U.S. patent application number 14/219304 was filed with the patent office on 2014-07-24 for thiophenyl and pyrrolyl azepines as serotonin 5-ht2c receptor ligands and uses thereof.
This patent application is currently assigned to ABT Holding Company. The applicant listed for this patent is ABT Holding Company. Invention is credited to Youssef L. Bennani, David C. Bom, Michael J. Robarge, L. Nathan Tumey.
Application Number | 20140206672 14/219304 |
Document ID | / |
Family ID | 38288237 |
Filed Date | 2014-07-24 |
United States Patent
Application |
20140206672 |
Kind Code |
A1 |
Tumey; L. Nathan ; et
al. |
July 24, 2014 |
THIOPHENYL AND PYRROLYL AZEPINES AS SEROTONIN 5-HT2C RECEPTOR
LIGANDS AND USES THEREOF
Abstract
The present invention generally relates to a series of
compounds, to pharmaceutical compositions containing the compounds,
and to use of the compounds and compositions as therapeutic agents.
More specifically, compounds of the present invention are
thiophenyl and pyrrolyl azepine compounds. These compounds are
serotonin receptor (5-HT.sub.2c) ligands and are useful for
treating diseases, disorders, and conditions wherein modulation of
the activity of serotonin receptors (5-HT.sub.2c) is desired (e.g.
addiction, anxiety, depression, obesity, and others).
Inventors: |
Tumey; L. Nathan; (New
Windsor, NY) ; Bom; David C.; (Broadview Heights,
OH) ; Bennani; Youssef L.; (Shaker Heights, OH)
; Robarge; Michael J.; (Burton, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABT Holding Company |
Cleveland |
OH |
US |
|
|
Assignee: |
ABT Holding Company
Cleveland
OH
|
Family ID: |
38288237 |
Appl. No.: |
14/219304 |
Filed: |
March 19, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13005395 |
Jan 12, 2011 |
8716276 |
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14219304 |
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11654979 |
Jan 17, 2007 |
7893051 |
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13005395 |
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60760240 |
Jan 19, 2006 |
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Current U.S.
Class: |
514/215 ;
540/586; 540/593 |
Current CPC
Class: |
A61P 25/18 20180101;
C07D 495/04 20130101; A61P 25/24 20180101; A61P 25/00 20180101;
A61P 3/04 20180101; A61P 25/06 20180101; A61P 25/20 20180101; A61P
3/10 20180101; A61P 25/22 20180101; A61P 25/30 20180101; A61P 43/00
20180101; A61P 25/08 20180101; A61P 3/06 20180101; C07D 495/06
20130101 |
Class at
Publication: |
514/215 ;
540/593; 540/586 |
International
Class: |
C07D 495/04 20060101
C07D495/04 |
Claims
1. A compound of the formula ##STR00028## X is NR.sub.11; R.sub.1
and R.sub.2 are independently selected from the group consisting of
H, halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
perhaloalkyl, C.sub.1-8 alkylperhalo alkyl, --CN, OR.sub.8,
SR.sub.8, --SO.sub.2R.sub.10, --C(.dbd.O)R.sub.10,
--C(.dbd.O)NR.sub.8R.sub.9, --NR.sub.8CO.sub.2R.sub.10,
--SO.sub.2NR.sub.8R.sub.9, --NR.sub.8SO.sub.2R.sub.10, aryl,
heteroaryl, C.sub.1-8 alkylaryl, C.sub.1-8 alkylheteroaryl,
--C.sub.1-8 alkyl-O--C.sub.1-8 alkyl, --C.sub.1-8 alkyl-O-aryl and
--C.sub.1-8 alkyl-O-heteroaryl; R.sub.1 and R.sub.2 taken together
with the atoms to which they are attached can form a 5-7-member
carbocycle or heterocycle optionally substituted with up to two
substituents selected from alkyl, CF.sub.3, and --OR.sub.8; R.sub.3
is selected from the group consisting of H, C.sub.1-8 alkyl,
OR.sub.8, aryl and heteroaryl; R.sub.3a is H or C.sub.1-8 alkyl; or
R.sub.3 and R.sub.3a taken together are --CH.sub.2CH.sub.2--;
R.sub.2 and R.sub.3 taken together with the atoms to which they are
attached form a 5-7-member carbocycle or heterocycle optionally
substituted with up to two substituents selected from alkyl,
CF.sub.3, and --OR.sub.8; R.sub.4 is H, C.sub.1-8 alkyl, or
OR.sub.8; R.sub.4a is H, C.sub.1-8 alkyl; or R.sub.4 and R.sub.4a
taken together are --CH.sub.2CH.sub.2--; R.sub.5 is selected from
the group consisting of H, --C.sub.1-8 alkyl, --C.sub.1-8
alkyl-O--C.sub.1-8 alkyl, C.sub.1-8 alkylaryl, --C.sub.1-8
alkylheteroaryl, --C.sub.1-8 alkyl-O-aryl and C.sub.1-8
alkyl-O-heteroaryl; R.sub.5a is H or --C.sub.1-8 alkyl; R.sub.6 is
selected from the group consisting of H, --C.sub.1-8 alkyl,
C.sub.1-8 alkyl-O--C.sub.1-8 alkyl, C.sub.1-9 alkylaryl, C.sub.1-9
alkylheteroaryl, --C.sub.1-8 alkyl-O-aryl and --C.sub.1-8
alkyl-O-heteroaryl; R.sub.6a is H or --C.sub.1-8 alkyl; R.sub.7 is
selected from the group consisting of H, --C.sub.1-8 alkyl,
--C.sub.1-8alkylaryl and --C.sub.1-8 alkylheteroaryl; R.sub.8 and
R.sub.9 are independently selected from the group consisting of H,
--C.sub.1-8 alkyl, --C.sub.2-8 alkenyl, --C.sub.2-8 alkynyl, aryl,
heteroaryl, --C.sub.1-8 alkylaryl, --C.sub.1-8 alkyl heteroaryl,
--C.sub.1-8 alkyl-O--C.sub.1-8 alkyl, --C.sub.1-8 alkyl-O-aryl and
--C.sub.1-8 alkyl-O-heteroaryl; or R.sub.8 and R.sub.9 taken
together with the atom to which they are attached form a 5-7-member
heterocycle; R.sub.10 is selected from the group consisting of
--C.sub.1-8 alkyl, --C.sub.2-8 alkenyl, --C.sub.2-8 alkynyl, aryl,
heteroaryl, --C.sub.1-8 alkylaryl, --C.sub.1-8 alkylheteroaryl,
--C.sub.1-8 alkyl-O--C.sub.1-8 alkyl, --C.sub.1-8 alkyl-O-aryl and
--C.sub.1-8 alkyl-O-heteroaryl; R.sub.11 is selected from the group
consisting of H, --C.sub.1-8 alkyl, --C.sub.1-8 alkyl-O--C.sub.1-8
alkyl, --SO.sub.2R.sub.10, --C(.dbd.O)R.sub.10,
--C(.dbd.O)OR.sub.10, aryl, heteroaryl, C.sub.1-8 alkylaryl and
C.sub.1-8 alkylheteroaryl; R.sub.11 and R.sub.1 together with the
atoms to which they are attached may form a 5-7-membered
heterocycle optionally substituted with up to two substituents
selected from --C.sub.1-8 alkyl, CF3, and --OR.sub.8; and R.sub.11
and R.sub.4 together with the atoms to which they are attached may
form a 5-7-membered heterocycle optionally substituted with up to
two substituents selected from --C.sub.1-8 alkyl, CF.sub.3, and
--OR.sub.8; wherein aryl and heteroaryl are optionally substituted
with up to two substituents selected from --C.sub.1-8 alkyl,
halogen, CN, and alkoxy, or a pharmaceutically acceptable salt
thereof.
2.
(R,S)-2-Bromo-3,3-dimethyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cycl-
openta[cd]azulene, or a pharmaceutically acceptable salt
thereof.
3. A pharmaceutical composition comprising at least one compound of
claim 1 and a pharmaceutically acceptable carrier.
4. A method of treating a disease, disorder and/or condition in a
patient wherein modulation of a 5-HT.sub.2C function is desired
comprising administering an effective amount of at least one
compound of claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention generally relates to a series of
compounds, to pharmaceutical compositions containing the compounds,
and to use of the compounds and compositions as therapeutic agents.
More specifically, compounds of the present invention are
thiophenyl and pyrrolyl azepine compounds. These compounds are
serotonin receptor (5-HT.sub.2c) ligands and are useful for
treating diseases, disorders, and conditions wherein modulation of
the activity of serotonin receptors (5-HT.sub.2c) is desired (e.g.
addiction, anxiety, depression, obesity and others).
BACKGROUND OF THE INVENTION
[0002] Serotonin has been implicated in a number of diseases,
disorders, and conditions that originate in the central nervous
system, including diseases, disorders, and conditions related to,
for example, sleeping, eating, perceiving pain, controlling body
temperature, controlling blood pressure, depression, anxiety,
addiction and schizophrenia. Serotonin also plays an important role
in peripheral systems, such as the gastrointestinal system, where
it has been found to mediate a variety of contractile, secretory,
and electrophysiologic effects.
[0003] Because of the broad distribution of serotonin within the
body, there is a need for drugs that affect serotonergic systems.
In particular, agonists, partial agonists, and antagonists of
serotonergic systems are of interest for the treatment of a wide
range of disorders, including anxiety, depression, hypertension,
migraine, obesity, compulsive disorders, schizophrenia, autism,
neurodegenerative disorders (e.g., Alzheimer's disease,
Parkinsonism, and Huntington's chorea), and chemotherapy-induced
vomiting.
[0004] The major classes of serotonin receptors (5-HT.sub.1-7)
contain one to seven separate receptors that have been formally
classified. See Glennon, et al., Neuroscience and Behavioral
Reviews, 1990, 14, 35; and D. Hoyer, et al. Phannacol. Rev. 1994,
46, 157-203.
[0005] For example, the 5-HT.sub.2 family of receptors contains
5-HT.sub.2a, 5-HT.sub.2b, and 5-HT.sub.2c subtypes, which have been
grouped together on the basis of primary structure, secondary
messenger system, and operational profile. All three 5-HT.sub.2
subtypes are G-protein coupled, activate phospholipase C as a
principal transduction mechanism, and contain a seven-transmembrane
domain structure. There are distinct differences in the
distribution of the three 5-HT.sub.2 subtypes in a mammal. The
5-HT.sub.2b and 5-HT.sub.2a receptors are widely distributed in the
peripheral nervous system, with 5-HT.sub.2a also found in the
brain. The 5-HT.sub.2c receptor has been found only in the central
nervous system, being highly expressed in many regions of the human
brain. See G. Baxter, et al. Trends in Pharmacol. Sci. 1995, 16,
105-110.
[0006] Subtype 5-HT.sub.2a has been associated with effects
including vasoconstriction, platelet aggregation, and
bronchoconstriction, as well as certain CNS effects, while subtype
5-HT.sub.2c has been associated with diseases that include
depression, anxiety, obsessive compulsive disorder, addiction,
panic disorders, phobias, psychiatric syndromes, and obesity. Very
little is known about the pharmocologic role of the 5-HT.sub.2b
receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs, 1998, 7,
1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769; J.
R. Martin, et al., The Journal of Pharmacology and Experimental
Therapeutics, 1998, 286, 913-924; S. M. Bromidge, et al., 1. Med.
Chem., 1998, 41, 1598-1612; G. A. Kennett, Drugs, 1998, 1, 4,
456-470; and A. Dekeyne, et al., Neurophannacology, 1999, 38,
415-423.
