U.S. patent application number 11/340282 was filed with the patent office on 2007-07-19 for androgen receptor modulator compounds and methods.
Invention is credited to Kristen L. Arienti, Thomas R. Caferro, Penghui Chen, Robert I. Higuchi, Neelakandha S. Mani, Barbara Pio, Lin Zhi.
Application Number | 20070167445 11/340282 |
Document ID | / |
Family ID | 22536855 |
Filed Date | 2007-07-19 |
United States Patent
Application |
20070167445 |
Kind Code |
A1 |
Higuchi; Robert I. ; et
al. |
July 19, 2007 |
Androgen receptor modulator compounds and methods
Abstract
Compounds, pharmaceutical compositions, and methods for
modulating processes mediated by steroid receptors. In particular,
preparation and methods of use of non-steroidal compounds and
compositions that are agonists, partial agonists, and antagonists
for the androgen receptor (AR) are described. Further, described
are the methods of making and use of critical intermediates
including a stereoselective synthetic route to intermediates for
the AR modulators.
Inventors: |
Higuchi; Robert I.; (Solana
Beach, CA) ; Arienti; Kristen L.; (La Mesa, CA)
; Mani; Neelakandha S.; (San Diego, CA) ; Pio;
Barbara; (Hillsborough, NJ) ; Zhi; Lin; (San
Diego, CA) ; Chen; Penghui; (Wilmington, DE) ;
Caferro; Thomas R.; (Holly Springs, NC) |
Correspondence
Address: |
FISH & RICHARDSON, PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
22536855 |
Appl. No.: |
11/340282 |
Filed: |
January 25, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10238363 |
Sep 9, 2002 |
|
|
|
11340282 |
Jan 25, 2006 |
|
|
|
09648684 |
Aug 25, 2000 |
6462038 |
|
|
10238363 |
Sep 9, 2002 |
|
|
|
60150988 |
Aug 27, 1999 |
|
|
|
Current U.S.
Class: |
514/230.5 ;
514/249; 544/105; 544/353 |
Current CPC
Class: |
A61P 5/26 20180101; C07D
471/04 20130101; C07D 513/04 20130101; A61P 19/10 20180101; A61P
5/24 20180101; A61P 7/06 20180101; A61P 17/14 20180101; A61P 17/10
20180101; A61P 5/00 20180101; A61P 15/16 20180101; A61P 15/10
20180101; A61P 15/08 20180101; A61P 7/00 20180101; C07D 498/04
20130101; A61P 13/08 20180101; A61P 5/28 20180101; A61P 35/00
20180101; C07D 498/14 20130101 |
Class at
Publication: |
514/230.5 ;
514/249; 544/105; 544/353 |
International
Class: |
A61K 31/538 20060101
A61K031/538; A61K 31/498 20060101 A61K031/498 |
Claims
1. A compound having the formula: ##STR41## wherein: R.sup.x is
selected from among C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
allyl, aryl, arylalkyl, heteroaryl, C.sub.2-C.sub.8 alkynyl, and
C.sub.2-C.sub.8 alkenyl, wherein the alkyl, cycloalkyl,
heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl,
alkynyl, and alkenyl are optionally substituted with halogen,
C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 haloalkyl; R.sup.4 is
selected from among hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl, heteroaryl,
C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8 alkenyl, wherein the
alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, alkynyl, and alkenyl are optionally substituted with
halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 haloalkyl; and
R.sup.13 is selected from among hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8
alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, cycloalkyl,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, and alkenyl
groups are optionally substituted.
2. A compound having the formula: ##STR42## wherein: R.sup.x is
selected from among C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
allyl, aryl, arylalkyl, heteroaryl, C.sub.2-C.sub.8 alkynyl, and
C.sub.2-C.sub.8 alkenyl, wherein the alkyl, cycloalkyl,
heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl,
alkynyl, and alkenyl are optionally substituted with halogen,
C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 haloalkyl; R.sup.4 is
selected from among hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl, heteroaryl,
C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8 alkenyl, wherein the
alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, alkynyl, and alkenyl are optionally substituted with
halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 haloalkyl;
R.sup.6 is selected from among hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C8
haloalkyl, aryl, arylalkyl, heteroaryl, C.sub.2-C.sub.8 alkynyl,
and C.sub.2-C.sub.8 alkenyl, wherein the alkyl, cycloalkyl,
heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and
alkenyl are optionally substituted with halogen, C.sub.1-C.sub.4
alkyl, or C.sub.1-C.sub.4 haloalkyl; and R.sup.13 is selected from
among hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, C.sub.3-C.sub.8 cycloalkyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, C.sub.2-C.sub.8 alkynyl,
and C.sub.2-C.sub.8 alkenyl, wherein the alkyl, heteroalkyl,
haloalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, alkynyl, and alkenyl groups are optionally
substituted.
3. A compound having the formula: ##STR43## wherein: R.sup.6 is
selected from among hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl, heteroaryl,
C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8 alkenyl, wherein the
alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, alkynyl, and alkenyl are optionally substituted with
halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 haloalkyl;
R.sup.7 is selected from among hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl, heteroaryl,
C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8 alkenyl, wherein the
alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, alkynyl, and alkenyl are optionally substituted with
halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 haloalkyl; and
R.sup.13 is selected from among hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8
alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, cycloalkyl,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, and alkenyl
groups are optionally substituted.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 10/238,363, filed Sep. 9, 2002, which is a divisional of U.S.
application Ser. No. 09/648,684, filed Aug. 25, 2000, now U.S. Pat.
No. 6,462,038, which claims the benefit of U.S. Provisional
Application Ser. No. 60/160,988, filed Aug. 27, 1999. The entire
disclosure of each of these applications is hereby incorporated by
reference herein.
FIELD OF THE INVENTION
[0002] This invention relates to non-steroidal compounds that are
modulators (i.e. agonists and antagonists) of androgen receptors,
and to methods for the making and use of such compounds.
BACKGROUND OF THE INVENTION
[0003] Intracellular receptors (IRs) form a class of
structurally-related genetic regulators scientists have named
"ligand dependent transcription factors." R. M. Evans, Science,
240:889 (1988). Steroid receptors are a recognized subset of the
IRs, including the progesterone receptor (PR), androgen receptor
(AR), estrogen receptor (ER), glucocorticoid receptor (GR) and
mineralocorticoid receptor (MR). Regulation of a gene by such
factors requires both the IR itself and a corresponding ligand,
which has the ability to selectively bind to the IR in a way that
affects gene transcription.
[0004] Ligands to the IRs can include low molecular weight native
molecules, such as the hormones progesterone, estrogen and
testosterone, as well as synthetic derivative compounds such as
medroxyprogesterone acetate, diethylstilbesterol and
19-nortestosterone. These ligands, when present in the fluid
surrounding a cell, pass through the outer cell membrane by passive
diffusion and bind to specific IR proteins to create a
ligand/receptor complex. This complex then translocates to the
cell's nucleus, where it binds to a specific gene or genes present
in the cell's DNA. Once bound to DNA, the complex modulates the
production of the protein encoded by that gene. In this regard, a
compound that binds an IR and mimics the effect of the native
ligand is referred to as an "agonist", while a compound that
inhibits the effect of the native ligand is called an
"antagonist."
[0005] Ligands to the steroid receptors are known to play an
important role in health of both women and men. For example, the
native female ligand, progesterone, as well as synthetic analogues,
such as norgestrel (18-homonorethisterone) and norethisterone
(17.alpha.-ethinyl-19-nortestosterone), are used in birth control
formulations, typically in combination with the female hormone
estrogen or synthetic estrogen analogues, as effective modulators
of both PR and ER. On the other hand, antagonists to PR are
potentially useful in treating chronic disorders, such as certain
hormone dependent cancers of the breast, ovaries, and uterus, and
in treating-non-malignant conditions such as uterine fibroids and
endometriosis, a leading cause of infertility in women. Similarly,
AR antagonists, such as cyproterone acetate and flutamide, have
proved useful in the treatment of prostatic hyperplasia and cancer
of the prostate.
[0006] The effectiveness of known modulators of steroid receptors
is often tempered by their undesired side-effect profile,
particularly during long-term administration. For example, the
effectiveness of progesterone and estrogen agonists, such as
norgestel and diethylstilbesterol respectively, as female birth
control agents must be weighed against the increased risk of breast
cancer and heart disease to women taking such agents. Similarly,
the progesterone antagonist, mifepristone (RU486), if administered
for chronic indications, such as uterine fibroids, endometriosis
and certain hormone-dependent cancers, could lead to homeostatic
imbalances in a patient due to its inherent cross-reactivity as a
GR antagonist. Accordingly, identification of compounds that have
good specificity for one or more steroid receptors, but have
reduced or no cross-reactivity for other steroid or intracellular
receptors, would be of significant value in the treatment of male
and female hormone responsive diseases.
[0007] A group of quinolinone and coumarin analogs having a fused
ring system of the aryl, piperidine, pyrrolidine, or indoline
series have been described as androgen modulators. See U.S. Pat.
No. 5,696,130; Int. Patent Appl. WO 97/49709; L. G. Hamann, et. al.
J. Med Chem., 41:623-639 (1998); J. P. Edwards, et. al., Bioorg.
Med Chem. Lett., 8:745-750 (1998).
[0008] In addition, novel enantioselective synthetic routes to
N-alkyl or N-aryl 3,4-dihydro-2H-1,4-benzoxazine compounds are
described. Such compounds are key intermediates in the preparation
of quinolinones and other fused ring structures of the instant
invention. Often, when such fused-ring compounds are chiral and
possess biological activity, only one enantiomer is biologically
active, or the enantiomers possess different biological activity.
Isolating and testing such enantiomers often yields a compound with
enhanced selectivity, lower toxicity, and greater potency.
Therefore, it would be highly advantageous to selectively prepare
these types of compounds in the desired configuration. See Atarashi
S., et al., J. Heterocyclic Chem., 28:329 (1991); Xie, L. J.,
Chinese Chemical Letters, 6:857 (1995); Mitscher, L. A., et al., J.
Med Chem., 30:2283 (1987).
[0009] The entire disclosures of the publications and references
referred to above and hereafter in this specification are
incorporated herein by reference.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to novel compounds,
pharmaceutical compositions, and methods for modulating processes
mediated by steroid receptors. More particularly, the invention
relates to non-steroidal compounds and compositions that are
high-affinity, high-specificity agonists, partial agonists (i.e.,
partial activators and/or tissue-specific activators) and
antagonists for the androgen receptor (AR). Also provided are
methods of making and using such compounds and pharmaceutical
compositions, as well as critical intermediates used in their
synthesis.
[0011] In another aspect of the invention, a stereoselective
synthetic route to intermediate compounds for these AR modulators
is described. This aspect of the invention relates to preparing
N-alkylated amino alcohol intermediates stereoselectively.
[0012] These and various other advantages and features of novelty
that characterize the invention are pointed out with particularity
in the claims annexed hereto and forming a part hereof. The
following detailed description of the invention provides a better
understanding of the invention, its advantages, and objects
obtained by its use, as well as preferred embodiments of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] In accordance with the present invention, we have developed
novel compounds, compositions, and methods of preparation of
non-steroidal compounds that are AR modulators. Specifically, we
have developed high affinity, high specificity agonists, partial
agonists (i.e., partial activators and/or tissue-specific
activators) and antagonists for the androgen receptor and methods
of preparing these compounds and compositions.
