
mmol) in N,N-dimethylformamide (50 mL) is heated to 50.degree. C.
under nitrogen. Homopiperazine (10.62 g, 106 mmol) is added and the
solution is heated at 100.degree. C. for 2.5 hours. The cold
solution is poured into saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The extracts are dried over anhydrous
magnesium sulfate and concentrated to a light brown oil (3.44 g).
The oil is flash chromatographed on silica Merck-60 eluting with a
gradient of methanol (5-15%) in dichloromethane containing 0.2%
ammonium hydroxide to provide the title compound (2.466) as a
yellow waxy solid.
[0288] MS [(+) ES, m/z]; 253.2 ([M+H].sup.+
Step B.
2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]m-
ethyl}-1,4-diazepan-1-yl)quinoline-6-carbonitrile
[0289] 2-(1,4-Diazepan-1-yl)quinoline-6-carbonitrile from Step A
(1.0 g, 3.96 mmol) is taken up in dimethylsulfoxide (10 mL) and
heated to 50.degree. C. under nitrogen.
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromob-
enzene sulfonate (1.78 g, 3.96 mmol) is added, followed by
triethylamine (0.58 mL, 4.16 mmol). The black solution is heated at
90.degree. C. for 21 hours. 1 N Sodium hydroxide is added to the
cold reaction mixture, which is then extracted with
dichloromethane. The extracts are dried over anhydrous magnesium
sulfate, and concentrated to give a black oil. The oil is flash
chromatographed on silica gel Merck-60 using 48% ethyl acetate/48%
hexane/2% methanol to provide a tan oil (0.492 g). The material is
further purified by prep HPLC [Primeshere CN, 5.times.25 cm column,
8:2 dichloromethane-methanol gradient in heptane, flow rate 20
mL/min, detection at 254 nm, purity>99.9%] to give the title
compound as an off white solid, m.p. 80-85.degree. C.
[0290] MS [(+)ES, m/z]: 466.2 ([M+H].sup.+
EXAMPLE 35
(2S)-2-{[4-(6-Trifluoromethoxy-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8--
methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0291] The title compound may be prepared according to Scheme VIII.
##STR27##
Step A. 2-[1,4-Diazepan-2-yl-6-trifluoromethoxy-quinoline
[0292] The title compound is being prepared in a manner analogous
to Example 33, Step A from 2-chloro-6-trifluoromethoxy-quinoline
and homopiperazine.
Step B.
(2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)-1,4-diazepan-1-yl]met-
hyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
[0293] The title compound is being prepared in a manner analogous
to Example 33, Step B from
2-[1,4-diazepan-2-yl-6-trifluoromethoxy-quinoline and
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4bro-
mobenzene sulfonate in dimethylsulfoxide.
EXAMPLE 36
2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,3-dihyd-
ro-[1,4]dioxino[2,3-f]quinoline
[0294] The title compound may be prepared according to Scheme IX.
##STR28##
Step A. 6-Fluoro-2-[1,4]diazepan-1-yl-quinoline
[0295] The title compound may be prepared in analogous manner to
Example 33, Step A from 2-chloro-6-fluoro-quinoline and
homopiperazine
Step B.
2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2-
,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0296] The title compound is being prepared in a manner analogous
to Example 33, Step B from 6-fluoro-2-[1,4]diazepan-1yl-quinoline
of Step A and
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-br-
omobenzene sulfonate in dimethylsulfoxide.
EXAMPLE 37
(2S)-2-{[4-(6-Bromo-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3--
dihydro[1,4]dioxino[2,3-f]quinoline
[0297] The title compound may be prepared according to Scheme X.
##STR29##
Step A. 6-Bromo-2-[1,4]diazepan-1-yl-quinoline
[0298] The title compound may be prepared in a manner analogous to
Example 33, Step A from 2-chloro-6-bromo-quinoline and
homopiperazine.
Step B.
2-[4-(6-Bromo-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,-
3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0299] The title compound may be prepared in a manner analogous to
Example 33, Step B from 6-bromo-2-[1,4]diazepan-1yl-quinoline of
Step A and
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-br-
omobenzene sulfonate in dimethylsulfoxide.
EXAMPLE 38
8-Methyl-2-(4-quinolin-2-yl-[1,4]diazepan-1-ylmethyl)-2,3-dihydro-[1,4]dio-
xino[2,3-f]quinoline
[0300] The compound may be prepared according to Scheme XI.
##STR30##
[0301] To a solution of 2-[1,4]-diazepan-1-yl-quinoline
(Z)-2-butenedioate (20.5 g, 1.45 mmol) in dimethylsulfoxide (5 mL)
is added
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4--
bromobenzene sulfonate (0.656 g, 1.456 mmol), followed by
triethylamine (1.13 mL, 11.2 mmol). The mixture is heated at
80.degree. C. under nitrogen for 17 hours, cooled, diluted ethyl
acetate, basified with saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The extracts are dried over anhydrous
magnesium sulfate, and concentrated to give a brown oil. The oil is
flash chromatographed on silica gel Merck-60 to provide the title
compound.
EXAMPLE 39
8-Methyl-2-[4-(4-methyl-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-2,3-dihyd-
ro[1,4]dioxino[2,3-f]quinoline
[0302] The compound may be prepared according to Scheme XII.
##STR31##
[0303] To a solution of 2-[1,4]diazepan-1-yl-4-methyl-quinoline
(0.70 g, 1.478 mmol) in dimethylsulfoxide (5 mL) is added
(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromob-
enzene sulfonate (0.600 g, 1.33 mmol), followed by triethylamine
(0.618 mL, 4.4 mmol). The mixture is heated at 75.degree. C. under
nitrogen overnight, cooled, diluted ethyl acetate, basified with
saturated aqueous sodium bicarbonate and extracted with ethyl
acetate. The extracts are dried over anhydrous magnesium sulfate,
and concentrated to give a brown oil. The oil is flash
chromatographed on silica gel Merck-60 to provide the title
compound.
[0304] 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.
[0305] The disclosures of each patent, patent application, and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0306] 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.
* * * * *