[0007] WO 93/13105, U.S. Pat. Nos. 5,691,330 and 5,532,240 disclose
thiophene derivatives; U.S. Pat. No. 4,414,225 discloses thiophene,
furan and pyrrole derivatives; U.S. Pat. No. 4,575,504 discloses
thienothiazole derivatives; U.S. Pat. No. 5,258,378 discloses
certain pyrroloazepine compounds; U.S. Pat. Nos. 4,414,225 and
4,904,653 disclose certain azepine derivatives; WO 2005/019179
discloses certain benzazepines, WO 2005/003096, WO 2005/042490, and
WO 2005/042491 disclose benzazepine derivatives; WO 96/11201
discloses furan derivatives; WO 2005/040169 discloses certain fused
pyrrole- and pyrazole-containing heterocyclic compounds which are
serotonin modulators; WO 2004/024065 discloses substituted bicyclic
thiophene derivatives. None of these patents or patent applications
disclose compounds of the instant invention.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to compounds of the
formula:
##STR00001## [0009] where [0010] X is S or NR.sub.11; [0011]
R.sub.1 and R.sub.2 are independently selected from the group
consisting of H, halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, perhalo alkyl, C.sub.1-8 alkylperhalo alkyl,
--CN, OR.sub.8, SR.sub.8, --SO.sub.2R.sub.10, --C(.dbd.O)R.sub.10,
--C(.dbd.O)NR.sub.8R.sub.9, --NR.sub.8CO.sub.2R.sub.10,
--SO.sub.2NR.sub.8R.sub.9, --NR.sub.8SO.sub.2R.sub.10, aryl or
heteroaryl, C.sub.1-8 alkylaryl or heteroaryl, --C.sub.1-8
alkyl-O--C.sub.1-8 alkyl, and --C.sub.1-8 alkyl-O-aryl or
heteroaryl; [0012] R.sub.1 and R.sub.2 taken together with the
atoms to which they are attached can form a 5-7-member carbocycle
or heterocycle optionally substituted with up to two substituents
selected from alkyl, CF.sub.3, and --OR.sub.8; [0013] R.sub.3 is
selected from the group consisting of H, C.sub.1-8 alkyl, OR.sub.8,
aryl and heteroaryl; [0014] R.sub.3a is H or C.sub.1-8 alkyl; or
R.sub.3 and R.sub.3a taken together are --CH.sub.2CH.sub.2--;
[0015] R.sub.2 and R.sub.3 taken together with the atoms to which
they are attached form a 5-7-member carbocycle or heterocycle
optionally substituted with up to two substituents selected from
alkyl, CF.sub.3, and --OR.sub.8; [0016] R.sub.4 is H, C.sub.1-8
alkyl, or OR.sub.8; [0017] R.sub.4a is H, C.sub.1-8 alkyl; or
R.sub.4 and R.sub.4a taken together are --CH.sub.2CH.sub.2--;
[0018] R.sub.5 is selected from the group consisting of H,
C.sub.1-8 alkyl, --C.sub.1-8 alkyl-O--C.sub.1-8 alkyl, C.sub.1-8
alkylaryl or heteroaryl, and --C.sub.1-8 alkyl-O-aryl or
heteroaryl; [0019] R.sub.5a is H or --C.sub.1-8 alkyl; [0020]
R.sub.6 is selected from the group consisting of H, --C.sub.1-8
alkyl, C.sub.1-8 alkyl-O--C.sub.1-8 alkyl, C.sub.1-9 alkylaryl or
heteroaryl, and --C.sub.1-8 alkyl-O-aryl or heteroaryl; [0021]
R.sub.6a is H or --C.sub.1-8 alkyl; [0022] R.sub.7 is selected from
the group consisting of H, --C.sub.1-8 alkyl, and
--C.sub.1-8alkylaryl or heteroaryl; [0023] R.sub.8, R.sub.9 are
independently selected from the group consisting of H, --C.sub.1-8
alkyl, --C.sub.2-8 alkenyl, --C.sub.2-8 alkynyl, aryl or
heteroaryl, --C.sub.1-8 alkylaryl or heteroaryl, [0024] --C.sub.1-8
alkyl-O--C.sub.1-8 alkyl, and --C.sub.1-8 alkyl-O-aryl or
heteroaryl; [0025] R.sub.8 and R.sub.9 taken together with the atom
to which they are attached form a 5-7-member heterocycle; [0026]
R.sub.10 is selected from the group consisting of --C.sub.1-8
alkyl, --C.sub.2-8 alkenyl, --C.sub.2-8 alkynyl, aryl or
heteroaryl, --C.sub.1-8 alkylaryl or heteroaryl, --C.sub.1-8
alkyl-O--C.sub.1-8 alkyl, and --C.sub.1-8 alkyl-O-aryl or
heteroaryl; [0027] R.sub.11 is selected from the group consisting
of H, --C.sub.1-8 alkyl, --C.sub.1-8 alkyl-O--C.sub.1-8 alkyl,
--SO.sub.2R.sub.10, --C(.dbd.O)R.sub.10, --C(.dbd.O)OR.sub.10,
aryl, and heteroaryl, or C.sub.1-8 alkylaryl or heteroaryl; [0028]
R.sub.11 and R.sub.1 together with the atoms to which they are
attached may form a 5-7-membered heterocycle optionally substituted
with up to two substituents selected from --C.sub.1-8 alkyl,
CF.sub.3, and --OR.sub.8; and [0029] R.sub.11 and R.sub.4 together
with the atoms to which they are attached may form a 5-7-membered
heterocycle optionally substituted with up to two substituents
selected from --C.sub.1-8 alkyl, CF.sub.3, and --OR.sub.8; [0030]
wherein aryl and heteroaryl are optionally substituted with up to
two substituents selected from --C.sub.1-8 alkyl, halogen, CN, and
alkoxy, and the pharmaceutically acceptable salts thereof.
[0031] Another embodiment of the present invention provides a
pharmaceutical composition comprising a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0032] Still another embodiment of the present invention provides a
method of treating a disease, disorder and/or condition in a mammal
(e.g., animal or human), wherein a 5-HT.sub.2c receptor is
implicated and modulation of a 5-HT.sub.2c function is desired. The
method comprises administering a therapeutically effective amount
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to the mammal.
[0033] Yet another embodiment of the present invention comprises a
method of modulating 5-HT receptor function with an effective
amount of compound of Formula (I), or a pharmaceutically acceptable
salt thereof.
[0034] A further embodiment of the present invention provides a
method of treating or preventing diseases, disorders, and/or
conditions of the central nervous system. The method comprises
administering a therapeutically effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, to the
mammal.
[0035] Specific diseases, disorders and/or conditions for which
compounds of the Formula (I) may have activity include obesity,
depression, schizophrenia, anxiety, obsessive compulsive disorder,
addiction, panic disorders, sleep disorders, migraine, Type II
diabetes, epilepsy, phobias and psychiatric syndromes.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The following definitions are used, unless otherwise
described:
[0037] As used herein, the term "alkyl" includes straight chained
and branched hydrocarbon groups containing the indicated number of
carbon atoms, typically methyl, ethyl, and straight chain and
branched propyl and butyl groups. The term "alkyl" also encompasses
cycloalkyl, i.e., a cyclic C.sub.3-C.sub.8 hydrocarbon group, such
as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Reference
to an individual group or moiety, such as "propyl," embraces only
the straight chain group or moiety. A branched chain isomer, such
as "isopropyl," is specifically referred to.
[0038] The term "alkenyl" as used herein, alone or in combination,
refers to a substituted or unsubstituted straight-chain or
substituted or unsubstituted branched-chain alkenyl radical
containing from 2 to 10 carbon atoms. Examples of such radicals
include, but are not limited to, ethenyl, E- and Z-pentenyl,
decenyl and the like.
[0039] The term "alkynyl" as used herein, alone or in combination,
refers to a substituted or unsubstituted straight or substituted or
unsubstituted branched chain alkynyl radical containing from 2 to
10 carbon atoms. Examples of such radicals include, but are not
limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl
and the like.
[0040] The term "alkoxy" as used herein, alone or in combination,
refers to an alkyl ether radical, wherein the term "alkyl" is as
defined above. Examples of suitable alkyl ether radicals include,
but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
[0041] The term "halo" is defined herein to include fluoro, chloro,
bromo, or iodo. Similarly, the term "halogen" is defined herein to
include fluorine, chlorine, bromine, and iodine.
[0042] The term "amino", alone or in combination, includes the
group --NH.sub.2 or --NR.sub.aR.sub.b wherein R.sub.a and R.sub.b
are independently hydrogen, alkyl, alkylaryl, or aryl.
[0043] The term "aryl," alone or in combination, is defined herein
as a monocyclic or bicyclic aromatic group (e.g., phenyl or
naphthyl) that can be unsubstituted or substituted, for example,
with one or more, and in particular one to three of the following
substituents selected from the group consisting of H, halo; CN,
NO.sub.2, CF.sub.3, N.sub.3, C.sub.1-6alkyl, OH, NR.sup.aR.sup.b,
OC.sub.1-6alkyl, OR.sup.a, C(.dbd.O)NR.sup.aR.sup.b,
C(.dbd.S)NR.sup.aR.sup.b, tetrazoyl, triazoyl, amidinyl,
guanidinyl, thioguanidinyl, cyanoguanadinyl, and aryl, wherein
R.sup.a and R.sup.b are independently hydrogen, alkyl, alkylaryl,
or aryl. Generally, "aryl" denotes a phenyl group, or an
ortho-fused bicyclic carbocyclic group having nine to ten ring
atoms in which at least one ring is aromatic (e.g. naphthyl or
tetrahydronaphthyl). The term "aryl" also is abbreviated in the
various chemical structures as "Ar."
[0044] The term "heteroaryl" is defined herein as a monocyclic,
bicyclic, or tricyclic ring system containing one, two, or three
aromatic rings and containing at least one nitrogen, oxygen, or
sulfur atom in an aromatic ring, and which can be unsubstituted or
substituted, for example, with one or more, and in particular one
to three, substituents, like halo, alkyl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino,
acylamino, alkylthio, alkylsulfonyl, and alkylsulfonyl. Examples of
heteroaryl groups include, but are not limited to, 2H-pyrrolyl,
3H-indolyl, 4H-quinolizinyl, 4H-carbazolyl, acridinyl,
benzo[b]thienyl, benzothiazolyl, 13-carbolinyl, carbazolyl,
chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl,
imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl,
isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,
naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl,
quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, triazolyl, and xanthenyl. In one embodiment the term
"heteroaryl" denotes a monocyclic aromatic ring containing five or
six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of non-peroxide
oxygen, sulfur, and N(Z) wherein Z is absent or is H, 0,
C.sub.1-4alkyl, phenyl or benzyl. In another embodiment heteroaryl
denotes an ortho-fused bicyclic heterocycle of about eight to ten
ring atoms derived therefrom, particularly a benz-derivative or one
derived by fusing a propylene, or tetramethylene diradical
thereto.
[0045] The term "Het" or "heterocycle" generally represents a
heterocyclic group, saturated or partially unsaturated, containing
at least one heteroatom selected from the group consisting of
oxygen, nitrogen, and sulfur, and optionally substituted with
C.sub.1-6alkyl or C(.dbd.O)OR.sup.6. Typically "Het" is a
monocyclic, bicyclic, or tricyclic group containing one or more
heteroatoms selected from the group consisting of oxygen, nitrogen,
and sulfur. A "Het" group also can contain an oxo group (.dbd.O)
attached to the ring. Nonlimiting examples of Het groups include
1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane,
2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl,
imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine,
piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl,
pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and
thiomorpholine.
[0046] Presently preferred compounds include: [0047]
2,2-Dimethyl-1-(3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)--
propan-1-one; [0048]
3-Bromo-2-(2,2,2-trifluoro-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azep-
ine; [0049]
2-Benzenesulfonyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;
[0050]
(R,S)-2-(2,2,2-Trifluoro-1-methyl-ethyl)-5,6,7,8-tetrahydro-4H-thi-
eno[2,3-d]azepine; [0051]
2-Ethanesulfonyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; [0052]
(R,S)-1-Trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza-cyclopenta-
[a]azulene; [0053]
(R,S)-3,3-Dimethyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-a-
za-cyclopenta[a]azulene; [0054]
2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d-
]azepine; [0055]
3-Bromo-4-methyl-2-(2,2,2-trifluoro-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2-
,3-d]azepine; [0056]
2-Ethanesulfonyl-3,4-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;
[0057]
(R,S)-2,2-Dimethyl-1-(4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]-
azepin-2-yl)-propan-1-one; [0058]
1-(3-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-2,2-d-
imethyl-propan-1-one; [0059]
(R,S)-2-(2,2,2-Trifluoro-ethyl)-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cy-
clopenta[cd]azulene; [0060]
(R,S)-2-Bromo-3,3-dimethyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclope-
nta[cd]azulene; [0061]
(R,S)-2-Bromo-5-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;
[0062]
4-Methyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza-cyclope-
nta[a]azulene; [0063]
3,3,4-Trimethyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza--
cyclopenta[a]azulene; [0064]
2,2-Dimethyl-1-(5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-propan-1--
one; and [0065]
1-(3-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-2,2-dimethyl--
propan-1-one.