[0014] In accordance with the present invention and as used herein,
the following structure definitions are provided for nomenclature
purposes. Furthermore, in an effort to maintain consistency in the
naming of compounds of similar structure but differing
substituents, the compounds described herein are named according to
the following general guidelines. The numbering system for the
location of substituents on such compounds is also provided.
[0015] The term "alkyl" refers to an optionally substituted
straight-chain or branched-chain hydrocarbon radical having from 1
to about 1I carbon atoms, more preferably from 1 to about 6 carbon
atoms, and most preferably from 1 to about 4 carbon atoms. Examples
of alkyl radical include methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl and
the like.
[0016] The term "alkenyl" refers to a straight-chain or
branched-chain hydrocarbon radical having one or more carbon-carbon
double-bonds and having from 2 to about 10 carbon atoms, preferably
from 2 to about 6 carbon atoms, and most preferably from 2 to about
4 carbon atoms. Preferred alkenyl groups include allyl. Examples of
alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the
like.
[0017] The term "allyl" refers to the radical
CH.sub.2.dbd.CH--CH.sub.2.
[0018] The term "alkynyl" refers to a straight-chain or
branched-chain hydrocarbon radical having one or more carbon-carbon
triple-bonds and having from 2 to about 10 carbon atoms, preferably
from 2 to about 6 carbon atoms, and most preferably from 2 to about
4 carbon atoms. Examples of alkynyl radicals include ethynyl,
propynyl, butynyl and the like.
[0019] The term aryl refers to optionally substituted aromatic ring
systems. The term aryl includes monocyclic aromatic rings,
polycyclic aromatic ring systems, and polyaromatic ring systems.
The polyaromatic and polycyclic ring systems may contain from two
to four, more preferably two to three, and most preferably two,
rings.
[0020] The term "heteroaryl" refers to optionally substituted
aromatic ring systems having one or more heteroatoms such as, for
example, oxygen, nitrogen and sulfur. The term heteroaryl may
include five- or six-membered heterocyclic rings, polycyclic
heteroaromatic ring systems, and polyheteroaromatic ring systems
where the ring system has from two to four, more preferably two to
three, and most preferably two, rings. The terms heterocyclic,
polycyclic heteroaromatic, and Polyheteroaromatic include ring
systems containing optionally substituted heteroaromatic rings
having more than one heteroatom as described above (e.g., a six
membered ring with two nitrogens), including polyheterocyclic ring
systems from two to four, more preferably two to three, and most
preferably two, rings. The term heteroaryl includes ring systems
such as, for example, pyridine, quinoline, furan, thiophene,
pyrrole, imidazole and pyrazole.
[0021] The term "alkoxy" refers to an alkyl ether radical wherein
the term alkyl is defined as above. Examples of alkoxy radicals
include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy and the like.
[0022] The term "aryloxy" refers to an aryl ether radical wherein
the term aryl is defined as above. Examples of aryloxy radicals
include phenoxy, benzyloxy and the like.
[0023] The term "cycloalkyl" refers to a saturated or partially
saturated monocyclic, bicyclic or tricyclic alkyl radical wherein
each cyclic moiety has about 3 to about 8 carbon atoms. Examples of
cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like.
[0024] The term "cycloalkylalkyl" refers to an alkyl radical as
defined above which is substituted by a cycloalkyl radical having
from about 3 to about 8 carbon atoms.
[0025] The term "arylalkyl" refers to an alkyl radical as defined
above in which one hydrogen atom is replaced by an aryl radical as
defined above, such as, for example, benzyl, 2-phenylethyl and the
like. Preferably, arylalkyl refers to arylmethyl.
[0026] The terms alkyl, alkenyl, and alkynyl include optionally
substituted straight-chain, branched-chain, cyclic, saturated
and/or unsaturated structures, and combinations thereof. The terms
cycloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and
alkenyl include optionally substituted cycloalkyl, allyl, aryl,
arylalkyl, heteroaryl, alkynyl, and alkenyl groups.
[0027] The terms haloalkyl, haloalkenyl and haloalkynyl include
alkyl, alkenyl and alkynyl structures, as described above, that are
substituted with one or more fluorines, chlorines, bromines or
iodines, or with combinations thereof.
[0028] The terms heteroalkyl, heteroalkenyl and heteroalkynyl
include optionally substituted alkyl, alkenyl and alkynyl
structures, as described above, in which one or more skeletal atoms
are oxygen, nitrogen, sulfur, or combinations thereof.
[0029] The substituents of an "optionally substituted" structure
include, for example, one or more, preferably one to four, more
preferably one to two, of the following preferred substituents:
alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy,
cycloalkyl, cycloalkylalkyl, arylalkyl, amino, alkylamino,
dialkylamino, F, Cl, Br, I, CN, NO.sub.2, NR.sup.10R.sup.11,
NHCH.sub.3, N(CH.sub.3).sub.2, SH, SCH.sub.3, OH, OCH.sub.3,
OCF.sub.3, CH.sub.3, CF.sub.3, C(O)CH.sub.3, CO.sub.2CH.sub.3,
CO.sub.2H and C(O)NH.sub.2, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.4 heteroalkyl,
and OR.sup.9.
[0030] A 2H-1,4-benzoxazin-3(4H)-one is represented by the
following structure: ##STR1##
[0031] A 2H-1,4-benzoxazine is represented by the following
structure: ##STR2##
[0032] 7H-[1,4]oxazino[3,2-g]quinolin-7-one is represented by the
following structure: ##STR3##
[0033] 1H-[1,4]oxazino[3,2-g]quinoline is represented by the
following structure: ##STR4##
[0034] A 1H-[1,4]oxazino[3,2-g]quinoline-2(3H)-one is represented
by the following structure: ##STR5##
[0035] A 3H-[1,4]oxazino[3,7-g]quinolin-2,7-dione is represented by
the following structure: ##STR6##
[0036] A pyrido[1',2':4,5][1,4]oxazino[3,2-g]quinolin-9(8H)-one is
represented by the following structure: ##STR7##
[0037] A 1H-pyrrolo[1',2':4,5][1,4]oxazino[3,2-g]quinolin-8(7H)-one
is represented by the following structure: ##STR8##
[0038] A quinoxalin-2(1H)-one is represented by the following
structure: ##STR9##
[0039] A quinoxaline is represented by the following structure:
##STR10##
[0040] A pyrazino[3,2-g]quinolin-2,7-dione is represented by the
following structure: ##STR11##
[0041] A pyrazino[3,2-g]quinolin-7(6H) one is represented by the
following structure: ##STR12##
[0042] Compounds of the present invention are represented by those
having the formulas: ##STR13## wherein:
[0043] R.sup.1 represents hydrogen, F, Cl, Br, I, NO.sub.2,
OR.sup.9, NR.sup.10R.sup.11, S(O).sub.mR.sup.9, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl, heteroaryl,
C.sub.2-C.sub.8 alkynyl, or C.sub.2-C.sub.8 alkenyl, wherein the
alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, alkynyl, and alkenyl groups may be optionally
substituted;
[0044] R.sup.2 is hydrogen, F, Cl, Br, I, CF.sub.3, CF.sub.2H,
CFH.sub.2, CF.sub.2OR.sup.9, CH.sub.2OR.sup.9, OR.sup.9,
S(O).sub.mR.sup.9, NR.sup.10R.sup.11, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl, heteroaryl,
C.sub.2-C.sub.8 alkynyl, or C.sub.2-C.sub.8 alkenyl, wherein the
alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, alkynyl, and alkenyl groups may be optionally
substituted;
[0045] R.sup.3 is hydrogen, F, Cl, Br, I, OR.sup.9,
S(O).sub.mR.sup.9, NR.sup.10R.sup.11, or C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 heteroalkyl, or C.sub.1-C.sub.6 haloalkyl and
wherein the alkyl, heteroalkyl, and haloalkyl groups may be
optionally substituted;
[0046] R.sup.4 and R.sup.5 each independently are hydrogen,
OR.sup.9, S(O).sub.mR.sup.9, NR.sup.10R.sup.11, C(Y)OR.sup.11,
C(Y)NR.sup.10R.sup.11, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
aryl, arylalkyl, heteroaryl, C.sub.2-C.sub.8 alkynyl, or
C.sub.2-C.sub.8 alkenyl, wherein the alkyl, cycloalkyl,
heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl,, and
alkenyl groups may be optionally substituted; or
[0047] R.sup.4 and R.sup.5 taken together can form a saturated or
unsaturated three- to seven-membered ring that may be optionally
substituted;
[0048] R.sup.6 and R.sup.7 each independently are hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8
heteroalkyl, C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl,
heteroaryl, C.sub.2-C.sub.8 alkynyl, or C.sub.2-C.sub.8 alkenyl,
wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,
arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be
optionally substituted; or
[0049] R.sup.6 and R.sup.7 taken together can form a saturated or
unsaturated three- to seven-membered ring that may be optionally
substituted; or
[0050] R.sup.6 and R.sup.5 taken together can form a saturated or
unsaturated three- to seven-membered ring that may be optionally
substituted;
[0051] R.sup.o is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
heteroalkyl, C.sub.1-C.sub.4 haloalkyl, F, Cl, Br, I, NO.sub.2,
OR.sup.9, NR.sup.10R.sup.11 or S(O).sub.mR.sup.9, wherein the
alkyl, heteroalkyl, and haloalkyl groups may be optionally
substituted;
[0052] R.sup.9 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl,
C.sub.2-C.sub.8 alkenyl or arylalkyl, wherein the alkyl,
heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl
groups may be optionally substituted;
[0053] R.sup.10 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.1-C6 haloalkyl, aryl, heteroaryl,
C.sub.2-C.sub.8 alkenyl, arylalkyl, SO.sub.2R.sup.12 or
S(O)R.sup.12, wherein the alkyl, heteroalkyl, haloalkyl, aryl,
heteroaryl, alkenyl and arylalkyl groups may be optionally
substituted;
[0054] R.sup.11 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl,
C.sub.2-C.sub.8 alkenyl or arylalkyl, wherein the alkyl,
heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl
groups may be optionally substituted;
[0055] R.sup.12 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl,
C.sub.2-C.sub.8 alkenyl or arylalkyl, wherein the alkyl,
heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl
groups may be optionally substituted;
[0056] R.sup.13 is hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
aryl, heteroaryl, or arylalkyl, wherein the alkyl, heteroalkyl,
haloalkyl, aryl, heteroaryl and arylalkyl groups may be optionally
substituted; or
[0057] R.sup.13 and R.sup.4 taken together can form a saturated or
unsaturated three- to seven-membered ring that may be optionally
substituted;
[0058] R.sup.14 and R.sup.15 each independently are hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8
heteroalkyl, C.sub.1-C.sub.8 haloalkyl, aryl, heteroaryl,
arylalkyl, C.sub.2-C.sub.8 alkynyl or C.sub.2-C.sub.8 alkenyl,
wherein the alkyl, cycloalkyl; heteroalkyl, haloalkyl, aryl,
heteroaryl, arylalkyl, alkynyl and alkenyl groups may be optionally
substituted;
[0059] R.sup.m is F, Br, Cl, I, CN, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, OR.sup.16,
NR.sup.16R.sup.17, SR.sup.16, CH.sub.2R.sup.16, COR.sup.17,
CO.sub.2R.sup.17, CONR.sup.17R.sup.17, SOR.sup.17 or
SO.sub.2R.sup.17, wherein the alkyl, heteroalkyl, and haloalkyl
groups may be optionally substituted;
[0060] R.sup.16 is hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
haloalkyl, C.sub.1-C.sub.8 heteroalkyl, COR.sup.17,
CO.sub.2R.sup.17 or CONR.sup.17R.sup.17, wherein the alkyl,
heteroalkyl; and haloalkyl groups may be optionally
substituted;
[0061] R.sup.17 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl or C.sub.1-C.sub.4 heteroalkyl, wherein the alkyl,
heteroalkyl, and haloalkyl groups may be optionally
substituted;.