[0066] Certain compounds of the invention may exist in different
isomeric (e.g. enantiomers and distereoisomers) forms. The
invention contemplates all such isomers both in pure form and in
admixture, including racemic mixtures. Enol forms are also
included.
[0067] The compounds of the invention can exist in unsolvated as
well as solvated forms, including hydrated forms, e.g.,
hemi-hydrate. In general, the solvated forms, with pharmaceutically
acceptable solvents such as water, ethanol, and the like are
equivalent to the unsolvated forms for the purposes of the
invention.
[0068] Certain compounds of the invention also form
pharmaceutically acceptable salts, e.g., acid addition salts. For
example, the nitrogen atoms may form salts with acids. Examples of
suitable acids for salt formation are hydrochloric, sulfuric,
phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,
furmaric, succinic, ascorbic, maleic, methanesulfonic and other
mineral carboxylic acids well known to those in the art. The salts
are prepared by contacting the free base form with a sufficient
amount of the desired acid to produce a salt in the conventional
manner. The free base forms may be regenerated by treating the salt
with a suitable dilute aqueous base solution such as dilute aqueous
hydroxide potassium carbonate, ammonia, and sodium bicarbonate. The
free base forms differ from their respective salt forms somewhat in
certain physical properties, such as solubility in polar solvents,
but the acid salts are equivalent to their respective free base
forms for purposes of the invention. (See, for example S. M. Berge,
et al., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19 (1977)
which is incorporated herein by reference.
[0069] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from a combination of the specified ingredients in
the specified amounts.
[0070] The compounds of the present invention can be used in the
form of pharmaceutically acceptable salts derived from inorganic or
organic acids. The phrase "pharmaceutically acceptable salt" means
those salts which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well-known in the art. For
example, S. M. Berge et al. describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable organic acid.
Representative acid addition salts include, but are not limited to
acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long
chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; arylalkyl halides like benzyl and
phenethyl bromides and others. Water or oil-soluble or dispersible
products are thereby obtained. Examples of acids which can be
employed to form pharmaceutically acceptable acid addition salts
include such inorganic acids as hydrochloric acid, hydrobromic
acid, sulphuric acid and phosphoric acid and such organic acids as
oxalic acid, maleic acid, succinic acid and citric acid.
[0071] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium and aluminum salts and the like and
nontoxic quaternary ammonia and amine cations including ammonium,
tetramethylammonium, tetraethylammonium, methylammonium,
dimethylammonium, trimethylammonium, triethylammonium,
diethylammonium, and ethylammonium among others. Other
representative organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
[0072] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which can be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0073] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention can be varied so as
to obtain an amount of the active compound(s) which is effective to
achieve the desired therapeutic response for a particular patient,
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0074] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
present invention can be employed in pure form or, where such forms
exist, in pharmaceutically acceptable salt, ester or prodrug form.
Alternatively, the compound can be administered as a pharmaceutical
composition containing the compound of interest in combination with
one or more pharmaceutically acceptable excipients. The phrase
"therapeutically effective amount" of the compound of the invention
means a sufficient amount of the compound to treat disorders, at a
reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood, however, that the total daily usage of the
compounds and compositions of the present invention will be decided
by the attending physician within the scope of sound medical
judgement. The specific therapeutically effective dose level for
any particular patient will depend upon a variety of factors
including the disorder being treated and the severity of the
disorder; activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well known in the medical arts. For example, it is well
within the skill of the art to start doses of the compound at
levels lower than required to achieve the desired therapeutic
effect and to gradually increase the dosage until the desired
effect is achieved.
[0075] The total daily dose of the compounds of this invention
administered to a human or lower animal may range from about 0.0001
to about 1000 mg/kg/day. For purposes of oral administration, more
preferable doses can be in the range of from about 0.001 to about 5
mg/kg/day. If desired, the effective daily dose can be divided into
multiple doses for purposes of administration; consequently, single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose.
[0076] The present invention also provides pharmaceutical
compositions that comprise compounds of the present invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions can be
specially formulated for oral administration in solid or liquid
form, for parenteral injection or for rectal administration.
[0077] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally," as used herein,
refers to modes of administration which include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous and
intraarticular injection and infusion.
[0078] In another aspect, the present invention provides a
pharmaceutical composition comprising a component of the present
invention and a physiologically tolerable diluent. The present
invention includes one or more compounds as described above
formulated into compositions together with one or more non-toxic
physiologically tolerable or acceptable diluents, carriers,
adjuvants or vehicles that are collectively referred to herein as
diluents, for parenteral injection, for intranasal delivery, for
oral administration in solid or liquid form, for rectal or topical
administration, among others.
[0079] The compositions can also be delivered through a catheter
for local delivery at a target site, via an intracoronary stent (a
tubular device composed of a fine wire mesh), or via a
biodegradable polymer. The compounds may also be complexed to
ligands, such as antibodies, for targeted delivery.
[0080] Compositions suitable for parenteral injection may comprise
physiologically acceptable, sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
vegetable oils (such as olive oil), injectable organic esters such
as ethyl oleate, and suitable mixtures thereof.
[0081] These compositions can also contain adjuvants such as
preserving, wetting, emulsifying, and dispensing agents. Prevention
of the action of microorganisms can be ensured by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium
chloride and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, for example, aluminum monostearate and
gelatin.
[0082] Suspensions, in addition to the active compounds, may
contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances, and the
like.
[0083] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This can be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0084] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0085] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0086] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound may be mixed with at least one inert,
pharmaceutically acceptable excipient or carrier, such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol and silicic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0087] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0088] The solid dosage forms of tablets, dragees, capsules, pills
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0089] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0090] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan and mixtures thereof.
[0091] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfumingagents.
[0092] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0093] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals which are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients and the like. The
preferred lipids are natural and synthetic phospholipids and
phosphatidyl cholines (lecithins) used separately or together.
[0094] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y. (1976), p. 33 et seq.
[0095] The term "pharmaceutically acceptable prodrugs" as used
herein represents those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention. Prodrugs
of the present invention may be rapidly transformed in vivo to the
parent compound of the above formula, for example, by hydrolysis in
blood. A thorough discussion is provided in T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and
Pergamon Press (1987), hereby incorporated by reference.
[0096] The compounds of the present invention may be prepared by
the procedures set forth in Schemes 1 through 7. The general
analytical conditions set forth after the Schemes were utilized in
all examples.
##STR00002##
##STR00003##
##STR00004##
##STR00005##
##STR00006##
##STR00007##
##STR00008##
General Analytical Conditions
[0097] The following general analytical conditions were utilized in
the examples: HPLC analysis and purification was performed using a
Waters 2525 binary gradient pump, Waters 2767 sample manager,
waters 2487 UV detector (220 and 254 nM), and Waters Micromass ZQ
electrospray mass spec detector. The Micromass ZQ was set for both
positive and negative ionization (cone voltage=25 and 50,
respectively). Analytical HPLC analysis was performed as follows:
[0098] Waters XTerra MS C18 50.times.4.6 mm 3.5 nm column [0099]
Mobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and
Acetonitrile [0100] Acetonitrile: 10 to 75% at 3.5 minutes, 75 to
99% at 3.9 minutes, 99% hold to 4.2 minutes, 99 to 10% at 4.5
minutes, re-equilibrate.
[0101] Preparative HPLC was performed as follows: [0102] Waters
XTerra Prep MS C18 50.times.19 mm 5 nm column [0103] Mobile Phase:
10 mM Ammonium Acetate buffer at pH 5.75 and Acetonitrile [0104]
Acetonitrile: 10 to 99% at 8 minutes, 99% hold to 9 minutes, 99 to
10% at 9.5 minutes, re-equilibrate NMR analysis was performed using
a Bruker BioSpin UltraShield NMR (300 MHz).
[0105] The following examples are illustrative of the preparation
of representative compounds of the present invention:
Example 1
2,2-Dimethyl-1-(3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-p-
ropan-1-one (Scheme 1)
##STR00009##
[0106] a.) [Ethoxycarbonyl-(2-thiophen-2-yl-ethyl)-amino]-acetic
acid ethyl ester
[0107] 2-Thiophen-2-yl-ethylamine (21.0 g, 165 mmol) was stirred in
1 liter of DCM. Ethyl glyoxylate (165 mmol, 50% in toluene) was
added followed by 50 uL HOAc. The reaction was stirred for 10
minutes after which time NaBH(OAc).sub.3 (214 mmol, 45 g) was added
slowly. After 15 minutes HOAc was added (214 mmol) and the reaction
was stirred for 20 minutes. The reaction was concentrated and the
crude material was redissolved in 500 mL each of THF and water.
NaHCO.sub.3 (42 g, 500 mmol) was added followed by ethyl
chloroformate (21 mL, 214 mmol). Saturated NaHCO.sub.3 was added
slowly to the reaction until the gas evolution was minimal After
stirring overnight, the reaction was diluted with EtOAc (400 mL).
The product was extracted 2.times. into EtOAc, dried over
MgSO.sub.4 and concentrated to the sub-title product as a dark
oil.
b.) [Ethoxycarbonyl-(2-thiophen-2-yl-ethyl)-amino]-acetic acid
[0108] The crude material from step (a) (165 mmol, .about.47 g) was
dissolved in EtOH (700 mL) and treated with 600 mL of 1M NaOH.
After stirring overnight, the reaction was acidified with
concentrated HCl to pH-1. The crude reaction was diluted with EtOAc
(400 mL) and washed with water. The water was back-extracted with
EtOAc. The combined organic extracts were washed with water
(2.times.) and dried over MgSO.sub.4. Concentration and evaporation
from toluene (2.times.) gave the sub-title product as a solid.
c.) 4-Oxo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid
ethyl ester
[0109] The product of step (b) (.about.165 mmol, .about.42 g) was
dissolved in 1 L of DCM. DMF (100 uL) was added followed slowly by
oxalyl chloride (21.7 mL, 247 mmol). After 1 hour, the reaction was
concentrated to dryness and the crude material was re-dissolved in
DCE (1 L). AlCl3 (55 g, 410 mmol) was carefully added and the
reaction was stirred at room temperature for 1/2 hour. The crude
reaction was quenched with ice, washed with water (3.times.), and
dried over MgSO4. The title product was purified by silica gel
chromatography (30% EtOAc in Hexanes) to give 10.5 grams of the
sub-title compound as a white solid. MS: ESI (positive): 240
(M+H).
d.) 4,5,7,8-Tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid ethyl
ester
[0110] AlCl3 (3.95 g, 29.7 mmol) was added to 50 mL DCM at
0.degree. C. Borane-t-butyl amine complex (5.2 g, 59.5 mmol) was
added followed by the product of step (c) (2.37 g, 9.9 mmol)
dissolved in DCM (50 mL). The reaction was stirred for 2 hours at
room temperature after which time another 3.95 g (29.7 mmol) of
AlCl3 was added. After stirring for 10 minutes, the reaction was
quenched carefully with 0.1 M HCl (.about.50 mL). After
concentration of the organic solvent, the crude reaction mixture
was partitioned between 1M HCl and EtOAc (70 mL each). The aqueous
layer was back extracted 1.times.EtOAc. The combined organic layers
were dried over MgSO4 and concentrated. The sub-title product (1.45
g) was obtained after purification by silica gel chromatography (0
to 35% EtOAc in Hexanes). MS: ESI (positive): 226 (M+H).
e.)
2,3-Dibromo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0111] The product of step (d) (1.45 g, 6.44 mmol) and NaHCO.sub.3
(3.2 g, 38.6 mmol) were stirred in 60 mL cyclohexane. Bromine (1.0
mL, 19.3 mmol) was added slowly and the reaction was stirred in the
dark for 15 minutes. The reaction was quenched with 5%
Na.sub.2SO.sub.3 and stirred rapidly for 15 minutes. The sub-title
compound was extracted into EtOAc (2.times.). Drying over
MgSO.sub.4 and concentration gave the sub-title compound (2.6 g) as
a yellow oil.
f.) 3-Bromo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0112] The product of step (e) (1.3 g, 3.39 mmol) was dissolved in
1:1 HOAc:water (40 mL), treated with Zn dust (0.44 g, 6.79 mmol),
and heated to reflux for 1 hour. The reaction was cooled, diluted
with water and extracted 2.times.EtOAc. The organic extracts were
dried over MgSO.sub.4 and concentrated to give 0.76 g of the
sub-title compound.
g.) 3-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0113] The product of step (f) (375 mg, 1.23 mmol) was dissolved in
4 mL dioxane and treated with Me.sub.2Zn (1.25 mL of 2M in toluene)
and Pd(dppf).sub.2Cl.sub.2. After heating to 100.degree. C. for 3
h, the reaction was cooled, quenched with water, filtered through
silica gel (washing with EtOAc), and concentrated to give 337 mg of
the sub-title compound as an oil.
h.)