[0062] m is 0, 1 or 2;
[0063] n is 1 or 2;
[0064] V is O, S or CR.sup.14R.sup.15;
[0065] W is O, S(O).sub.m, NR.sup.13, NC(Y)R.sup.11, or
NSO.sub.2R.sup.11
[0066] X and Z each independently are O, S(O).sub.m, NR.sup.11,
NC(Y)R.sup.11, NSO.sub.2R.sup.12 or NS(O)R.sup.12;
[0067] Y is O or S; and
[0068] any two of R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.13
taken together can form a saturated or unsaturated three- to
seven-membered ring that may be optionally substituted;
[0069] and pharmaceutically acceptable salts thereof
[0070] Preferred R.sup.1 groups include hydrogen, F, Cl, Br, I,
NO.sub.2, OR.sup.9, NR.sup.10R.sup.11, S(O).sub.mR.sup.9,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 cycloalkyl, C.sub.1-C.sub.8
heteroalkyl C.sub.1-C.sub.8 haloalkyl, allyl, C.sub.1-C.sub.8 aryl,
C.sub.1-C.sub.8 arylalkyl, C.sub.1-C.sub.8 heteroaryl,
C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8 alkenyl. The alkyl,
cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl,
heteroaryl, alkynyl, and alkenyl groups may be optionally
substituted. More preferred R.sup.1 groups include H, F, Cl,
OR.sup.9, NR.sup.10R.sup.11, S(O).sub.mR.sup.9, and C.sub.1-C.sub.2
alkyl. Particularly preferred R.sup.1 groups include H, F, and
Cl.
[0071] Preferred R.sup.2 groups include hydrogen, F, Cl, Br, I,
CF.sub.3, CF.sub.2Cl, CF.sub.2H, CFH.sub.2, CF.sub.2OR.sup.9,
CH.sub.2OR.sup.9, OR.sup.9, S(O).sub.mR.sup.9, NR.sup.10R.sup.11,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8,
heteroalkyl, C.sub.1-C.sub.8 haloalkyl, allyl, aryl, arylalkyl,
heteroaryl, C.sub.2-C.sub.8 alkynyl, or C.sub.2-C.sub.8 alkenyl.
The alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl,
arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be
optionally substituted. More preferred. R.sup.2 groups include H,
F, Cl, methyl, ethyl, CF.sub.3, CF.sub.2H, CF.sub.2Cl, CFH.sub.2,
and OR.sup.9. Particularly preferred R.sup.2 groups include H, Cl,
methyl, ethyl, CF.sub.3, CF.sub.2H, CF.sub.2Cl.
[0072] Preferred R.sup.3 groups include hydrogen, F, Cl, Br, I,
OR.sup.9, S(O)mR.sup.9, NR.sup.19R.sup.11, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 heteroalkyl and C.sub.1-C.sub.6 haloalkyl. The
alkyl, heteroalkyl, and haloalkyl groups may be optionally
substituted. More preferred R.sup.3 groups include hydrogen, F, Cl,
OR.sup.9, NR.sup.10R.sup.11, and S(O).sub.mR.sup.9.
[0073] Preferred R.sup.4 groups include H, OR.sup.9, C(Y)OR.sup.11,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8
heteroalkyl, C.sub.1-C.sub.8 haloalkyl, C.sub.2-C.sub.8 alkynyl,
C.sub.2-C.sub.8 alkenyl, aryl, arylalkyl, and heteroaryl. The
alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkynyl,-alkenyl, aryl,
arylalkyl and heteroaryl groups may be optionally substituted. More
preferred R.sup.4 groups include H, OR.sup.9, C(Y)OR.sup.11,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 heteroalkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.2-C.sub.4 alkynyl, and C.sub.2-C.sub.4 alkenyl.
Particularly preferred R.sup.4 groups include H, OR.sup.9,
C(Y)OR.sup.11, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
and where R.sup.4 and R.sup.13 together form a five- or
six-membered ring.
[0074] Also preferred are compounds where R.sup.4 and R.sup.13
together form a saturated or unsaturated three- to seven-membered
ring optionally substituted with 1-2 substituents. Examples of such
substituents include, for example, hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.4
heteroalkyl, C.sub.1-C.sub.4 haloalkyl, OR.sup.9 and
NR.sup.10R.sup.11. The alkyl, cycloalkyl, heteroalkyl, haloalkyl
groups may be optionally substituted.
[0075] Also preferred are compounds where R.sup.4 and R.sup.13
together form a five- to seven-membered ring optionally substituted
with 1-2 substituents. Examples of such substituents include F,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 heteroalkyl, C.sub.1-C.sub.4
haloalkyl, and OR.sup.9. The alkyl, heteroalkyl, and haloalkyl
groups may be optionally substituted.
[0076] Preferred R.sup.5 groups include H, OR.sup.9, C(Y)OR.sup.11,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8
heteroalkyl, C.sub.1-C.sub.8 haloalkyl, C.sub.2-C.sub.8 alkynyl,
C.sub.2-C.sub.8 alkenyl, aryl, arylalkyl, and heteroaryl. The
alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl,
arylalkyl and heteroaryl groups may be optionally substituted. More
preferred R.sup.5 groups include hydrogen, OR.sup.9, C(Y)OR.sup.11,
C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 haloalkyl.
[0077] Also preferred are compounds where R.sup.4 and R.sup.5 taken
together form a saturated or unsaturated three- to seven-membered
ring that may be optionally substituted.
[0078] Preferred R.sup.6 groups include hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, allyl, C.sub.1-C.sub.8
heteroalkyl, C.sub.1-C.sub.8 haloalkyl, C.sub.2-C.sub.8 alkynyl,
C.sub.2-C.sub.8 alkenyl, aryl, arylalkyl and heteroaryl. The alkyl,
cycloalkyl, allyl, heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl,
arylalkyl and heteroaryl groups may be optionally substituted. More
preferred R.sup.6 groups include hydrogen, CH.sub.3, and
CH.sub.2CH.sub.3.
[0079] Also preferred are compounds where R.sup.6 and R.sup.5 taken
together form a saturated or unsaturated three- to seven-membered
ring that may be optionally substituted.
[0080] Preferred R.sup.7 groups include hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 heteroalkyl,
C.sub.1-C.sub.8 haloalkyl, C.sub.2-C.sub.8 alkynyl, C.sub.2-C.sub.8
alkenyl, aryl, arylalkyl-and heteroaryl. The alkyl, cycloalkyl,
heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and
heteroaryl groups may be optionally substituted. More preferred
R.sup.7 groups include hydrogen, CH.sub.3, and
CH.sub.2CH.sub.3.
[0081] Also preferred are compounds where R.sup.6 and R.sup.7 taken
together form a saturated or unsaturated three- to seven-membered
ring that may be optionally substituted.
[0082] Preferred R.sup.8 groups include hydrogen, F, Cl, Br, I,
NO.sub.2, OR.sup.9, S(O).sub.mR.sup.9, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 heteroalkyl, C.sub.1-C.sub.4 haloalkyl, and
NR.sup.10R.sup.11. The alkyl, heteroalkyl and haloalkyl groups may
be optionally substituted. More preferred R.sup.8 groups include
hydrogen and F.
[0083] Preferred R.sup.9 groups include hydrogen, C(Y)R.sup.12,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, arylalkyl, C.sub.2-C.sub.8 alkynyl and
C.sub.2-C.sub.8 alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl,
heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be
optionally substituted. More preferred R.sup.9 groups include
hydrogen, C(Y)R.sup.12, and C.sub.1-C.sub.6 alkyl. Particularly
preferred R.sup.9 groups include CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.3, and C(O)CH.sub.3.
[0084] Preferred R.sup.10 groups include hydrogen, C(Y)R.sup.12,
C(Y)OR.sup.12.sub.1 SO.sub.2R.sup.12, S(O)R.sup.12, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.1.sub.6 haloalkyl, aryl,
heteroaryl, arylalkyl, C.sub.2-C.sub.8 alkynyl, and C.sub.2-C.sub.8
alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl,
arylalkyl, alkynyl, and alkenyl groups may be optionally
substituted. More preferred R.sup.10 groups include hydrogen,
C.sub.1-C.sub.6 alkyl, C(Y)R.sup.12, C(Y)OR.sup.12,
SO.sub.2R.sup.12.
[0085] Preferred R.sup.11 groups include hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6 haloalkyl,
aryl, heteroaryl, arylalkyl, C.sub.2-C.sub.8 alkynyl, and
C.sub.2-C.sub.8 alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl,
heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be
optionally substituted. More preferred R.sup.11 groups include
hydrogen and C.sub.1-C.sub.4 alkyl.
[0086] Preferred R.sup.12 groups include hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6 haloalkyl,
aryl, heteroaryl, allyl, arylalkyl, C.sub.2-C.sub.8 alkynyl,
C.sub.2-C.sub.8 alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl,
heteroaryl, allyl, arylalkyl, alkynyl, and alkenyl groups may be
optionally substituted. More preferred R.sup.12 groups include
hydrogen and C.sub.1-C.sub.4 alkyl.
[0087] Preferred R.sup.13 groups include hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, C.sub.2-C.sub.8 akynl, and C.sub.2-C.sub.8
alkenyl. The alkyl, heteroalkyl, haloalkyl, cycloalkyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, and alkenyl groups
may be optionally substituted. More preferred R.sup.13 groups
include C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 heteroalkyl and
C.sub.1-C.sub.4 haloalkyl. Particularly preferred R.sup.13 groups
include CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2(CH.sub.3),
CH.sub.2(cyclopropyl), CH.sub.2CClF.sub.2, CH.sub.2CHF.sub.2, and
CH.sub.2CF.sub.3.
[0088] Preferred R.sup.14 groups include hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
C.sub.2-C.sub.8 alkynyl, C.sub.2-C.sub.8 alkenyl, aryl, arylalkyl,
and heteroaryl. The alkyl, heteroalkyl, haloalkyl, aryl,
heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be
optionally substituted. More preferred R.sup.14 groups include
hydrogen and C.sub.1-C.sub.4 alkyl.