2-Bromo-3-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0114] The product of step (g) (337 mg, 1.4 mmol) was dissolve in
10 mL of 1:1 CHCl.sub.3:HOAc and treated with NBS (301 mg, 1.7
mmol). After stirring for 1/2 hour, the reaction was diluted with
DCM and washed with water (50 mL) and 1M NaOH (2.times.50 mL). The
crude product was purified by silica gel chromatography to give 235
mg of the sub-title compound.
i.)
2,2-Dimethyl-1-(3-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-y-
l)-propan-1-one
[0115] The product of step (h) (60 mg, 0.19 mmol) was dissolve in 2
mL THF and cooled to -78.degree. C. Butyl lithium (0.15 mL of 1.6M)
was added and the reaction was stirred for 5 minutes.
Trimethylacetyl chloride (36 uL, 0.3 mmol) was added and the
reaction was warmed to room temperature. The reaction was quenched
with water (5 mL) and the product was extracted into DCM
(2.times.). The extracts were concentrated to dryness and treated
with 4 mL of 1:1 EtOH:40% KOH (aq) and heated to 100.degree. C. for
14 hours. The reaction was cooled and diluted with water. The
product was extracted into DCM (2.times.5 mL). The extracts were
concentrated and the title compound was purified by preparative
HPLC-MS. 1H NMR (CD3OD) .delta. 3.38-3.31 (m, 4H), 3.23 (t, J=5.1
Hz, 2H), 3.04 (t, J=5.2 Hz, 2H), 2.30 (s, 3H), 1.32 (s, 9H); MS:
ESI (positive): 252 (M+H).
Example 2
3-Bromo-2-(2,2,2-trifluoro-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepi-
ne (Scheme 2)
##STR00010##
[0116] a.)
3-Bromo-2-(2,2,2-trifluoro-acetyl)-4,5,7,8-tetrahydro-thieno[2,-
3-d]azepine-6-carboxylic acid ethyl ester
[0117] The product of Example 1, step (e) (200 mg, 0.52 mmol) was
dissolved in 5 mL THF, cooled to -78.degree. C. and treated with
BuLi (0.33 mL of 1.6 M). After stirring for 15 minutes at
-78.degree. C., trifluoroacetyl 2,2,2-trifluoroethanol (132 uL,
0.68 mmol) was added and the reaction was allowed to warm to room
temperature. The reaction was quenched with water (50 uL) and
concentrated. The residue was purified by silica gel chromatography
to give 73 mg of the sub-title compound.
b.)
3-Bromo-2-(2,2,2-trifluoro-ethyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azep-
ine-6-carboxylic acid ethyl ester
[0118] The product of step (a) (73 mg, 0.18 mmol) was stirred in 3
mL EtOH and treated with NaBH.sub.4 (20 mg, 0.5 mmol). After
stirring for 20 minutes, the reaction was quenched with HOAc until
no bubbling was observed. The reaction was diluted with water (5
mL) and the crude product was extracted into DCM (3.times.5 mL).
The combined organic extracts were concentrated and the residue was
dissolved in HOAc (2 mL) and concentrated HCl (1 mL). SnCl.sub.2
(225 mg, 1 mmol) was added and the reaction was heated to
80.degree. C. for 2 hours. The crude reaction was diluted with
water (10 mL) and the product was extracted into DCM (3.times.5
mL). The combined organic extracts were concentrated to dryness and
used without further purification.
c.)
3-Bromo-2-(2,2,2-trifluoro-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]a-
zepine
[0119] The product of step (b) (0.18 mmol) was dissolved in CHCl3
(3 mL) and treated with TMSI (1 mmol, 200 uL). After heating for
1/2 hour at 70.degree. C., another 200 uL of TMSI was added and
heating was continued for 1/2 hour. The reaction was cooled and
carefully quenched with 0.5 mL each of EtOH and water. The reaction
was diluted with 1M NaOH (3 mL) and the product was extracted into
DCM (2.times.5 mL). The organic extracts were concentrated and the
residue was purified by preparative HPLC-MS. 1H NMR (CD3OD) .delta.
3.75 (q, J=10.5 Hz, 2H), 3.43-3.34 (m, 4H), 3.26 (t, J=5.4 Hz, 2H),
3.16 (t, J=5.4 Hz, 2H), 3.16 (t, J=5.4 Hz, 2H); MS: ESI (positive):
316, 314 (M+H).
Example 3
2-benzenesulfonyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine
(Scheme 1)
##STR00011##
[0121] The product of Example 1, step (d) (75 mg, 0.33 mmol) was
dissolved in 2 mL DCE and treated with phenyl sulfonyl chloride (83
uL, 0.66 mmol) followed by AlCl3 (88 mg, 0.66 mmol). After heating
to 80.degree. C. for 1/2 hour, the reaction was cooled and quenched
carefully with 1M NaOH. The product was extracted into DCM
(2.times.). The organic extracts were concentrated and the residue
was dissolved in 3 mL each EtOH and 40% aqueous KOH. The reaction
was heated to 100.degree. C. for 14 hours, cooled, and diluted with
water. The title compound was extracted into DCM (2.times.5 mL) and
purified by preparative HPLC-MS. 1H NMR (CD3OD) .delta. 7.96 (d,
J=8.1 Hz, 2H), 7.67-7.56 (m, 3H), 5.56 (s, 1H), 3.38-3.32 (m, 4H),
3.27-3.23 (m, 2H), 3.09 (t, J=5.4 Hz, 2H); MS: ESI (positive): 294
(M+H).
Example 4
(R,S)-2-(2,2,2-Trifluoro-1-methyl-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3--
d]azepine (Scheme 2)
##STR00012##
[0122] a.)
2-(2,2,2-Trifluoro-acetyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azep-
ine-6-carboxylic acid ethyl ester
[0123] The product of Example 1, step (d) (410 mg, 1.82 mmol) was
dissolved in 20 mL DCE and treated with trifluoroacetic anhydride
(510 uL, 3.64 mmol) and AlCl.sub.3 (484 mg, 3.64 mmol). The
reaction was heated to 50.degree. C. for 2 hours, then cooled and
quenched with excess water. The product was extracted into DCM
(2.times.15 mL), dried over MgSO.sub.4 and concentrated to give 360
mg of the sub-title compound as a semisolid.
b.)
2-(1-Trifluoromethyl-vinyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6--
carboxylic acid ethyl ester
[0124] Triphenyl phosphonium bromide (393 mg, 1.1 mmol) was stirred
in 7 mL THF. KHMDS (199 mg, 1.0 mmol) was added and the yellow
solution was stirred for 30 minutes at room temperature. The
product of step (a) (180 mg, 0.56 mmol) was dissolved in in 7 mL
THF and added to the above reaction. The solution was allowed to
stir for 1 hour at room temperature, then diluted with EtOAc (25
mL) and washed with water (2.times.20 mL). The crude product was
purified by silica gel chromatography (30% EtOAc in Hex) to give
100 mg of the sub-title compound.
c.)
(R,S)-2-(2,2,2-Trifluoro-1-methyl-ethyl)-4,5,7,8-tetrahydro-thieno[2,3-
-d]azepine-6-carboxylic acid ethyl ester
[0125] The product of step (b) (40 mg, 0.12 mmol) was dissolved in
5 mL EtOH and treated with 10 mg of 10% Pd/C (wet, Degussa grade
E101). The reaction was stirred rapidly under an atmosphere of
hydrogen for 14 hours. Filtration through celite and concentration
gave 37 mg of the sub-title compound.
d.)
(R,S)-2-(2,2,2-Trifluoro-1-methyl-ethyl)-5,6,7,8-tetrahydro-4H-thieno[-
2,3-d]azepine
[0126] The product of step (c) (37 mg, 0.11 mmol) was dissolved in
1 mL CHCl3 and treated with TMSI (47 uL, 0.35 mmol). After heating
to 60.degree. C. for 2 hours, the reaction was cooled and
concentrated. Purification of the crude residue by preparative
HPLC-MS gave the title compound. 1H NMR (CD3OD) .delta. 6.86 (s,
1H), 3.80 (sept., J=7.9 Hz, 1H), 3.39-3.30 (m, 4H), 3.17 (t, J=5.2
Hz, 2H), 3.05 (t, J=5.2 Hz, 2H), 1.48 (d, J=7.2 Hz, 3H); MS: ESI
(positive): 250 (M+H).
Example 5
2-Ethanesulfonyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (Scheme
1)
##STR00013##
[0127] a.)
2-Bromo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid
ethyl ester
[0128] The product of Example 1, step (d) (80 mg, 0.35 mmol) was
dissolved in 2 mL of 1:1 CHCl.sub.3:HOAc and treated with NBS (62
mg, 0.35 mmol). After 15 minutes, the reaction was concentrated to
dryness, dissolved in a minimal amount of EtOAc and filtered
through a pad of silica gel. The filtrate was evaporated to give
105 mg of the sub-title compound.
b.)
2-Ethylsulfanyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0129] The product of step (a) (105 mg, 0.35 mmol) was dissolved in
1 mL NMP and treated with NaSEt (59 mg, 0.7 mmol), KI (5 mg, 0.03
mmol), and CuO (14 mg, 0.18 mmol). The reaction was heated to
120.degree. C. for 24 hours. Additional NaSEt (59 mg, 0.7 mmol), KI
(5 mg, 0.03 mmol), and CuO (14 mg, 0.18 mmol) was added and the
heating was continued for 24 hours. The reaction was diluted with
water and DCM (.about.5 mL each) and filtered to remove the dark
powdery precipitate. The crude product was extracted into DCM
(3.times.5 mL) and concentrated to .about.1 mL. The crude residue
was diluted with DCM (2 mL) and treated with Et.sub.3N (140 uL,
1.05 mmol) and ethyl chloroformate (50 uL, 0.52 mmol). After
stirring overnight, the reaction was diluted with EtOAc (5 mL) and
washed with water (5.times.) in order to remove the residual NMP.
The organic solution was concentrated to give 80 mg of the
sub-title compound which was used without further purification.
c.)
2-Ethanesulfonyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0130] The product of step (b) (80 mg, 0.28 mmol) was dissolved in
3 mL HOAc and treated with H.sub.2O.sub.2 (300 uL of 30%, .about.3
mmol). After stirring at room temperature for 3 days, the reaction
was diluted with EtOAc and washed 4.times. with water. The organic
extract was dried over MgSO.sub.4 and concentrated to give 62 mg of
the sub-title compound which was used without further
purification.
d.) 2-Ethanesulfonyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine
[0131] The product of step (c) (21 mg, 0.066 mmol) was dissolved in
2 mL EtOH and treated with 2 mL of 40% KOH and subsequently heated
to 100.degree. C. in a sealed vessel overnight. The reaction was
cooled and diluted with water. The title compound was extracted
into DCM (3.times.) and purified by preparative HPLC-MS. 1H NMR
(CD3OD) .delta. 7.47 (s, 1H), 3.25 (q, J=7.2 Hz, 2H), 3.24-3.01 (m,
8H), 1.28 (t, J=7.2 Hz, 3H); MS: ESI (positive): 246 (M+H).
Example 6
(R,S)-1-Trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza-cyclopenta[-
a]azulene (Scheme 3)
##STR00014##
[0132] a.)
(R,S)-4,4,4-Trifluoro-3-(5,6,7,8-tetrahydro-4H-thieno[2,3-d]aze-
pin-2-yl)-butyric acid
[0133] Triethylphosphonoacetate (56 mg, 0.25 mmol) and the product
of Example 4, step (a) (40 mg, 0.12 mmol) were stirred in 2 mL THF.
The reaction was treated with LiHMDS (0.2 mL of 1M) and stirred at
room temperature for 1 hour. The reaction was quenched with 5 mL
water and the product was extracted into DCM (2.times.5 mL) and
dried over MgSO.sub.4. The organic extract was concentrated to
dryness and the residue was dissolved in 5 mL EtOH and treated with
.about.10 mg of 10% Pd/C (wet, Degussa grade E101). After stirring
under hydrogen for 3 days, the reaction was filtered through celite
and treated with 1M NaOH (1 mL). After stirring for 2 hours at
60.degree. C., the reaction was diluted with water and the product
was extracted into DCM (3.times.5 mL) to give 45 mg of the
sub-title compound which was used without further purification.
b.)