[0089] Preferred R.sup.15 groups include hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
C.sub.2-C.sub.8 alkynyl, C.sub.2-C.sub.8 alkenyl, aryl, arylalkyl,
and heteroaryl. The alkyl, heteroalkyl, haloalkyl, aryl,
heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be
optionally substituted. More preferred R.sup.15 groups include
hydrogen and C.sub.1-C.sub.4 alkyl.
[0090] Preferred R.sup.16 groups include hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
C.sub.2-C.sub.8 alkynyl, C.sub.2-C.sub.8 alkenyl, COR.sup.17,
CO.sub.2R.sup.17, CONR.sup.17R.sup.17, aryl, and heteroaryl. The
alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkynyl, and
alkenyl groups may be optionally substituted. More preferred
R.sup.16 groups include hydrogen and C.sub.1-C.sub.4 alkyl.
[0091] Preferred R.sup.A groups include hydrogen, F, Cl, Br, I, CN,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6
haloalkyl, OR.sup.16, NR.sup.16R.sup.17, SR.sup.16,
CH.sub.2R.sup.16, COR.sup.17, CO.sub.2R.sup.17,
CONR.sup.17R.sup.17, SOR.sup.17, and SO.sub.2R . The alkyl,
heteroalkyl, and haloalkyl groups may be optionally substituted.
More preferred RA groups include hydrogen, F, Cl, CN, and
OR.sup.16.
[0092] Preferably n is 1 or 2. More preferably, n is 1.
[0093] Preferably, m is 1 or 2. More preferably, m is 1:
[0094] Preferred V groups include O and S. More preferably, V is
O.
[0095] Preferred W groups include O, S(O).sub.m, NR.sup.13,
NC(Y)R.sup.11, and NSO.sub.2R.sup.11. More preferred W groups
include NR.sup.13, NC(Y)R.sup.11, and NSO.sub.2R.sup.11.
Particularly preferred W groups include NR.sup.13.
[0096] Preferred X groups include O, S(O).sub.m, NR.sup.11,
NC(Y)R.sup.11, NSO.sub.2R.sup.12 and NS(O)R.sup.12. More preferred
X groups include O, S(O).sub.m, and NR.sup.11. Particularly
preferred X groups include O and S(O).sub.m. Most preferably, X is
O.
[0097] Preferably Y is O.
[0098] Preferred Z groups include O, S(O).sub.m, NR.sup.11,
NC(Y)R.sup.11, NSO.sub.2R.sup.12 and NS(O)R.sup.12. More preferred
Z groups include O, S(O).sub.m, and NR.sup.11. Most preferably, Z
is NH.
[0099] In one aspect, compounds of formula I are preferred.
[0100] In another aspect, compounds of formula II are
preferred.
[0101] In still another aspect, compounds of formula III are
preferred.
[0102] In yet another aspect, compounds of formula IV are
preferred.
[0103] In one preferred aspect, R.sup.3 and R.sup.8 are each
hydrogen; X and Y are each independently O or S; W is NR.sup.13;
and Z is NR.sup.11.
[0104] In another preferred aspect, R.sup.3 and R.sup.8 are each
hydrogen; X and Y are each O, W is NR.sup.13; and Z is
NR.sup.11.
[0105] In still another preferred aspect, R.sup.3 and R.sup.8 are
each hydrogen; R.sup.2 is CF.sub.3, X and Y are each O, W is
NR.sup.13; and Z is NR.sup.11.
[0106] In yet another preferred aspect, R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.11 and R.sup.A are each
hydrogen, R.sup.2 is CF.sub.3, R.sup.13 is C.sub.1-C.sub.8 alkyl, W
is NR.sup.13, Z is NR.sup.11, X and y are each O; and m is 1 or
2.
[0107] In yet another preferred aspect, R.sup.1 R.sup.3, R.sup.6,
R.sup.7, R.sup.8, R.sup.11 and R.sup.A are each hydrogen, R.sup.2
is CF.sub.3, R.sup.4, R.sup.5 and R.sup.13 are each C.sub.1-C.sub.8
alkyl, W is NR.sup.13, Z is NR.sup.11, X and Y are each O; and m is
1 or 2.
[0108] In yet another preferred aspect, R.sup.1 R.sup.3, R.sup.4,
R.sup.5, R.sup.8, R.sup.11 and R.sup.A are each hydrogen, R.sup.2
is CF.sub.3, R.sup.6 R.sup.7 and R.sup.13 are each C.sub.1-C.sub.8
alkyl, W is NR.sup.13, Z is NR.sup.11, X and Y are each O; and m is
1 or 2.
[0109] In a preferred aspect, the present invention provides a
pharmaceutical compositions comprising an effective amount of an
androgen receptor modulating compound of formulas I through VI
shown above wherein R.sup.1 through R.sup.17, R.sup.A, V, W, X, Y,
Z, m and n all have the same definitions as given above.
[0110] In a further preferred aspect, the present invention
comprises methods of modulating processes mediated by androgen
receptors comprising administering to a patient an effective amount
of a compound of the formulas I through VI shown above, wherein
R.sup.1 through R.sup.17, R.sup.A, V, W, X, Y, Z, m and n all have
the same definitions as those given above.
[0111] Any of the compounds of the present invention can be
synthesized as pharmaceutically acceptable salts for incorporation
into various pharmaceutical compositions. As used herein,
pharmaceutically acceptable salts include, for example,
hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric,
citric, maleic, acetic, lactic, nicotinic, succinic, oxalic,
phosphoric, malonic, salicylic, phenyatcetic, stearic, pyridine,
ammonium, piperazine, diethylamine, nicotinamide, formic, urea,
sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic,
methylamino, methanesulfonic, picric, tararic, triethylamino,
dimethylamino, and tris(hydroxymethyl)aminomethane. Additional
pharmaceutically acceptable salts are known to those skilled in the
art.
[0112] AR agonist, partial agonist and antagonist compounds
(including compounds with tissue-selective AR modulator activity)
of the present invention-will prove useful in the treatment of acne
(antagonist), male-pattern baldness (antagonist), male hormone
replacement therapy (agonist), wasting diseases (agonist),
hirsutism (antagonist), stimulation of hematopoiesis (agonist),
hypogonadism (agonist), prostatic hyperplasia (antagonist),
osteoporosis (agonist) male contraception (agonist), impotence
(agonist), sexual dysfunction (agonist), cancer cachexia (agonist),
various hormone-dependent cancers, including, without limitation,
prostate (antagonist) and breast cancer and as anabolic agents
(agonist). It is understood by those of skill in the art that a
partial agonist may be used where agonist activity is desired, or
where antagonist activity is desired, depending upon the AR
modulator profile of the particular partial agonist.
[0113] It is understood by those skilled in the art that while the
compounds of the present invention will typically be employed as a
selective agonists, partial agonists or antagonists, that there may
be instances where a compound with a mixed steroid receptor profile
is preferred. For example, use of a PR agonist (i.e., progestin) in
female contraception often leads to the undesired effects of
increased water retention and acne flare-ups. In this instance, a
compound that is primarily a PR agonist, but also displays some AR
and MR modulating activity, may prove useful. Specifically, the
mixed MR effects would be useful to control water balance in the
body, while the AR effects would help to control any acne flare-ups
that occur.
[0114] Furthermore, is understood by those skilled in the art that
the compounds of the present invention, including pharmaceutical
compositions and formulations contain these compounds, can be used
in a wide variety of combination therapies to treat the conditions
and diseases described above. Thus, the compounds of the present
invention can be used in combination with other hormones and other
therapies, including, without limitation, chemotherapeutic agents
such as cytostatic and cytotoxic agents, immunological modifiers
such as interferons, interleukins, growth hormones and other
cytokines, hormone therapies, surgery and radiation therapy.
[0115] Representative AR modulator compounds (i.e., agonists and
antagonists) according to the present invention include: ##STR14##
##STR15## ##STR16## ##STR17## ##STR18## ##STR19## ##STR20##
##STR21## ##STR22## ##STR23## ##STR24## ##STR25##
[0116] Compounds of the present invention, comprising classes of
heterocyclic nitrogen compounds and their derivatives, can be
obtained by routine chemical synthesis by those skilled in the art,
e.g., by modification of the heterocyclic nitrogen compounds
disclosed or by a total synthesis approach.
[0117] The sequences of steps for several general schemes to
synthesize the compounds of the present invention are shown below.
In each of the schemes the R groups (e.g., R.sup.1, R.sup.1, etc.)
correspond to the specific substitution patterns noted in the
Examples. *However, it will be understood by those skilled in the
art that other functionalities: disclosed herein at the indicated
positions of compounds of formulas I through VI also comprise
potential substituents for the analogous positions on the
structures within the schemes.
[0118] The synthesis of 7H-[1,4]oxazino[3,2-g]quinolin-7-one
compounds (e.g., Structures 6 and 7), is depicted in Scheme I. The
process of Scheme I begins with a cyclization of a haloacetyl
halide onto 2-amino5-nitrophenol (Structure: 1) with, for example,
chloroacetyl chloride to afford a lactam (Structure 2). See. D. R
Shridhar, et al., Org. Prep. Proc. Int., 14:195 (1982). The amide
is then reduced to the coresponding amine (Structure 3), with, for
example, borane dimethyl sulfide. See Y. Matsumoto, et. al., Chem.
Pharm. Bull., 44:103-114 (1996). Treatment of a compound such as
Structure 3 with an aldehyde or its corresponding hydrate or
hemiacetal, for example trifluoroacetaldehyde hydrate in the
presence of a reducing agent, for example, sodium cyanoborohydride,
in a carboxylic acid, for example trifluoroacetic acid, affords a
compound such as Structure 4. The nitro derivative is reduced to
the correspoding aniline, with a reducing agent, for example, zinc
and calcium chloride, to afford Structure 5. Treatment of the
aniline with a .beta.-ketoester or corresponding hydrate, for
example 4,4,4-trifluoroacetoacetate, at elevated temperatures,
followed by treatment with an acid, for example, sulfuric acid,
affords a major product (Structure 6). The cyclization of anilines
as described above is known as a Knorr cyclization. See, G. Jones,
Comprehensive Hererocyclic Chemistry, Katritzky, A. R.; Rees, C.
W., eds. Pergamon, New York, 1984. Vol. 2, chap. 2.08, pp 421-426,
the disclosure of which is herein incorporated by reference. In
turn, the quinolinone nitrogen may be alkylated by, for example,
treatment with sodium hydride followed by iodomethane, to afford a
compound of Structure 7. Alternatively, a quinolinone compound of
Structure 6 can be convered to the corresponding quinoline by
treatment with a dehydrating agent, for example, oxyphosphoryl
chloride, to afford a compound of Structure 7A.
[0119] Alternatively, a quinolinone compound of Structure 6 can be
transformed to the corresponding thio-compound by treatment with,
for example, Lawesson's reagent
[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4disulfide]
to give a 7H-[1,4]oxazino[3,2-g]quinolin-thione (e.g., Structure
8). See J. Voss, Encyclopedia of Reagents for Organic Synthesis,
Paquette, L. A., Ed. John Wiley and Sons, New York, 1995; Vol. 1,
pp 530-533, the disclosure of which is herein incorporated by
reference. Alternatively, a compound of Structure 6 (or chiral
synthetic precursors of Structure 6) can be separated into its
corresponding enantiomers, (+)-6 and (-)-6 by chiral HPLC, with,
for example, a preparative Chiralpak AD column eluted with
hexanes:isopropanol. ##STR26##
[0120] An alternate synthesis of
7H-[1,4]oxazino[3,2-g]quinolin-7-one compounds (e.g., Structures 10
and 11) is shown in Scheme II. The process of Scheme II begins with
a Knorr cyclization of
7-amino-3,4-dihydro-4-p-methoxybenzyl-2H-1,4-benzoxazine, and a
.beta.-ketoester promoted by an acid, for example, sulfuric acid to
afford a compound of Structure 10. Alkylation of the quinolinone
nitrogen may be achieved by treatment with an aldehyde or its
corresponding hydrate, for example cyclopropanecarboxaldehyde in
the presence of a reducing agent, for example, sodium
cyanoborohydride, to afford the alkylated derivative of the
corresponding quinolinone compound (e.g., Structure 11). ##STR27##
##STR28##
[0121] An additional synthetic route into quinoline compounds
(e.g., Structures 16 and 18) is shown in Scheme III. The process of
Scheme III begins with reductive amination of
2-methoxy-4-nitroaniline with an aldehyde or its corresponding
hydrate, for example trifluoroacetaldehyde hydrate in the presence
of a reducing agent, for example, sodium cyanoborohydride, in an
acid, for example trifluoroacetic acid, to afford the corresponding
N-alkylated amine. The nitro derivative is reduced to the
corresponding aniline, with a reducing agent, for example, zinc and
calcium chloride, to afford a compound of Structure 13. Knorr
cyclization of the aniline by heating with a .beta.-ketoester or
corresponding hydrate, for example 4,4,4-trifluoroacetoacetate,
followed by treatment with an acid, for example, sulfuric acid,
affords a product of Structure 14. Protection of the pyridone ring,
with, for example isopropyl iodide mediated by a base, for example,
cesium fluoride, affords the corresponding imino ether. See T.
Sato, et al., Synlett 1995, 845-846. Demethylation of the anisole
is accomplished by treatment with, for example, sodium
thiophenolate to afford a compound of Structure 15. See C. Hansson,
et al., Synthesis 1975, 191. Treatment of aminophenol derivative 15
with an .alpha.-bromoester, for example, ethyl bromoacetate, and a
base, with for example, potassium-carbonate, affords a quinolinone
compound (Structure 16). Treatment of quinolinone compounds such as
Structure 16 with an alkylidenation reagent, for example, Tebbe's
reagent, followed by reduction with, for example, sodium
cyanoborohydride, in an acid, for example acetic acid, affords a
quinoline compound (e.g., Structure 17). See S. H. Pine, et. al.,
J. Org. Chem. 1985, 50, 1212, for the methylenation of amides.
Deprotection can be accomplished in one of two ways. Treatment of
the iminoether (Structure 17) with a mineral acid, for example
hydrochloric acid, affords a 7H-[1,4]oxazino[3,2-g]quinolin-7-one
compound (Structure 18). Alternatively, this transformation can be
carried out with a Lewis acid, for example boron trichloride, to
afford Structure 18. See T. Sala, et al., J. Chem. Soc., Perkin
Trans. I, 1979, 2593. Quinolinone compounds of Structure 18(or any
chiral synthetic precursor of 18) can be separated into their
corresponding enantiomers, (+)-18 and (-)-18 by chiral HPLC, with,
for example, a preparative Chiralpak AD column eluted with
hexanes:isopropanol. ##STR29##
[0122] The process of converting quinolinone compounds (e.g.,
Structure 16) into corresponding hydroxyalkyl quinoline compounds
(e.g., Structure 19) and then further converting into corresponding
hydroxyalkyl, acyloxyalkyl, and alkyloxyalkyl quinolinone
derivatives (e.g., Structures 20, 21, and 23 respectively) is shown
in Scheme IV. The process of Scheme IV begins with a Tebbe
olefination of a quinolinone compound (e.g., Structure 16) followed
by hydroboration of the resultant enamine to afford a hydroxyalkyl
quinoline compound (Structure 19). See C. T. Goralski, et. al.
Tetrahedron Lett. 1994, 33, 3251, for the hydroboration of
enamines. Hydrolysis of the imino ether with an acid, for example
hydrochloric acid, affords a hydroxy quinolinone compound (e.g.,
Structure 20).
[0123] Alternatively, hydrolysis of the imino ether of a
hydroxyalkyl quinoline compound (e.g., Structure 19) can be carried
out with an acid, for example hydrochloric acid, in acetic acid, to
afford an acyloxyalkyl quinolinone compound (Structure 21)
[0124] Alternatively, a hydroxy quinoline compound (e.g., Structure
19) can be O-alkylated by treatment with a base, for example,
sodium hydride, and an alkylating agent, with, for example methyl
iodide, to afford an alkoxyalkyl quinoline compound (e.g.,
Structure 22). Imino ether hydrolysis of Structure 22 with an acid,
for example hydrochloric acid in acetic acid, affords an
alkoxyalkyl quinoline compound (Structure 23). Compound such as
Structures 20, 21, or 23 can be separated into their corresponding
enantiomers, (+)-20 and (-)-20, (+)-21 and (-)-21, or (+)-23 and
(-)-23 by chiral HPLC, with, for example, a preparative Chiralpak
AD column eluted with hexanes:isopropanol. ##STR30##
[0125] Quinolinone compounds (e.g., Structure 16) may be converted
into corresponding quinoline-diones (e.g., Structure 24), hydroxy
quinolinones (e.g., Structure 25), and quinoline-thiones (e.g.,
Structures 26 and 27) by the processes shown in Scheme V. The
process of Scheme V begins with the deprotection of the imino ether
of Structure 16 by treatment with a mineral acid, for example,
hydrochloric acid, to afford a quinolinedione compound of Structure
24. Alternatively, this transformation can be carried out with a
Lewis acid, for example, boron trichloride, to afford a
quinoline-dione compound (e.g., Structure 24). See T. Sala, et al.,
supra. A quinoline-dione compound (e.g., Structure 24) can be
converted to a hydroxy quinoline compound (e.g., Structure 25) by
addition of an organometallic reagent, for example, methyl lithium,
which affords a hydroxy quinoline compound (Structure 25).
[0126] Quinoline compounds (e.g., Structure 16) can optionally be
converted into corresponding thio-compounds (e.g., Structure 25) by
treatment with, for example, Lawesson's reagent
[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide].
Hydrolysis of the imino ether with a Lewis acid, for example, boron
trichloride, affords a quinoline-thione compound (Structure 26).
##STR31##
[0127] A synthesis of quinolinone compounds such as Structure 30 is
shown in Scheme VI. The process of Scheme VI begins with the
O-alkylation of an o-aminophenol, for example, a
6-amino-7-hydroxyquinoline, with a haloketone, for example,
chloroacetone, mediated by a base, for example, potassium
carbonate, followed by treatment with a reducing agent, for
example, sodium cyanoborohydride, in an acid, for example, acetic
acid, to afford a quinoline compound of Structure 29. Hydrolysis of
the imino ether of Structure 29 with an acid, for example,
hydrochloric acid in acetic acid, affords a quinolinone compound of
Structure 30. Alkylation of the quinolinone nitrogen is achieved by
treatment of quinolione compounds (e.g., Structure 30) with an
aldehyde or its corresponding hydrate, for example,
cyclopropanecarboxaldehyde, with a reducing agent, for example,
sodium cyanoborohydride, in an acid, for example, acetic acid,
affords a compound of Structure 31. ##STR32##
[0128] An additional route to quinolinone compounds such as
Structure 31D is shown in Scheme VIA. The process of Scheme VIA
begins with the alkylation of a 6-aminoquinolinone with, for
example, 6-amino-7-methoxy-4-trifluoromethyl-1H-quinolin-2-one,
with an alkyl halide, for example, isopropyl iodide, mediated by a
base, for example, cesium fluoride, to afford a compound of
structure 31B. Demethylation of the methyl ether is accomplished by
treatment with, for example, sodium thiophenolate to afford a
compound of Structure 31C. Annulation of the oxazine ring can be
accomplished by treatment with a vicinal dihalide, for example,
1,2-dibromoethane, mediated by a base, for example potassium
carbonate, to afford the corresponding 1,4-oxazine, which in turn
is converted to a compound of Structure 31D by treatment with an
acid, for example, hydrochloric acid in acetic acid at elevated
temperatures. ##STR33##
[0129] Quinolinones (e.g., Structure 35) are prepared from
benzoxazines (e.g., Structure 34) by the synthetic route outlined
in Scheme VIII. Scheme VII begins with an alkylation of a
haloketone onto 2-amino-5-nitrophenol (Structure 1) with, for
example, 2-bromobutanone, mediated by a base, for example,
potassium carbonate, followed by treatment with a reducing agent,
for example, sodium cyanoborohydride, in an acid, for example
acetic acid, to afford a benzoxazine compound (e.g., Structure 32).
The benzoxazine is alkylated at the benzoxazine nitrogen by
treatment of a benzoxazine compound (e.g., Structure 32) with an
aldehyde, its corresponding hydrate or hemiacetal, with for
example, trifluoroacetaldehyde hydrate in the presence of a
reducing agent, for example, sodium cyanoborohydride, in an acid,
for example trifluoroacetic acid. This procedure affords an
alkylated benzoxazine compound (e.g., Structure 33). The nitro
derivative of the alkylated benzoxazine compound (Structure 33) is
reduced to the corresponding aniline by catalytic hydrogenation or
with a reducing agent, for example, zinc and calcium chloride, to
afford benzoxazine compound (e.g., Structure 34). Knorr cyclization
of an aminobenzoxazine (e.g., Structure 34) by heating with a
.beta.-ketoester or corresponding hydrate, with for example,
4,4,4-trifluoroacetoacetate, followed by treatment with an acid,
for example, sulfuric acid, affords a quinolinone product (e.g.,
Structure 35). ##STR34##
[0130] Compounds such as the 3,4dihydro-7-nitro-2H-1,4-benzoxazines
of Structure 33 are key intermediates in the preparation of
quinolinones and other fused ring structures. In accordance with
the current invention, we have developed a method to prepare these
3,4-dihydro-7-nitro-2H-1,4-benzoxazines in enantiomerically pure
form (Structure 39) from optically pure .beta.-aminoalcohols. A
synthetic method for the preparation of enantiomerically pure,
fused ring compounds, such as quinolinones 41, that lies upon such
intermediates is shown in Scheme VIII. ##STR35## ##STR36##
[0131] The asymmetric synthesis of Scheme VIII begins with the
chemo- and regioselective N-alkylation of a .beta.-aminoalcohol,
either as a single enantiomer (R or S) or its racemate, for
example, (R)-2-amino-1-propanol, onto a 3,4dihalonitrobenzene, for
example, 3,4-difluoronitrobenzene, mediated by a base, for example,
sodium bicarbonate, affords an optically pure arylamino alcohol
(e.g., Structure 36). Treatment of amino alcohol compounds such as
Structure 36 with an aldehyde or the corresponding hydrate or
hemiacetal, for example, trifluoroacetaldehyde ethyl hemiacetal, in
the presence of an acid catalyst, for example p-toluenesulfonic
acid, affords an optically pure oxazolidine compound (e.g.,
Structure 37). Treatment of an oxazolidine compound such as
Structure 37 with a reducing agent, for example, triethylsilane, in
the presence of an acid, for example, boron trifluoride etherate,
affords an N-alkyl substituted amino alcohol compound (e.g.,
Structure 38). Benzoxazine compounds (e.g., Structure 39), may then
be formed by cyclization of the N-alkyl substituted amino alcohol
compounds (e.g., Structure 38) by treatment with a base such as
sodium hydride. Reduction of nitro benzoxazine compounds (e.g.,
Structure 39) with a reducing agent, for example, zinc and calcium
chloride affords an amino benzoxazine compound (e.g., Structure
40). Treatment of an amino benzoxazine with a .beta.-ketoester or
its corresponding hydrate, for example ethyl
4,4,4-trifluoroacetoacetate, at elevated temperatures, affords the
corresponding acetanilide. Treatment of the acetanilide with an
acid, for example, sulfuric acid, affords an optically pure
quinolinone compound (e.g., Structure 41). An enantiomer of
Structure 41, or a racemic mixture may be obtained by the synthetic
route as described in Scheme VIII, by starting with the enantiomer
of the .beta.-aminoalcohol as shown (e.g., an (S)-.beta.-amino
alcohol), or a racemic mixture of the .beta.-aminoalcohol shown
(e.g., a (+)-.beta.-amino alcohol. Accordingly, an (S)-.beta.-amino
alcohol employed in Scheme VII, produces an (R)-quinolinone, an
(R)-.beta.-amino alcohol, employed in Scheme VII, produces an
(R)-quinolinone, and a racemic mixture of the .beta.-amino alcohol,
employed in Scheme VII, produces a racemic mixture of the
corresponding quinolinone.