(R,S)-3-Oxo-1-trifluoromethyl-2,3,4,5,7,8-hexahydro-1H-9-thia-6-aza-cy-
clopenta[a]azulene-6-carboxylic acid ethyl ester
[0134] The product of step (a) (45 mg, 0.12 mmol) was dissolved in
DCE (2 mL) and treated with oxalyl chloride (43 uL, 0.49 mmol) and
1 drop of DMF. After stirring for 5 minutes at room temperature,
the reaction was concentrated to dryness and dissolved in 2 mL DCM.
AlCl.sub.3 (66 mg, 0.50 mmol) was added and the reaction was
stirred for 5 minutes. The reaction was quenched with water and the
crude product was extracted into DCM (2.times.) to give 32 mg of a
dark oil that was used without further purification. The
enantiomers of the sub-title compound could be separated using a
Chiralpak.RTM. AD-RH.RTM. 20.times.250 mm column from Chiral
Technologies (MeOH mobile phase) giving enantiomer 1 (reaction
time=9.8 minutes) and enantiomer 2 (reaction time=11.5
minutes).
c.)
(R,S)-1-Trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza-cyclope-
nta[a]azulene
[0135] The product of step (b) (racemic, 32 mg, 0.10 mmol) was
dissolved in DCE (1 mL) and treated with ZnI2 (64 mg, 0.2 mmol) and
NaCNBH3 (44 mg, 0.7 mmol). A thick slurry formed after stirring
overnight. The reaction was filtered and the solid was washed with
DCM. The combined filtrates were washed with water (1.times.5 mL)
and concentrated to dryness. The residue was dissolved in CHCl3 (2
mL) and treated with TMSI (70 uL, 0.5 mmol). After heading to
60.degree. C. for 1 hour, an additional 50 uL of TMSI was added and
heating was continued for 14 hours. The reaction was cooled,
concentrated to dryness, and purified by preparative HPLC-MS to
give the title compound. 1H NMR (CD3OD) .delta. 4.02-3.97 (m, 1H),
3.40-3.33 (m, 4H), 3.18 (t, J=5.2 Hz, 2H), 2.97 (t, J=5.4 Hz, 2H),
2.83-2.65 (m, 3H), 2.57-2.47 (m, 1H); MS: ESI (positive): 262
(M+H).
Example 7
(R,S)-3,3-Dimethyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-az-
a-cyclopenta[a]azulene (Scheme 3)
##STR00015##
[0136] a.)
(R,S)-3,3-Dimethyl-1-trifluoromethyl-2,3,4,5,7,8-hexahydro-1H-9-
-thia-6-aza-cyclopenta[a]azulene-6-carboxylic acid ethyl ester
[0137] DCM (3 mL) was cooled to -78.degree. C. and treated with
TiCl.sub.4 (190 uL, 1.73 mmol) followed by Me.sub.2Zn (0.86 mL of
2M in toluene). After stirring the dark red suspension at
-78.degree. C. for 15 minutes, the product of example 6, step (b)
(racemic, 100 mg, 0.29 mmol) was added as a solution in 3 mL DCM.
The reaction was warmed to 0.degree. C. and stirred for 3 hours.
The solution was poured over ice and the product was extracted into
DCM (2.times.10 mL). The organic extract was dried over MgSO.sub.4
and concentrated to give 84 mg of the sub-title compound, which was
used without further purification.
b.)
(R,S)-3,3-Dimethyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia--
6-aza-cyclopenta[a]azulene
[0138] The product of step a) (37 mg, 0.10 mmol) was dissolved in
CHCl.sub.3 (2 mL) and treated with TMSI (1 mmol, 140 uL). After
heating to 60.degree. C. for 2 hours, the reaction was quenched
with MeOH and concentrated to dryness. The title compound was
obtained after purification of the crude residue by preparative
HPLC-MS. .sup.1H NMR (CD.sub.3OD) .delta. 4.09-3.94 (m, 1H),
3.41-3.32 (m, 4H), 3.17 (t, J=5.2 Hz, 2H), 3.08 (t, J=5.2 Hz, 2H),
2.53 (dd, J=9, 13.5 Hz, 1H), 2.31 (dd, J=6.6, 13.8 Hz, 1H), 1.39
(s, 3H), 1.31 (s, 3H); MS: ESI (positive): 290 (M+H).
Example 8
2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]-
azepine (Scheme 2)
##STR00016##
[0139] a.)
2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-4,5,7,8-tetrahydro-thien-
o[2,3-d]azepine-6-carboxylic acid ethyl ester
[0140] DCM (2 mL) was cooled to -78.degree. C. and treated with
TiCl.sub.4 (82 uL, 0.75 mmol) followed by Me.sub.2Zn (370 uL to 2
M). After stirring for 15 minutes at -78.degree. C., the product of
example 4, step (a) (40 mg, 0.125 mmol) was added as a solution in
3 mL DCM. The reaction was warmed to 0.degree. C. for 1 hour then
to room temperature for 6 hours. The reaction was quenched over ice
and extracted into DCM (2.times.5 mL). The organic extracts were
dried over MgSO.sub.4 and concentrated to give 34 mg of the
sub-title compound which was used without further purification.
b.)
2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,-
3-d]azepine
[0141] The product of step (a) (34 mg, 0.1 mmol) was dissolved in 2
mL CHCl.sub.3 and treated with TMSI (140 uL, 1 mmol). After heating
to 60.degree. C. for 2 hours, the reaction was concentrated to
dryness and the title compound was purified by preparative HPLC-MS.
.sup.1H NMR (CD.sub.3OD) .delta. 6.91 (s, 1H), 3.39-3.32 (m, 4H),
3.21-3.17 (m, 2H), 3.09-3.05 (m, 2H), 1.55 (s, 6H); MS: ESI
(positive): 264 (M+H).
Example 9
3-Bromo-4-methyl-2-(2,2,2-trifluoro-ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,-
3-d]azepine (Scheme 2)
##STR00017##
[0142] a.)
4-Methylene-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxyli- c
acid ethyl ester
[0143] Methyl triphenylphosphonium bromide (6.3 g, 17.6 mmol) was
dissolved in 150 mL THF and cooled to 0.degree. C. KHMDS (3.2 g,
16.2 mmol) was added portionwise and the reaction was stirred for
1/2 hour. The product of Example 1, step (c) (3.0 g, 12.5 mmol) was
added as a solution in 25 mL THF. The reaction was warmed to room
temperature and stirred for 1 hour. The mixture was concentrated
and the title product was purified by silica gel chromatography (0%
to 40% EtOAc in hexanes) to give 2.6 g of the sub-title
compound.
b.)
(R,S)-4-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0144] The product of step (a) was dissolved in 100 mL EtOH and
treated with 0.5 g of 10% Pd/C (wet, Degussa type E101). After
stirring rapidly for 14 hours under an atmosphere of hydrogen, the
reaction was filtered through celite and concentrated to give 2.3 g
of the sub-title compound as a clear oil. MS: ESI (positive): 240
(M+H).
c.)
2,3-Dibromo-4-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxy-
lic acid ethyl ester
[0145] The product of step (b) (5.6 g, 23.4 mmol) was dissolved in
250 mL cyclohexane and treated with NaHCO.sub.3 (11.8 g, 140 mmol).
Bromine (3.6 mL, 70.3 mmol) was added slowly and the reaction was
stirred for 1/2 hour at room temperature after which time it was
quenched with Na.sub.2SO.sub.3 (180 mL of 5% aqueous). After
stirring rapidly for 15 minutes, EtOAc was added (.about.100 mL)
and the organic layer was removed and dried over MgSO.sub.4 to give
the sub-title compound. The two enantiomers were separated using a
Chiralpak.RTM. AD-RH.RTM. 20.times.250 mm column from Chiral
Technologies (10 mL/min MeOH mobile phase) to give enantiomer 1
(reaction time=9.8 minutes) and enantiomer 2 (reaction time=11.4
minutes) of the subtitle compound.
d.)
3-Bromo-4-methyl-2-(2,2,2-trifluoro-acetyl)-4,5,7,8-tetrahydro-thieno[-
2,3-d]azepine-6-carboxylic acid ethyl ester
[0146] The product of step (c) (enantiomer 2, 60 mg, 0.15 mmol) was
dissolved in 2 mL dry THF and cooled to -78.degree. C. Butyl
lithium (0.11 mL of 1.6 M) was added and the solution was stirred
for 5 minutes then quenched with trifluoroacetyl
2,2,2-trifluoroethanol (50 uL, 0.24 mmol). After warming to room
temperature, the reaction was filtered through a pad of silica gel
(washing with EtOAc). The filtrate was evaporated to give 62 mg of
the sub-title compound that was used without further
purification.
e.)
3-Bromo-4-methyl-2-(2,2,2-trifluoro-ethyl)-4,5,7,8-tetrahydro-thieno[2-
,3-d]azepine-6-carboxylic acid ethyl ester
[0147] The product of step (d) (62 mg, 0.15 mmol) was dissolved in
2 mL EtOH and treated with NaBH.sub.4 (0.6 mmol). After 15 minutes,
the reaction was quenched with HOAc till the bubbling ceased and
diluted with water. The product was extracted into DCM (2.times.5
mL), dried over MgSO.sub.4 and concentrated. The crude residue was
dissolved in 3 mL of 1:1 HOAc:concentrated HCl and treated with
SnCl.sub.2 (225 mg, 1 mmol). The reaction was heated to 70.degree.
C. for 1 hour and then stirred at room temperature for 3 days. The
reaction was diluted with EtOAc (10 mL) and washed with water
(2.times.) and 1M NaOH (2.times.). The organic solution was
concentrated to dryness giving 40 mg of the sub-title compound that
was used without further purification.
f.)
3-Bromo-4-methyl-2-(2,2,2-trifluoro-ethyl)-5,6,7,8-tetrahydro-4H-thien-
o[2,3-d]azepine
[0148] The product of step (e) (40 mg, 0.10 mmol) was deprotected
and purified according to the procedure described for Example 2,
step (c). 1H NMR (CD3OD) .delta. 3.75 (q, J=10.4 Hz, 2H), 3.63-3.55
(m, 3H), 3.42-3.31 (m, 2H), 3.24-3.15 (m, 2H), 1.35 (d, J=7.2 Hz,
3H); MS: ESI (positive): 328, 330 (M+H).
Example 10
2-Ethanesulfonyl-3,4-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine
(Scheme 4)
##STR00018##
[0149] a.)
3-Bromo-4-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carb-
oxylic acid ethyl ester
[0150] The product of Example 9, step (c) (enantiomer 2, 0.75 g,
1.9 mmol) and Zn (0.25 g, 3.8 mmol) were heated to reflux in 20 mL
each water and HOAc. After 1/2 hour, the reaction was cooled,
diluted with EtOAc, and washed 2.times. with water. The organic
layer was dried over MgSO.sub.4 and concentrated to give 490 mg of
the sub-title compound as an oil.
b.)
3,4-Dimethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0151] The product of step (a) (150 mg, 0.47 mmol) was dissolved in
3 mL dioxane and treated with Me.sub.2Zn (0.47 mL of 2M in toluene)
and Pd(ddf).sub.2Cl.sub.2 (11 mg, 0.014 mmol). After heating to
100.degree. C. for 3 hours, the reaction was quenched with water
and filtered. The filtrate was partitioned between EtOAc and water
(7 mL each). The organic layer was dried over MgSO.sub.4 and
concentrated to give 92 mg of the sub-title compound, which was
used without further purification.
c.)
2-Bromo-3,4-dimethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxy-
lic acid ethyl ester
[0152] The product of step (b) (92 mg, 0.36 mmol) was dissolved in
4 mL of 1:1 HOAc/CHCl.sub.3 and treated with NBS (67 mg, 0.38
mmol). After stirring for 1/2 hour, the reaction was diluted with
EtOAc (70 mL) was washed with water (3.times.30 mL) and 1M NaOH
(2.times.30 mL). The organic solution was dried over MgSO.sub.4 and
concentrated. The crude product was purified by silica gel
chromatography (EtOAc/Hex) to give 90 mg of the sub-title
compound.
d.)