[0132] Introduction of an N-alkyl or N-methylaryl group through the
reductive cleavage of oxazolidine 37, as outlined in Scheme VIII,
is generally applicable to the preparation of enantiomerically pure
arylamino alcohol compounds such as Structure 38. Furthermore, the
introduction of an N-(2-haloethyl) group through the reductive
cleavage of an aryl oxazolidine is a novel process that has general
utility in organic synthesis.
Preparation of N-Alkyl or N-Methylaryl Arylamino Alcohols
[0133] ##STR37##
[0134] In the above process sequence, R.sup.4-7 may optionally
represent hydrogen or alkyl or aryl groups, including
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8
heteroalkyl, C.sub.1-C.sub.8 haloalkyl, aryl, arylalkyl,
heteroaryl, C.sub.2-C.sub.8 alkynyl, or C.sub.2-C.sub.8 alkenyl and
wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,
arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4
haloalkyl;
[0135] R may represent C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.8 heteroalkyl, C.sub.1-C.sub.8 haloalkyl,
allyl, aryl, arylalkyl, heteroaryl, C.sub.2-C.sub.8 alkynyl, or
C.sub.2-C.sub.8 alkenyl and wherein the alkyl, cycloalkyl,
heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl,
alkynyl, and alkenyl are optionally substituted with halogen,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl.
[0136] Ar represents optionally substituted aryl or heteroaryl
groups, including mono- and polycyclic structures, optionally
substituted at one or more positions.
[0137] Additional substitutions are also possible and can be
readily determined by one skilled in the art.
[0138] The above process sequence begins with an arylamino alcohol
which is then converted into an oxazolidine with an aldehyde or the
corresponding hydrate or hemiacetal in the presence of an acid
catalyst. The oxazolidine is then converted to an N-alkylarylamino
alcohol by addition of a reducing agent such as triethylsilane or
sodium cyanoborohydride in the presence of a Lewis acid such as
boron trifluoride etherate or a protic acid such as trifluoroacetic
acid as a catalyst. Additional aldehydes and their corresponding
hydrates as well as reducing agents may be used and are readily
determined by those skilled in the art. ##STR38##
[0139] Scheme IX describes an alternative to the route of Scheme
VII for formation of enantiomerically pure benzoxazine compounds
such as Structure 39. The route of Scheme IX offers direct access
to compounds of Structure 39 in which R.sup.4 and R.sup.13 taken
together form a ring structure. The process of Scheme IX begins
with reaction of a secondary aminoalcohol, either a single
enantiomer (R or S) or its racemate, for example
2-piperidinemethanol, with a 3,4-dihalonitrobenzene, for example,
3,4-difluoronitrobenzene, to afford an N-aryl substituted tertiary
aminoalcohol compound such as Structure 42. Cyclization of
Structure 42, mediated by treatment with a base, for example,
sodium hydride, affords a benzoxazine compound (e.g., Structure
39). Benzoxazine compounds such as Structure 39 may then further be
employed in the synthesis of quinolinone compounds as described
herein. ##STR39##
[0140] Pyrazino-quinolinone compounds (e.g., Structure 49) may be
prepared by the process described in Scheme X. The process of
Scheme X begins with the alkylation of a 1,2-phenylenediamine, for
example, 1,2-phenylenediamine, with an .alpha.-haloester, for
example ethyl 2-bromoisobutyrate, mediated by a base, for example
diisopropylethylamine, to afford a compound of Structure 44.
Nitration of 44 with, for example, nitric acid in sulfuric acid,
affords a compound of Structure 45. The nitro group of 45 can be
reduced to the corresponding aniline, with, for example, palladium
on carbon under a hydrogen atmosphere, to afford a compound of
Structure 46. Treatment of the aniline with a .beta.-ketoester or
its corresponding hydrate, for example 4,4,4-trifluoroacetoacetate,
at elevated temperatures, affords the corresponding acetanilide.
Treatment of the acetanilide with an acid, for example, sulfuric
acid, affords a compound of Structure 47. Protection of the
pyridone ring, with, for example isopropyl iodide mediated by a
base, for example, cesium fluoride, affords the corresponding imino
ether (Structure 48). Reduction of the amide with, for example,
borane dimethyl sulfide, affords the corresponding amine.
Hydrolysis of this imino ether with an acid, for example,
hydrochloric acid in acetic acid, affords a pyrazinoquinolinone
compound such as Structure 49. ##STR40##
[0141] Thiazino-quinolinone compounds (e.g., Structure 56) are
prepared as shown in Scheme XI. The process of Scheme XI begins
with the treatment of an aniline, for example,
4-bromo-3-chloroaniline, with a .beta.-ketoester or its
corresponding hydrate, for example 4,4,4-trifluoroacetoacetate, at
elevated temperatures, to afford the corresponding acetanilide.
Treatment of the acetanilide with an acid, for example, sulfuric
acid, affords the corresponding 1H-quinolin-2-one (an example of a
Knorr cyclization as described further herein). Protection of the
pyridone ring, with, for example, isopropyl iodide, mediated by a
base, for example, cesium fluoride, affords a compound of Structure
51. Treatment of a compound (e.g., Structure 51) with a
.beta.-aminothiol, for example, 2-aminoethanethiol hydrochloride,
mediated by a base, for example, sodium hydride, affords a compound
of Structure 52. Treatment of a compound of Structure 52 with a
ligated transition metal, for example palladium acetate and BINAP,
in the presence of a base, for example sodium t-butoxide, at
elevated temperatures, affords a compound of Structure 53. See S.
Wagaw, et al., J. Am. Chem Soc. 1997, 119, 8451-8458. Treatment of
a compound of Structure 53 with an aldehyde or its corresponding
hydrate or hemiacetal, for example, formaldehyde, affords a
compound of Structure 55. Hydrolysis of the imino ether can be
accomplished by treatment of a compound of Structure 55 with an
acid, for example hydrochloric acid, at elevated temperatures, to
afford a thiazino-quinolinone compound such as Structure 56.
Alternatively, a compound of Structure 53 can be deprotected with
an acid, for example hydrochloric acid, at elevated temperatures,
to afford a thiazino-quinolinone compound such as Structure 54.
[0142] The compounds of the present invention also include
racemates, stereoisomers and mixtures of said compounds, including
isotopically-labeled and radio-labeled compounds. Such isomers can
be isolated by standard resolution techniques, including fractional
crystallization and chiral column chromatography.
[0143] As noted above, any of the steroid modulator compounds of
the present invention can be combined in a mixture with a
pharmaceutically acceptable carrier to provide pharmaceutical
compositions useful for treating the biological conditions or
disorders noted herein in mammalian, and more preferably, in human
patients. The particular carrier employed in these pharmaceutical
compositions may take a wide variety of forms depending upon the
type of administration desired, e.g., intravenous, oral, topical,
suppository or parenteral.
[0144] In preparing the compositions in oral liquid dosage forms
(e.g., suspensions, elixirs and solutions), typical pharmaceutical
media, such as water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like can be employed.
Similarly, when preparing oral solid dosage forms (e.g., powders,
tablets and capsules), carriers such as starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like will be employed. Due to their ease of administration,
tablets and capsules represent the most advantageous oral dosage
form for the pharmaceutical compositions of the present
invention.
[0145] For parenteral administration, the carrier will typically
comprise sterile water, although other ingredients that aid in
solubility or serve as preservatives, may also be included.
Furthermore, injectable suspensions may also be prepared, in which
case appropriate liquid carriers, suspending agents and the like
will be employed.
[0146] For topical administration, the compounds of the present
invention may be formulated using bland, moisturizing bases, such
as ointments or creams. Examples of suitable ointment bases are
petrolatum, petrolatum plus volatile silicones, lanolin, and water
in oil emulsions such as Eucerin (Beiersdorf). Examples of suitable
cream bases are Nivea.TM. Cream (Beiersdorf), cold cream (USP),
Purpose Cream.TM. (Johnson & Johnson), hydrophilic ointment
(USP), and Lubriderm.TM. (Warner-Lambert).
[0147] The pharmaceutical compositions and compounds of the present
invention will generally be administered in the form of a dosage
unit (e.g., tablet, capsule etc.) at from about 1 .mu.g/kg of body
weight to about 500 mg/kg of body weight, more preferably from
about 10 .mu.g/kg to about 250 mg/kg, and most preferably from
about 20 .mu.g/kg to about 100 mg/kg. As recognized by those
skilled in the art, the particular quantity of pharmaceutical
composition according to the present invention administered to a
patient will depend upon a number of factors, including, without
limitation, the biological activity desired, the condition of the
patient, and tolerance for the drug.
[0148] The compounds of this invention also have utility when
radio- or isotopically-labeled as ligands for use in assays to
determine the presence of AR in a cell background or extract. They
are particularly useful due to their ability to selectively
activate androgen receptors, and can therefore be used to determine
the presence of such receptors in the presence of other steroid
receptors or related intracellular receptors.
[0149] Due to the selective specificity of the compounds of this
invention for steroid receptors, these compounds can be used to
purify samples of steroid receptors in vitro. Such purification can
be carried out by mixing samples containing steroid receptor with
one or more of the compounds of the present invention so that the
compounds bind to the receptors of choice, and then separating out
the bound ligand/receptor combination by separation techniques
which are known to those of skill in the art. These techniques
include column separation, filtration, centrifugation, tagging and
physical separation, and antibody completing, among others.