2-Ethylsulfanyl-3,4-dimethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-
-carboxylic acid ethyl ester
[0153] The product of step (c) (60 mg, 0.18 mmol) was dissolved in
2 mL NMP and treated with NaSEt (45 mg, 0.54 mmol), KI (3 mg, 0.018
mmol), and CuO (7 mg, 0.09 mmol). After heating for 2 days at
120.degree. C., an additional quantity of NaSEt (45 mg, 0.54 mmol),
KI (3 mg, 0.018 mmol), and CuO (7 mg, 0.09 mmol) was added and
heating was continued for 3 days. The reaction was diluted with 2
mL each of DCM and water. The resulting black precipitate was
filtered and discarded. The filtrate was evaporated to dryness
under vacuum, then diluted with DCM (4 mL) and treated with
Et.sub.3N (111 uL, 0.8 mmol) and ethyl chloroformate (70 uL, 0.7
mmol). After stirring for 1/2 hour, the reaction was diluted with
DCM (5 mL) and washed with water (2.times.5 mL). Concentration of
the organic layer gave approximately 55 mg of the sub-title
compound, which was used without further purification.
e.)
2-Ethanesulfonyl-3,4-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepi-
ne
[0154] The product of step (d) (55 mg, 0.17 mmol) was dissolved in
2 mL HOAc and treated with 30% H2O2 (220 uL, 2 mmol). After heating
to 70.degree. C. for 1 hour, the reaction was diluted with water (8
mL) and the product was extracted into DCM (3.times.5 mL). The
crude reside was dissolved in 4 mL of 1:1 EtOH:40% KOH (aq) and
heated to 100.degree. C. for 14 hours. The reaction was cooled and
diluted with water. The product was extracted into DCM (2.times.5
mL) and purified by preparative HPLC-MS to give the title compound.
1H NMR (CD3OD) .delta. 3.64-3.19 (m, 7H), 3.25 (q, J=7.5 Hz, 2H),
2.44 (s, 3H), 1.36 (d, J=7.2 Hz, 3H), 1.27 (t, J=7.4 Hz, 3H); MS:
ESI (positive): 274 (M+H).
Example 11
(R,S)-2,2-Dimethyl-1-(4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-
-yl)-propan-1-one (Scheme 4)
##STR00019##
[0155] a.)
(R,S)-2-Bromo-4-methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine--
6-carboxylic acid ethyl ester
[0156] The product of Example 9, step (b) (racemic, 80 mg, 0.35
mmol) was dissolved in 2 mL of 1:1 CHCl.sub.3/HOAc.
N-Bromo-succinamide (62 mg, 0.35 mmol) was added and the reaction
was stirred for 15 minutes. Concentration and purification by
silica gel chromatography gave the sub-title compound as a yellow
oil.
b.)
(R,S)-2,2-Dimethyl-1-(4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azep-
in-2-yl)-propan-1-one
[0157] The product of step (a) (55 mg, 0.17 mmol) was dissolved in
THF (2 mL) and cooled to -78.degree. C. Butyl lithium (0.16 mL of
1.6M) was added and the reaction was stirred for 15 minutes. After
quenching with trimethyl acetyl chloride (41 uL, 0.34 mmol) the
reaction was warmed to room temperature and concentrated. The crude
residue was dissolved in 2 mL EtOH and treated with 2 mL of 40% KOH
(aq). After heating overnight to 100.degree. C., the reaction was
cooled and diluted with water. The product was extracted into DCM
(2.times.) and the title compound was purified by preparative
HPLC-MS. 1H NMR (CD3OD) .delta. 7.69 (s, 1H), 3.51-3.12 (m, 7H),
1.46 (d, J=7.2H, 3H), 1.36 (s, 9H); MS: ESI (positive): 252
(M+H).
Example 12
1-(3-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-2,2-di-
methyl-propan-1-one (Scheme 4)
##STR00020##
[0158] a.)
3-Bromo-2-(2,2-dimethyl-propionyl)-4-methyl-4,5,7,8-tetrahydro--
thieno[2,3-d]azepine-6-carboxylic acid ethyl ester
[0159] The product of Example 9, step (c) (enantiomer 2, 200 mg,
0.50 mmol) was dissolved in 5 mL THF and cooled to -78.degree. C.
Butyl lithium (0.31 mL of 1.6M) was added and the reaction was
stirred for 15 minutes. After quenching with trimethyl acetyl
chloride (90 uL, 0.75 mmol) the reaction was warmed to room
temperature and concentrated. Purification of the crude residue by
silica gel chromatography gave 170 mg of the sub-title
compound.
b.)
1-(3-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-2,-
2-dimethyl-propan-1-one
[0160] The product of step (a) (56 mg, 0.14) was stirred in 2 mL
CHCl3 and treated with TMSI (57 uL, 0.42 mmol). After heating to
70.degree. C. for 1 hour, another 0.42 mmol of TMSI was added and
the heating was continued for 1 hour. The reaction was cooled and
partitioned between 1M NaOH and CHCl3. The organic layer was
concentrated and purified by HPLC-MS gave the title compound. 1H
NMR (CD3OD) .delta. 3.74-3.56 (m, 4H), 3.43-3.20 (m, 3H), 1.35 (d,
J=7.2 Hz, 3H), 1.30 (s, 9H); MS: ESI (positive): 330, 332
(M+H).
Example 13
(R,S)-2-(2,2,2-Trifluoro-ethyl)-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyc-
lopenta[cd]azulene (Scheme 5)
##STR00021##
[0161] a.)
(E,Z)-4-Ethoxycarbonylmethylene-4,5,7,8-tetrahydro-thieno[2,3-d-
]azepine-6-carboxylic acid ethyl ester
[0162] A 1.6M LHMDS solution in THF (15 mL) was added to the
product from Example 1, step (c) (2.0 g, 8.37 mmol) and triethyl
phosphonoacetate (4 mL, 16.74 mmol) in anhydrous THF (100 mL). The
reaction was stirred at room temperature overnight then treated
with additional LHMDS solution (3.2 mL of 1.6 M) and
triethylphosphonoacetate (800 .mu.L, 3.3 mmol). After stirring for
3 hours, the reaction was quenched with water and diluted with DCM.
The organic layer was dried over MgSO.sub.4 and concentrated to
give the sub-title compound, which was used without further
purification. MS: ESI (positive): 310 (M+H).
b.)
(R,S)-4-Ethoxycarbonylmethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-
-carboxylic acid ethyl ester
[0163] The product of step (a) (2.47 g, 8 mmol) was stirred with
2.0 g of 10% Pd/C (wet, Degussa grade E101) in methanol (8 mL)
under H.sub.2 (1 atm) for 72 hours. The reaction was filtered over
celite and concentrated to dryness to give the sub-title compound
as an oil, which was used without further purification. MS: ESI
(positive): 312 (M+H).
c.)
(R,S)-4-Carboxymethyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carbox-
ylic acid ethyl ester
[0164] The product of step (b) (2.47 g, 8 mmol) was stirred in
ethanol (60 mL) with 1M NaOH (30 mL) at ambient temperature
overnight. The reaction acidified with 1M HCl and partitioned
between DCM and water. The organic layer was washed with water,
dried over MgSO.sub.4, and concentrated to dryness to give the 2.13
g of the sub-title compound as a yellow oil. MS: ESI (positive):
284 (M+H).
d.)
(R,S)-3-Oxo-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclopenta[cd]azulene--
6-carboxylic acid ethyl ester
[0165] Oxalyl chloride (3 mL, 37.7 mmol) and a catalytic amount of
DMF were added to a solution of the product from step c) (2.13 g,
7.54 mmol) in DCM (40 mL) and the reaction was stirred at ambient
temperature for 1 hour. The reaction was concentrated to dryness
and redissolved in dichloroethane (100 mL). AlCl.sub.3 (2.0 g, 15.1
mmol) was added to the solution and the reaction was stirred at
ambient temperature overnight. The reaction was quenched with ice
and partitioned between DCM and water. The organic layer was
concentrated to give the sub-title compound, which was purified by
chromatography (EtOAc/Hex, isolated 1.02 g) prior to use in
subsequent steps. MS: ESI (positive): 266 (M+H).
e.)
(R,S)-3,4,4a,5,7,8-Hexahydro-1-thia-6-aza-cyclopenta[cd]azulene-6-carb-
oxylic acid ethyl ester
[0166] AlCl.sub.3 (627 mg, 4.72 mmol) was added to
BH.sub.3tBuNH.sub.2 (492 mg, 5.66 mmol) in DCM (2 mL) at 0.degree.
C. The solution was stirred for 10 minutes then treated with the
product from step (d) (250 mg, 0.943 mmol) as a solution in DCM (1
mL). After warming to room temperature, the reaction was quenched
with 0.1M HCl dropwise and concentrated to dryness. The reaction
was diluted in 1M HCl and extracted into EtOAc. The organic layer
was concentrated to give the sub-title compound, which was purified
by chromatography (EtOAc/Hex) prior to use in subsequent steps. MS:
ESI (positive): 252 (M+H).
f.)
(R,S)-2-Bromo-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclopenta[cd]azulen-
e-6-carboxylic acid ethyl ester
[0167] The sub-title compound was prepared by the method of Example
1, step (h) using the product from step (e) and was used in crude
form without purification.
g.)
(R,S)-2-(2,2,2-Trifluoro-acetyl)-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-c-
yclopenta[cd]azulene-6-carboxylic acid ethyl ester
[0168] A solution of 1.6M nBuLi in hexane (130 .mu.L) was added to
a solution of the product of step f) (69 mg, 0.208 mmol) in
anhydrous THF (mL) at -78.degree. C. and stirred for 15 minutes.
Trifluoro-acetic acid 2,2,2-trifluoro-ethyl ester (50 .mu.L, 0.270
mmol) was added and the reaction was warmed to ambient temperature.
The reaction was quenched with water, extracted into ethyl acetate
and the organic layers were combined and concentrated.
Trifluoroacetic anhydride (750 .mu.L, 5.36 mmol) and AlCl3 (600 mg,
4.51 mmol) were added to a solution of the crude product in
dichloroethane (10 mL) and the reaction was heated to 80.degree. C.
overnight. The reaction was cooled to ambient temperature, quenched
with water and extracted into DCM. The organic layer was
concentrated to give the sub-title compound that was used in crude
form without purification. MS: ESI (positive): 348 (M+H).
h.)
(R,S)-2-(2,2,2-Trifluoro-ethyl)-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cy-
clopenta[cd]azulene-6-carboxylic acid ethyl ester
[0169] NaBH.sub.4 (15 mg, 0.208 mmol) and a catalytic amount of
acetic acid were added to the product from step (g) (72 mg, 0.208
mmol) in ethanol (3 mL) and the reaction was stirred at ambient
temperature for 20 minutes. The reaction was quenched with acetic
acid (dropwise) and partitioned between water and DCM. The organic
layer was concentrated. Tin chloride dihydrate (187 mg, 0.832 mmol)
was added to the crude product in acetic acid (2 mL) and the
reaction was heated to 80.degree. C. for 2 hours. Additional
SnCl.sub.2 was added (150 mg) and the reaction was heated for an
additional 4 hours. The reaction was then diluted with water and
extracted into DCM. The organic layer was concentrated to give the
sub-title compound that was used without further purification.
i.)
(R,S)-2-(2,2,2-Trifluoro-ethyl)-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-
-cyclopenta[cd]azulene
[0170] TMSI (45 .mu.L) was added to the product from step (h) in
DCM (2 mL) and heated to 50.degree. C. in the dark for 2 hours. The
reaction was cooled to ambient temperature and quenched with
methanol. The reaction was concentrated and purified by preparative
LCMS to give the title compound. 1H NMR (CD3OD) .delta. 3.58-3.71
(m, 2H), 3.51 (q, J=10.8 Hz, 2H), 3.07-3.16 (m, 3H), 2.99-3.04 (m,
4H), 1.91-2.07 (m, 2H). MS: ESI (positive): 262 (M+H).
Example 14
(R,S)-2-Bromo-3,3-dimethyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopen-
ta[cd]azulene (Scheme 5)
##STR00022##
[0171] a.)
(R,S)-3,3-Dimethyl-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclopen-
ta[cd]azulene-6-carboxylic acid ethyl ester
[0172] A solution of 2M Me2Zn in toluene (1 mL) was added to TiCl4
(380 mg, 2.02 mmol) in DCM at -78.degree. C. and stirred for 10
minutes. The product from Example 13, step (d) (89 mg, 0.336 mmol)
was added and the reaction was warmed to 0.degree. C. and stirred
cold for 1 hour. The reaction was quenched with water and extracted
into DCM. The organic layer was concentrated to give the sub-title
compound that was purified by preparative LCMS prior to use in
subsequent steps. MS: ESI (positive): 280 (M+H).
b.)