[0150] The compounds and pharmaceutical compositions of the present
invention can advantageously be used in the treatment of the
diseases and conditions described herein. In this regard, the
compounds and compositions of the present invention will prove
particularly useful as modulators of male sex steroid-dependent
diseases and conditions such as the treatment of acne, male-pattern
baldness, male hormone replacement therapy, sexual dysfunction,
wasting diseases, hirsutism, stimulation of hematopoiesis,
hypogonadism, prostatic hyperplasia, osteoporosis, male
contraception, impotence, cancer cachexia, various
hormone-dependent cancers, including, without limitation, prostate
and breast cancer and as anabolic agents.
[0151] The compounds and pharmaceutical compositions of the present
invention possess a number of advantages over previously identified
steroidal and non-steroidal compounds.
[0152] Furthermore, the compounds and pharmaceutical compositions
of the present invention possess a number of advantages over
previously identified steroid modulator compounds. For example, the
compounds are extremely potent activators of AR, preferably
displaying 50% maximal activation of AR at a concentration of less
than 100 nM, more preferably at a concentration of less than 50 nM,
more preferably yet at a concentration of less than 20 nM, and most
preferably at a concentration of 10 nM or less. Also, the selective
compounds of the present invention generally do not display
undesired cross-reactivity with other steroid receptors, as is seen
with the compound mifepristone (RU486; Roussel Uclaf), a known PR
antagonist that displays an undesirable cross reactivity on GR and
AR, thereby limiting its use in long-term, chronic administration.
In addition, the compounds of the present invention, as small
organic molecules, are easier to synthesize, provide greater
stability and can be more easily administered in oral dosage forms
than other known steroidal compounds.
[0153] The invention will be further illustrated by reference to
the following non-limiting Examples.
EXAMPLE 1
1,2,3,6-Tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quin-
olin-7-one (Compound 101, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R=trifluoromethyl, R.sup.6.dbd.H, R.sup.x.dbd.H)
[0154] General Method 1: Cyclization of an .alpha.-chloroacetyl
chloride to 2-amino-5-nitrophenol. To a solution of
2-amino-5-nitrophenol (1.0 equiv), NaHCO.sub.3 (2.4 equiv) in
4-methyl-2-pentanone (0.6 mL/mmol) and water (0.6 mL/mmol) was
added an .alpha.-chloroacetyl chloride derivative (1.15equiv) via
syringe pump over 45 min at 0.degree. C. The reaction mixture was
allowed to warm to room temperature and then refluxed overnight.
The crude reaction mixture was allowed to cool to room temperature,
filtered and washed with water (3.times.1.2 mL/mmol) to afford the
desired product as a tan solid.
[0155] 7-Nitro-2H-1,4-benzoxazin-3(4H)-one (Structure 2 of Scheme
I, where R.sup.6.dbd.H). This compound was prepared by General
Method 1 from 2-amino-5-nitrophenol (6.0 g, 39 mmol), NaHCO.sub.3
(7.8 g, 93 mmol), and chloroacetyl chloride (3.58 mL, 45 mmol) to
afford 6.91 g (91%) of 7-nitro-2H-1,4-benzoxazin-3(4H)-one. Data
for 7-nitr-2H-1,4-benzoxazin-3(4H)-one: R.sub.f 0.44 (11.5:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.31 (brs, 1H,7.90 (dd, 1H, J=8.7, 2.6), 7.76 (d, 1H, J=2.5),7.06
(d, 1H, J=8.7), 4.73 (s, 2H).
[0156] General Method 2: Reduction of an amide Structure 2 to an
amine of Structure 3. To a solution of a
2H-1,4-benzoxazin-3(4H)-one of Structure 2 (1.0 equiv) in THF (10
mL/mmol) was added borane dimethylsulfide (2.0 M or 10.0 M in THF,
4 equiv) at rt, then the solution was heated to reflux for 16-18
hrs. The mixture was cooled to room temperature, quenched slowly
with methanol until gas evolution stops, then refluxed for an
additional 30 min. The solvent was removed under reduced pressure
and the compound purified by flash chromatography as indicated.
[0157] 3,4-Dihydro-7-nitro-2H-1,4-benzoxazine (Structure 3 of
Scheme I, where R.sup.6.dbd.H). This compound was prepared by
General Method 2 from 7-nitro-2H-1,4-benzoxazin-3(4H)-one (2.0 g,
10 mmol) and borane dimethylsulfide (2.0 M in THF, 24 mL, 48 mmol)
and purified on silica gel (20:1 CH.sub.2Cl.sub.2:MeOH) to afford
1.84. (98%) of 3,4-dihydro-7-nitro-2H-1,4-benzoxazine, an orange
solid. Data for 3,4-dihydro-7-nitro-2H-1,4-benzoxazine: R.sub.f
0.76 (11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.74 (dd, 1H, J=8.7, 2.5), 7.69 (d, 1H, J=2.5),
6.52 (d, 1H, J=8.7), 4.56 (1br s, 1H), 426 (t, 2H, J=4.4), 3.54
(td, 2H, J 4.4, 2.5)
[0158] General Method 3: Reductive amination of a
3,4-dihydro-2H-1,4-benzoxazine derivative with sodium
cyanoborohydride in acetic acid. To a solution of a
3,4-dihydro-7-nitro-2H-1,4-benzoxazine (1.0 equiv) in acetic acid
(7.8 mL/mmol) was added an aldehyde component (1.0 equiv) and the
mixture was stirred at rt for 1 h. To this mixture was added
portionwise sodium cyanoborohydride (4.8 equiv) and stirred at room
temperature overnight. The resulting mixture was poured over ice
and neutralized with 6M NaOH to pH 7.0, extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL/mmol), washed with pH 7 phosphate
buffer (50 mL/mmol) and brine (50 mL/mmol). The organic solution
was dried (MgSO.sub.4) and concentrated under reduced pressure to
afford the desired product as a yellow solid.
[0159] 3.4-Dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine (Structure 4
of Scheme I, where R.sup.6.dbd.H, R.sup.x.dbd.H. This compound was
prepared by General Method 3 from
3,4-dihydro-7-nitro-2H-1,4-benzoxazine (1.15 g, 6.38 mmol),
paraformaldehyde (1.92 g, 64.1 mmol) and NaBH.sub.3CN (1.95 g, 30.9
mmol) to afford 1.21 g (98%) of
3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine, a yellow solid.
Data for 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine:
R.sub.f0.83 (11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz,
CDCl3) .delta. 7.82 (dd, 1H, J=9.0, 2.6), 7.65 (d, 1H, J=3.4), 6.56
(d, 1H, J=8.9), 4.27 (t, 2H, J=4.6), 3.46 (t, 2H, J=4.5), 3.05 (s,
3H).
[0160] General Method 4: Hydrogenation of a
4-alkyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine. To a solution of a
4-alkyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine in 1:1 EtOAc:EtOH
(13 mL/mmol) was added 10% Pd--C (6% by wt). The flask was flushed
and evacuated with N.sub.2 (3.times.), then stirred under an
atmosphere of H.sub.2 overnight. The reaction mixture was filtered
through Celite, washed with EtOAc (2.times.20 mL/mmol) and
concentrated under reduced pressure to give the desired product as
a light purple/tan solid, which was purified on silica gel as
indicated.
[0161] 7-Amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine. (Structure
5 of Scheme I, where R.sup.6.dbd.H, R.sup.x.dbd.H). This compound
was prepared by General Method 4 from
3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine (262 mg, 1.35 mmol)
and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH, 20:1)
to afford 167 mg (75%) of
7-amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine. Data for
7-amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine: R.sub.f0.36
(11.5:1 CH.sub.2Cl.sub.2:MeOH) H NMR (400 MHz, CDCl.sub.3) .delta.
6.55 (d, 1H, J=8.2), 6.25 (d, 1H, J=2.6), 6.22. (dd, 1H, J=7.0,
2.7), 4.28 (t, 2H, J=4.4), 3.32 (br s, 2H), 3.13 (t, 2H, J=4.5),
2.79 (s, 3H).
[0162] General Method 5: Condensation of a
7-amino-3,4-dihydro-2H-1,4-benzoxazine with acetoacetates or their
corresponding hydrates followed by Knorr reaction mediated by
polyphosphoric acid. To a solution of a
7-amino-3,4-dihydro-2H-1,4-benzoxazine of Structure 5 (1.0 equiv)
in benzene (10 mL/mmol) under N.sub.2 at room temperature was added
an acetoacetate derivative (1.2 equiv) and the reaction was heated
at reflux for 12-16 hrs, whereupon the mixture was concentrated
under reduced pressure. The crude reaction mixture was diluted in
polyphosphoric acid (8 mL/mmol) and heated to 100.degree. C. for
12-16 hrs. The resulting mixture was poured over ice and
neutralized with 6M NaOH solution to pH 7.0, extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL/mmol), washed with pH 7 phosphate
buffer (50 mL/mmol) and brine (50 mL/mmol). The organic solution
was dried (MgSO.sub.4) and concentrated under reduced pressure.
Purification by flash chromatography (silica gel, 20:1,
CH.sub.2Cl.sub.2/MeOH) afforded the desired quinolone as a
fluorescent-yellow solid.
[0163]
1,2,3,6-Tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,-
2-g]quinolin-7-one (Compound 101, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.H). This compound was prepared by General Method 5 from
7-amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine (162 mg, 0.98
mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.19 mL, 1.28 mmol)
and purified by flash chromatography (19:1 CH.sub.2Cl.sub.2:MeOH)
to afford 125 mg (44%) of Compound 101. Data for Compound 101:
R.sub.f0.44 (EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
10.65 (br s, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 4.39
(t, 2H, J=4.6), 3.31 (t, 2H, J=4.5), 2.94 (s, 3H).
EXAMPLE 2
1,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]-
quinolin-7-one (Compound 102, Structure 7 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.H)
[0164] General Method 6: N-Methylation of a pyridone (compounds of
Structure 6) to form a compound of Structure 7. To an oven dried rb
flask containing a pyridone of Structure 6 (1.0 equiv) in THF (5
mL/mmol) was added portionwise sodium hydride (60% dispersion in
mineral oil, 1.2 equiv) under N.sub.2. After 30 min, iodomethane
(1.2 equiv) was added and the mixture was allowed to stir under
N.sub.2 an additional 8-10 hrs. The reaction mixture was then
diluted with pH 7 phosphate buffer (50 mL/mmol), extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL) and washed with brine (50
mL/mmol). The organic solution was dried (MgSO.sub.4) and
concentrated under reduced pressure. Purification by flash
chromatography (silica gel, 20:1, CH.sub.2Cl.sub.2:MeOH) afforded
the desired product as a fluorescent-yellow solid.