(R,S)-2-Bromo-3,3-dimethyl-3,4,4a,5,7,8-hexahydro-1-thia-6-aza-cyclope-
nta[cd]azulene-6-carboxylic acid ethyl ester
[0173] The sub-title compound was prepared by the method of example
5, step (a) using the product from step (a) and was used in crude
form without purification.
c.)
(R,S)-2-Bromo-3,3-dimethyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cycl-
openta[cd]azulene
[0174] The title compound was prepared by the method described in
example 5, step (d) using the product from step (b) and purified by
preparative HPLC-MS. .sup.1H NMR (CD.sub.3OD) .delta. 3.31-3.58 (m,
3H), 2.85-3.07 (m, 3H), 2.63 (t, J=10.5 Hz, 1H), 2.24 (dd, J=6.9
Hz, J=12.3 Hz, 1H), 1.86-1.95 (m, 1H), 1.44 (s, 3H) 1.26 (s, 3H).
MS: ESI (positive): 288 (M+H).
Example 15
(R,S)-2-Bromo-5-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine
(Scheme 6)
##STR00023##
[0175] a.)
(R,S)-5-Methyl-4-oxo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6--
carboxylic acid ethyl ester
[0176] The product of Example 1, step (c) (1.06 g, 4.4 mmol) was
dissolved in 20 mL THF and treated with LHMDS (5.3 mL of 1M in
THF). After stirring for 1 hour at room temperature, MeI (326 uL,
5.3 mmol) was added and the reaction was stirred 1 hour at room
temperature. The reaction was evaporated onto silica gel and
purified by silica gel chromatography (10% to 30% EtOAc in hexanes)
to give 175 mg of the sub-title compound.
b.)
(R,S)-5-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic
acid ethyl ester
[0177] The product of step (a) (75 mg, 0.30 mmol) was dissolved in
DCE (3 mL) and treated with ZnI.sub.2 (143 mg, 0.45 mmol) followed
by NaCNBH3 (132 mg, 2.1 mmol). After stirring for 3 days at room
temperature, the reaction was filtered and the filtrate was washed
with DCM and discarded. The organic washes were combined, washed
with water (2.times.10 mL), and dried over MgSO.sub.4.
Concentration gave 22 mg of a mixture of the sub-title compound and
the alcohol corresponding to mono-reduction of the ketone starting
material. The mixture was carried directly into the subsequent
steps.
c.)
(R,S)-2-Bromo-5-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine
[0178] The product of step (b) (22 mg, 0.092 mmol) was dissolved in
2 mL of 1:1 HOAc:CHCl3 and treated with NBS (25 mg, 0.14 mmol).
After stirring for 1/2 hour, the reaction was concentrated to
dryness and treated with 2 mL EtOH and 2 mL of 40% KOH. After
heating to 100.degree. C. for 24 hours and then to 120.degree. C.
for an additional 24 hours, the reaction was cooled, diluted with
water, and extracted 3.times. with DCM. Purification by preparative
HPLC-MS gave the title compound. MS: ESI (positive): 248 (M+H).
Example 16
4-Methyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza-cyclopen-
ta[a]azulene (Scheme 3)
##STR00024##
[0179] a.)
4-Methyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid
ethyl ester
[0180] The product of Example 9, step (c) (enantiomer 2, 1.0 g,
2.51 mmol) was dissolved in 100 mL EtOH and treated with 1 g of
Pd/C (wet, Degussa grade E101) and stirred rapidly under 1 atm of
H.sub.2 for 2 hours. The reaction was filtered through celite and
concentrated to give 600 mg of the sub-title compound.
b.)
4-Methyl-2-(2,2,2-trifluoro-acetyl)-4,5,7,8-tetrahydro-thieno[2,3-d]az-
epine-6-carboxylic acid ethyl ester
[0181] The product of step (a) was dissolved in DCE (100 mL) and
treated with AlCl.sub.3 (3.3 g, 25 mmol) followed by
triflouroacetic anhydride (3.5 mL, 25 mmol). After heating to
80.degree. C. for 2 hours, another portion of AlCl.sub.3 and
trifluoroacetic anhydride was added (25 mmol each). After stirring
for 1 hour at 80.degree. C., the reaction was quenched over ice and
carefully made basic by the cautious addition of Et.sub.3N. The
thick precipitate was filtered and discarded. The resulting mixture
was extracted with DCM (3.times.100 mL). After concentration of the
extracts to approximately 100 mL, 0.5 mL each of ethyl
chloroformate and DIEA was added. After stirring for 1/2 hour, the
solution was washed with water, concentrated and purified by silica
gel chromatography (25% EtOAc/Hex) to give 460 mg of the sub-title
compound.
c.)
2-(1-Carboxymethyl-2,2,2-trifluoro-ethyl)-4-methyl-4,5,7,8-tetrahydro--
thieno[2,3-d]azepine-6-carboxylic acid ethyl ester
[0182] The product of step (b) (460 mg, 1.37 mmol) was dissolved in
25 mL THF and treated with triethylphosphonacetate (550 uL, 2.74
mmol) and LHMDS (2.2 mL of 1M in THF). After stirring for 15
minutes, the reaction was quenched with water (100 mL) and the
product was extracted into DCM (2.times.50 mL). After drying the
extracts over MgSO4 and concentration, the crude residue was
dissolved in EtOH (50 mL) and treated with 300 mg Pd/C (10%, wet,
Degussa grade E101). After stirring under 1 atm of H.sub.2 for 2
hours, the reaction was filtered through celite and treated with 1M
NaOH (10 mL). After stirring overnight at room temperature, the
reaction was acidified with 1M HCl and the product was extracted
into DCM (2.times.25 mL). The extracts were dried over MgSO.sub.4
and concentrated to give 0.5 g of the sub-title compound, which was
used without further purification.
d.)
4-Methyl-3-oxo-1-trifluoromethyl-2,3,4,5,7,8-hexahydro-1H-9-thia-6-aza-
-cyclopenta[a]azulene-6-carboxylic acid ethyl ester
[0183] The product of step (c) (500 mg, 1.3 mmol) was dissolved in
DCM (20 mL) and treated with DMF (50 uL) followed by oxalyl
chloride (240 uL, 1.45 mmol). After stirring for 1/2 hour, an
additional quantity of oxalyl chloride (240 uL) was added. After
stirring for an additional 1 hour, the reaction was concentrated to
dryness and the residue was re-dissolved in DCM (5 mL). AlCl.sub.3
(360 mg, 2.7 mmol) was added and the reaction was stirred for 1
hour at room temperature. The reaction was quenched with ice water
(10 mL) and the product was extracted into DCM/EtOH (4:1,
2.times.30 mL). The extracts were dried over MgSO.sub.4 and
concentrated to give 468 mg of the sub-title compound, which was
used without further purification. The diastereomers could be
separated by silica gel chromatography (25% to 35% EtOAc in Hex) to
give diastereomer 1 (top spot, first eluting product) and
diastereomer 2 (bottom spot, second eluting product).
e.)
4-Methyl-1-trifluoromethyl-2,3,4,5,7,8-hexahydro-1H-9-thia-6-aza-cyclo-
penta[a]azulene-6-carboxylic acid ethyl ester
[0184] The product of step (d) (mixture of diastereomers, 234 mg,
1.54 mmol) was dissolved in 5 mL EtOH and treated with NaBH.sub.4
(117 mg, 3.1 mmol). After stirring for 15 minutes, the reaction was
quenched with HOAc and diluted with water (10 mL). The product was
extracted into DCM (2.times.25 mL) and the extracts were
concentrated to dryness. The crude residue was dissolved in HOAc (8
mL) and concentrated HCl (4 mL) and treated with SnCl.sub.2 (1.4 g,
6.2 mmol). After heated to 80.degree. C. for 1 hour, the reaction
was cooled and diluted with water (15 mL). The product was
extracted into DCM (3.times.25 mL) and the extracts were dried over
MgSO.sub.4 and concentrated to dryness. The diastereomers were
separated by HPLC (Novapak C-18, 19.times.300 mm, 55%
CH.sub.3CN/water, 10 mL/min) to give diastereomer 1 (rt=23.0 min)
and diastereomer 2 (rt=24.2 min) giving approximately 20 mg of each
diastereomer.
f.)
4-Methyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza-cycl-
openta[a]azulene
[0185] The product of step (e) (diastereomer 1 and diastereomer 2,
separately, 20 mg, 0.06 mmol) was dissolved in 3 mL CHCl.sub.3 and
treated with TMSI (40 uL, 0.29 mmol). After heating to 70.degree.
C. overnight, the reaction was quenched with MeOH (5 mL) and 1 M
NaOH (2 mL). The title compound was extracted into CHCl.sub.3
(2.times.10 mL) and subsequently purified by preparative
HPLC-MS.
[0186] Diastereomer 1: .sup.1H NMR (CD.sub.3OD) .delta. 4.01-3.90
(m, 1H), 3.43-2.95 (m, 8H), 2.87-2.64 (m, 3H), 2.56-2.44 (m, 1H),
1.33-1.31 (m, 3H). MS: ESI (positive): 276 (M+H).
[0187] Diastereomer 2: .sup.1H NMR (CD.sub.3OD) .delta. 4.01-3.90
(m, 1H), 3.42-2.94 (m, 8H), 2.84-2.64 (m, 3H), 2.55-2.45 (m, 1H),
1.32-1.29 (m, 3H). MS: ESI (positive): 276 (M+H).
Example 17
3,3,4-Trimethyl-1-trifluoromethyl-1,2,3,4,5,6,7,8-octahydro-9-thia-6-aza-c-
yclopenta[a]azulene (Scheme 3)
##STR00025##
[0189] DCM (5 mL) was cooled to -78.degree. C. and treated with
TiCl.sub.4 (91 uL, 0.83 mmol) and Me.sub.2Zn (0.4 mL of 2M in
toluene). After stirring for 10 minutes, the product of Example
16,.sup.1 step (d) (diastereomer 1 and diastereomer 2, separately,
50 mg each, 0.14 mmol) was dissolved in 5 mL DCM and added to the
resulting dark slurry. The reaction was warmed to room temperature
and stirred for 3 days. The reaction was quenched over ice and the
product was extracted into DCM (2.times.15 mL). After drying over
MgSO.sub.4, the extracts were concentrated, re-dissolved in
CHCl.sub.3 (10 mL), and treated with TMSI (80 uL, 0.58 mmol). The
reaction was heated overnight to 70.degree. C. and subsequently
quenched with MeOH (5 mL) and 1 M NaOH (2 mL). The title compound
was extracted into CHCl.sub.3 (2.times.10 mL) and purified by
preparative HPLC-MS. .sup.1 The original "Examples" referred to
Example 28, which is clearly a typo since there are only 19
example. We think it should be Example 16, but we are not 100%
sure.
[0190] Diastereomer 1: .sup.1H NMR (CD.sub.3OD) .delta. 4.20-3.89
(m, 1H), 3.49-3.34 (m, 3H), 3.28-3.89 (m, 4H), 2.54 (dd, J=9.3,
13.8 Hz, 1H), 2.32 (dd, J=5.4, 13.5 Hz, 1H), 1.39 (s, 3H), 1.35 (s,
3H), 1.34 (d, J=6.3 Hz, 3H). MS: ESI (positive): 304 (M+H).
[0191] Diastereomer 2: .sup.1H NMR (CD.sub.3OD) .delta. 3.98
(sext., J=8.1 Hz, 1H), 3.52-3.34 (m, 3H), 3.27-2.88 (m, 4H), 2.46
(dd, J=8.4, 13.2 Hz, 1H), 2.33 (dd, J=6.0, 13.5 Hz, 1H), 1.42 (s,
3H), 1.38-1.33 (m, 3H), 1.29 (s, 3H). MS: ESI (positive): 304
(M+H).
Example 18
2,2-Dimethyl-1-(5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-propan-1-o-
ne (Scheme 1)
##STR00026##
[0192] a.)
2-(2,2-Dimethyl-propionyl)-4,5,7,8-tetrahydro-thieno[2,3-d]azep-
ine-6-carboxylic acid ethyl ester
[0193] A solution of the product from Example 1, step (d) (160 mg,
0.71 mmol) in dichloroethane (5 ml) at 0.degree. C. was treated
with trimethyl acetyl chloride (0.17 ml, 1.42 mmol) and AlCl.sub.3
(190 mg, 1.42 mmol). The reaction mixture was allowed to stir at
0.degree. C. for 30 minutes and then allowed to warm to room
temperature. The reaction mixture was quenched by the addition of
saturated solution of NaHCO.sub.3 (30 ml) and extracted with
dichloromethane (3.times.30 ml). The combined organic extracts were
washed with brine (50 ml), dried (MgSO.sub.4), and solvent
evaporated in vacuo to give a tan oil. The crude oil was purified
by silica gel chromatography (0% to 50% EtOAc in Hex) to give the
subtitle compound as a clear oil (60 mg, 27%). MS: ESI (positive):
310 (M+H).
b.)
2,2-Dimethyl-1-(5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-propan-
-1-one
[0194] A solution of the product from step a) (50 mg, 0.16 mmol) in
methanol (5 ml) was treated with Ba(OH).sub.2 (200 mg, 1.2 mmol).
The reaction mixture was heated in a sealed tube for 30 hours and
then allowed to cool to room temperature. The reaction mixture was
concentrated in vacuo and neutralized by the addition of 1N HCl. An
aliquot of this solution was purified by preparative HPLC-MS to
give the title compound that was converted into its HCl salt.
.sup.1H NMR (300 MHz, DMSO-d6) .delta. 9.62 (br s, 2H); 7.81 (s,
1H); 3.08-3.23 (m, 8H); 1.30 (s, 9H); MS: ESI (positive): 238
(M+H).
Example 19
1-(3-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-2,2-dimethyl-p-
ropan-1-one (Scheme 7)
##STR00027##
[0195] a.) (4,5-Dichloro-thiophen-2-yl)-oxo-acetic acid ethyl
ester
[0196] At 5-10.degree. C., Chloro-oxo-acetic acid ethyl ester (5.43
ml, 48.7 mmol) was added to 2,3-Dichlorothiophene (5 g, 32.6 mmol).
A solution of AlCl.sub.3 (6.49 g, 48.7 mmol) dissolved in
nitromethane (13 ml) was added dropwise such that the internal
reaction temperature did not rise above 10.degree. C. After 1 hour,
the reaction mixture was poured into ice water and extracted with
CH.sub.2Cl.sub.2 (2.times.100 ml). The organic layer was washed
with 10% NaHCO.sub.3 (2.times.50 ml), water (1.times.50 ml) and
brine (1.times.50 ml). Drying (Na.sub.2SO.sub.4) and concentration
provided a light orange solid that was purified by silica gel
chromatography (EtOAc/hexane-gradient) providing 6.8 g (82%) of the
subtitle compound.
b.) (4,5-Dichloro-thiophen-2-yl)-hydroxy-acetic acid ethyl
ester
[0197] A solution of the product from step a) (23.0 g, 90.9 mmol)
in THF (500 ml) was treated with NaBH(OAc).sub.3 (23.1 g, 109 mmol)
and AcOH (250 .mu.l) at 60.degree. C. for 1 hour. The reaction was
quenched with AcOH (8 ml) and concentrated to .about.250 ml. The
contents were diluted with H.sub.2O (400 ml) and extracted with
CH.sub.2Cl.sub.2 (1.times.400 ml; 1.times.100 ml). The organic
layer was dried (MgSO.sub.4) and concentrated providing 23 g of the
subtitle compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.91
(s, 1H); 5.25 (dd, J.sub.1=6 Hz, J.sub.2=1 Hz, 1H); 4.22-4.40 (m,
2H); 3.52-3.60 (br m, 1H); 1.33 (t, J=7 Hz, 3H).
c.) (4,5-Dichloro-3-methoxycarbonylmethyl-thiophen-2-yl)-acetic
acid ethyl ester
[0198] A solution of the product from step (b) (12.2 g, 48.0 mmol)
in decalin (145 ml) was treated with trimethylorthoacetate (24.5
ml, 192 mmol) and hexanoic acid (0.61 ml). The flask was equipped
with a vigreux column and heated to 180.degree. C. Additional
hexanoic acid (3 ml) was periodically added over 6 h and the
reaction was heated overnight. The reaction was concentrated on the
rotavap and the residue was extracted with MeOH (100 ml.times.2).
The MeOH extracts were concentrated and purified by silica gel
chromatography (EtOAc/Hexane-gradient) providing 4.36 g (29%) of
the subtitle compound. MS: ESI (positive): 311, 313 (M+H).
d.) (3-Carboxymethyl-4,5-dichloro-thiophen-2-yl)-acetic acid
[0199] A solution of the product from step (c) (1.14 g, 3.66 mmol)
in MeOH (7 ml) at 0.degree. C. was treated dropwise with 2M NaOH
(3.8 ml). The reaction was warmed to 22.degree. C. and stirred
overnight. The solvent was evaporated and the residue was dissolved
in 2 M NaOH (50 ml) and extracted with ether (2.times.50 ml). The
basic layer was cooled to 0.degree. C. and acidified to pH 1 with 6
M HCl. The acidic layer was back extracted EtOAc (4.times.100 ml)
and the organic layer was dried (MgSO.sub.4) and concentrated. The
crude solid was triturated with hexanes and filtered providing 2.75
g (73%) of the subtitle compound.
[0200] MS: ESI (negative): 267, 269 (M-H).
e.) 2-[4,5-Dichloro-3-(2-hydroxy-ethyl)-thiophen-2-yl]-ethanol
[0201] A solution of the product from step (d) (2.5 g, 9.33 mmol)
in THF (85 ml) was cooled to 0.degree. C. and a 1M solution of
BH.sub.3-THF (46.6 ml, 46.6 mmol) was added dropwise over 10 min.
and stirred for an additional 20 minutes after the addition was
complete. The reaction was warmed to 22.degree. C. and stirred for
2 hours. The reaction was poured into ice cold sat. NaHCO.sub.3
(150 ml) and extracted with EtOAc. The crude was passed through a
plug of silica gel washing with EtOAc. Concentration of the eluent
provided 1.99 g (88%) of the subtitle compound.
f.) Methanesulfonic acid
2-[4,5-dichloro-2-(2-methanesulfonyloxy-ethyl)-thiophen-3-yl]-ethyl
ester
[0202] A solution of the product from step (e) (1.99 g, 8.25 mmol)
in CH.sub.2Cl.sub.2 (41 ml) was cooled to 0.degree. C. and treated
with triethylamine (3.4 ml, 24.7 mmol) followed by dropwise
addition of methanesulfonyl chloride (1.4 ml, 18.1 mmol) over 10
min. After 45 minutes, the crude reaction was diluted with
CH.sub.2Cl.sub.2 (100 ml) and washed with ice water (25 ml), 10%
citric acid (2.times.25 ml), sat. NaHCO.sub.3 (2.times.25 ml) and
brine (1.times.25 ml). The organic layer was dried (MgSO.sub.4),
concentrated to 20 ml and diluted with anhydrous dioxane (76 ml).
This mixture was concentrated to remove remaining CH.sub.2Cl.sub.2
and the resulting dioxane solution was carried forward to the next
reaction.
g.)
6-Benzyl-2,3-dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine
[0203] The bismesylate dioxane solution generated in step (f) was
transferred to a 3-neck reaction flask equipped with a dropping
funnel and condenser. Anhydrous potassium carbonate (4.93 g, 35.7
mmol) was added and the contents were heated to reflux. Next, a
solution of benzylamine (2.71 g, 25.3 mmol) in anhydrous dioxane
(27 ml) was added dropwise over 45 minutes and heating was
continued for 16 hours. The salts were filtered off and the solvent
was concentrated. The crude was purified by silica gel
chromatography (EtOAc/Hexane-gradient) providing 1.43 g (62%) of
the subtitle compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.20-7.40 (m, 5H); 3.73 (s, 2H); 2.68-2.89 (m, 8H); MS: ESI
(positive): 312, 314 (M+H).
h.)
1-(6-Benzyl-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-2-
,2-dimethyl-propan-1-one
[0204] The product from step (g) (109 mg, 0.35 mmol) in anhydrous
THF (5 ml) was cooled to -78.degree. C. under a nitrogen atmosphere
and treated with 1.6 M n-butyl lithium in hexane (0.25 ml). The
reaction mixture was stirred at -78.degree. C. for 5 minutes
followed by the addition of trimethyl acetyl chloride (0.22 ml,
1.75 mmol). After 10 additional minutes at -78.degree. C., the
reaction mixture was allowed to warm to room temperature. The
reaction was quenched with saturated NaHCO.sub.3 (20 ml) and
extracted with ethyl acetate (3.times.20 ml). The combined organic
extracts were washed with brine (50 ml), dried (MgSO.sub.4), and
solvent evaporated in vacuo to give the subtitled compound as an
orange oil which was used in the next step without further
purification. MS: ESI (positive): 362, 364 (M+H).
i.)
1-(3-Chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-2-yl)-2,2-dimeth-
yl-propan-1-one
[0205] A solution of the product from step (h) (assumed 0.35 mmol)
in anhydrous dichloroethane (2 ml) was cooled to 0.degree. C.,
treated with K.sub.2CO.sub.3 (.about.50 mg) and 1-chloroethyl
chloroformate (0.38 ml, 3.5 mmol). The reaction was allowed to
warmed to 22.degree. C. for 18 hours. The reaction diluted with
CH.sub.2Cl.sub.2 (50 ml) and washed with sat. NaHCO.sub.3
(2.times.50 ml), brine (50 ml), dried (MgSO.sub.4) and solvent
evaporated in vacuo providing an oily residue, which was dissolved
in anhydrous MeOH (10 ml) and refluxed for 1.5 hours. The MeOH was
evaporated in vacuo to give the crude product. A portion of the
crude was purified by preparative HPLC-MS to give the title
compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.25 (br s,
1H); 3.05-3.19 (m, 8H); 1.34 (s, 9H); MS: ESI (positive): 272, 274
(M+H).
[0206] The following procedure was utilized to evaluate
representative compounds of the present invention as 5HT2c receptor
agonists. The results of this assay are set forth in Table 1.
Cell Culture
[0207] HEK 293 EBNA expressing the human 5HT2c receptor (VNV
Isoform) (Burns et al., NATURE 387:30308, 1997 Fitzgerald et al.,
NEUROPSYCHO-PHARMACOLOGY 21:825-905, 1999) were grown in DMEM
containing 10% dialysed FBS, 9 .mu.g/ml blasticidin at 37.degree.
C. in 5% CO2 atmosphere.
Calcium Mobilization
[0208] HEK 293 EBNA cells expressing human 5HT.sub.2 receptor
(2.times.10.sup.4/well) were seeded in black 384-well collagen
coated plates and incubated overnight at 37.degree. C. in a 5%
CO2/95% atmosphere. After removing medium, cells were treated with
HBSS buffer (137 mM NaCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mM Hepes,
pH 7.5, 2.1 mM MgCl.sub.2, 0.3 mM CaCl.sub.2, 0.02 mM MgSO.sub.4,
3.0 mM NaHCO.sub.3, and 0.64 mM KH.sub.2PO.sub.4) containing the
Calcium3 dye (Molecular Device, CA), 2.5 mM probenecid and 0.08%
pluronic acid for 60 minutes according to manufacturer's
instruction. Compounds were diluted in CsCl Ringers buffer (58.3 mM
CsCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mM Hepes, pH 7.5, 2.1 mM
MgCl.sub.2, 1.2 mM CaCl.sub.2). 5HT was utilized as a positive
control. Ligand-induced calcium release and consequent fluorescence
was measured on a Fluorometric Imaging Plate Reader (FLIPR,
Molecular Device, CA).
Data Analysis
[0209] All data were analyzed by nonlinear least square curve
fitting using Prism 4.0 software. Agonist stimulation of
calcium-induced fluorescence in FLIPR was fitted to sigmoidal dose
response using equation Y=Bottom+(Top-Bottom)/(1+10 ((LogEC50-X))),
where X is the logarithm of concentration of compounds and Y is the
fluorescent response.
TABLE-US-00001 TABLE 1 Example 5-HT2c EC50 Number (hVNV, .mu.M) 1
<0.1 2 <0.01 3 <0.01 4 <0.01 5 <0.01 6 <0.01 (for
both enantiomers) 7 <1 (for both enantiomers) 8 <0.1 9
<0.1 (for both enantiomers) 10 <0.1 (for both enantiomers) 11
<0.1 12 <0.1 13 <0.1 14 <1 15 <1 16 <0.1 (for
both diastereomers) 17 Diastereomer 1 <0.1 Diastereomer 2 <1
18 <0.01 19 <0.1
* * * * *