[0165]
1,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazin-
o[3,2-g]quinolin-7-one (Compound 102, Structure 7 of Scheme I,
where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.H). This compound was prepared by General Method 6 from
3,4-dihydro-4-methyl-6-(trifluoromethyl)-8-pyridone-[5,6-g]-2H-1,4-benzox-
azine (23.9 mg, 0.08 mmol), iodomethane (6.3 .mu.L, 0.10 mmol) and
sodium hydride (4.0 mg, 0.10 mmol) and purified by flash
chromatography (19:1 CH.sub.2Cl.sub.2:MeOH) to afford 13.7 mg (55%)
of Compound 102. Data for Comrpound 102: R.sub.f 0.54 (11.5:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
6.96 (s, 1H), 6.95 (s, 1H), 6.93 (s, 1H), 4.42 (t, 2H, J=4.4), 3.66
(s, 3H), 3.31 (t, 2H, J=4.6), 2.95 (s, 3H).
EXAMPLE 3
1-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quino-
lin-7-one (Compound 103, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.CH.sub.3)
[0166] 4-Ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (Structure 4
of Scheme I, where R.sup.6.dbd.H, R.sup.x.dbd.CH.sub.3). This
compound was prepared by General Method 3 (EXAMPLE 1) from
3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (1.15 g, 6.39
mmol), acetaldehyde (3.59 mL, 64.2 mmol) and NaBH.sub.3CN (1.95 g,
31 mmol) to afford 984 mg (74%) of
4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid.
Data for 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine:
R.sub.f0.85 (11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.81 (dd, 1H, J=9.6,2.6), 7.66 (d, 1H, J=2.7),
6.29 (d, 1H, J=9.2), 4.23 (t, 2H, J=4.7), 3.47 (t, 2H, J=4.7), 3.45
(q, 2H, J=7.2), 1.22 (t, 3H, J=7.0).
[0167] 7-Amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine (Structure 5
of Scheme I, where R.sup.6.dbd.H, R.sup.x.dbd.CH). This compound
was prepared by General Method 4 (EXAMPLE 1) from
4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (264, mg, 1.3 mmol)
and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH, 20:1)
to afford 173 mg (77%) of
7-amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine. Data for
7-amino-4ethyl-3,4-dihydro-2H-1,4-benzoxazine: R.sub.f0.52 (11.5:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
6.56 (d, 1H, J=8.1), 6.26-6.22 (m, 2H), 4.23 (t, 2H, J=4.4), 3.29
(br s, 2H), 3.24 (q, 2H, J=7.1), 3.19 (t, 2H, J=4.4), 1.11 (t, 3H,
J=7.0).
[0168]
1-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)7H-[1,4]oxazino[3,2--
g]quinolin-7-one (Compound 103, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl. R.sup.6.dbd.H,
R.sup.x.dbd.CH.sub.3). This compound was prepared by General Method
5 (EXAMPLE 1) from 7-amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine
(170 mg, 0.95 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.16
mL, 1.14 mmol) and purified by flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH) to afford 100 mg (35%) of Compound 103. Data
for Compound 103: R.sub.f0.21 (11.5:1 CH.sub.2Cl.sub.2:MeOH);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.47 (brs, 1H), 6.92 (s,
1H), 6.88 (s, 1H), 6.81 (s, 1H), 4.35 (t, 2H, J=4.5), 3.4 (q, 2H,
J=7.1), 3.34 (t, 2H, J=4.5), 1.19 (t, 3H, J=7.1). Anal. Calcd for
C.sub.14H.sub.13F.sub.3N.sub.2O.sub.2: C, 56.38; H, 4.39; N, 9.39.
Found: C, 56.04; H. 4.32; N, 9.22.
EXAMPLE 4
1-Ethyl-1,2,3,6-tetrahydro-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,-
2-g]quinolin-7-one (Compound 104, Structure 7 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.CH.sub.3)
[0169] This compound was prepared by General Method 6 (EXAMPLE 2)
from Compound 103 (18.5 mg, 0.06 mmol), iodomethane (5.8 .mu.L,
0.09 mmol) and sodium hydride (3.6 mg, 0.09 mmol) and purified by
flash chromatography (19:1 CH.sub.2Cl.sub.2:MeOH) to afford 13.5 mg
(71%) of Compound 104. Data for Compound 104: R.sub.f 0.57 (2:3
EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.98 (s,
1H), 6.93 (s, 1H), 6.85 (s, 1H), 4.38 (t, 2H, J=4.5), 3.66 (s, 3H),
3.4 (q, 2H, J=7.1), 3.35 (t, 2H, J=4.6), 1.19 (t, 3H, J=7.1).
EXAMPLE 5
1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]ox-
azino[3.2-g]quinolin-7-one (Compound 105, Structure 6 of Scheme I,
where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.CF.sub.3)
[0170] General Method 7: Reductive amination of a
7-nitro-2H-1,4-benzoxazine in trifluoroacetic acid. To a solution
of a 7-nitro-3,4-dihydro-2-1,4-benzoxazine (1.0 equiv) in
trifluoroacetic acid (0.5 mL/mmol) was added an aldehyde or its
corresponding hydrate (10 equiv) and the mixture was stirred at rt
for 2 h. To this mixture was added portionwise sodium
cyanoborohydride (4.8 equiv) and stirred at room temperature
overnight. The resulting mixture was poured over ice and
neutralized with 6M NaOH solution to pH 7.0, extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL/mmol), washed with pH 7 phosphate
buffer (50 mL/mmol) and brine (50 mL/mmol). The organic solution
was dried (MgSO.sub.4) and concentrated under reduced pressure to
afford the desired product as a yellow solid.
[0171]
3,4-Dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine
(Structure 4 of Scheme I, where R.sup.6.dbd.H,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
7 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (388 mg,
2.1 mmol), 2,2,2-trifluoroacetaldehyde monohydrate (2.51 g, 21.6
mmol) and NaBH.sub.3CN (656 mg, 10.4 mmol) to afford 500 mg (88%)
of 3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,
a yellow solid. Data for
3,4-dihydro-7-nitro-4-(2,2,2-trifluoroyl)-2H-1,4-benzoxazine:
R.sub.f0.59 (3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.81 (dd, 1H, J=8.8, 2.6), 7.72 (d, 1H, J=2.6), 6.72 (d,
1H, J=9.1), 4.27 (t, 2H, J=4.5), 3.94 (q, 2H, J=8.6), 3.61 (t, 2H,
J=4.5).
[0172]
7-Amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine
(Structure 5 of Scheme I, where R.sup.6.dbd.H,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
4 (EXAMPLE 1) from
3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine
(3.12 g, 12 mmol) and purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH, 20:1) to afford 2.7 g (98%) of
7-amino-3,4-dihydro-4-2,2,2-trifluoroethyl)-2H-1,4-benzoxazine.
Data for
7-amino-3,4-dihydro4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:
R.sub.f 0.47 (3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.56 (d, 1H, J=8.2), 6.30-6.20 (m, 2H), 4.16 (t, 2H, J=4.3)
3.65 (q, 2H, J=9.1), 3.39 (t, 2H, J=4.4), 3.36 (brs, 1H).
[0173]
1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-
-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 105, Structure 6 of
Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.H, R.sup.x.dbd.CF.sub.3). This compound was prepared by
General Method 5 (EXAMPLE 1) from
7-amino-4(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (2.7 g, 11.6
mmol), and ethyl 4,4,4-trifluoroacetoacetate (2.04 mL, 14 mmol) and
purified by flash chromatography (3:2 EtOAc:hexanes) and
recrystallized from MeOH to afford 790 mg (19%) of Compound 105.
Data for Compound 105: R.sub.f0.25 (11.5:1 CH.sub.2Cl.sub.2:MeOH);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.95 (br s, 1H), 7.04
(br s, 1H), 6.91 (s, 1H), 6.90 (s, 1H), 4.33 (t, 2H, J=4.5), 3.88
(q, 214, J.=8.9), 3.56 (t, 2H, J=4.5). Anal. Calcd for
C.sub.14H.sub.F.sub.6N.sub.2O.sub.2: C, 47.74; H. 2.86; N, 7.95.
Found: C, 47.81; H, 2.80; N, 7.87.
EXAMPLE 6
8-Fluoro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7-
H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 106, Structure 6 of
Scheme I, where R.sup.1=F, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.CF.sub.3)
[0174] This compound was prepared by General Method 5 (EXAMPLE 1)
from 7-amino
3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine EXAMPLE 5)
(24 mg, 0.1 mmol), and ethyl
2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate (27 mg, 0.12 mmol) and
purified by flash chromatography (1:1 EtOAc:hexanes) to afford 8 mg
(21%) of Compound 106. Data for Compound 106: R.sub.f 0.15 (19:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.38 (br s, 1H), 7.08 (s, 1H), 6.86 (s, 1H), 4.32 (t, 2H, J=4.5),
3.88 (q, 2H, J=8.8), 3.56 (t, 2H, J=4.4)
EXAMPLE 7
8-Chloro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7-
H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 107, Structure 6 of
Scheme I, where R.sup.1.dbd.Cl, R.sup.2=trifluoromethyl,
R.sup.6.dbd.H, R.sup.x=CF.sub.3)
[0175] This compound was prepared by General Method 5 (EXAMPLE 1)
from
7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine
(EXAMPLE 5) (21 mg, 0.1 mmol), and ethyl
2-chloro-4,4,4-trifluoroacetoacetate (23 mg, 0.1 mmol) and purified
by reverse phase HPLC (ODS, 75:25 MeOH:water, 3 mL/min) to afford 2
mg (6%) of Compound 107. Data for Compound 107:. R.sub.f0.12 (19:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
10.22 (br s, 1H), 7.15 (s, 1H), 6.75 (s, 1H), 4.33 (t, 2H, J=4.5),
3.87 (q, 2H, J=8.7), 3.56 (t, 2H, J=4.4).
EXAMPLE 8
9-(Difluoromethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-7H-[1,4]oxa-
zino[3,2-g]quinolin-7-one (Compound 108, Structure 6 of Scheme I,
where R.sup.1.dbd.H, R.sup.2=difluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.CF.sub.3)
[0176] This compound was prepared by General Method 5 (EXAMPLE 1)
from
7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine
(EXAMPLE 5) (310 mg, 1.3 mmol), and ethyl 4,4-difluoroacetoacetate
(243 mg, 1.5 mmol) and purified by flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH) to afford 50 mg (11%) of Compound 108. Data
for Compound 108: R.sub.f0.22 (3:2 EtOAc:hexanes); .sup.1H NMR (400
MHz, CDCl.sub.3) 10.92.(br s, 1H), 7.06 (s, 1H), 6.82 (s, 1H), 6.72
(t, 1H, J=54.2), 6.71 (s, 1H), 4.32 (t, 2H, J=4.4), 3.85 (q, 2H,
J=8.9), 3.54 (t, 2H, J=4.4).
EXAMPLE9
1,2,3,6-Tetrahydro-6-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7-
H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 109, Structure 7 of
Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.H, R.sup.x.dbd.CF.sub.3)
[0177] This compound was prepared by General Method 6 (EXAMPLE 2)
from Compound 105 (EXAMPLE 5) (85.0 mg, 0.24 mmol), iodomethane (18
.mu.L, 0.29 mmol) and sodium hydride (11.6 mg, 0.29 mmol) and
purified by flash chromatography (3:2 EtOAc:hexanes) to afford 73
mg (83%) of Compound 109. Data for Compound 109: R.sub.f 0.47 (3:2
EtOAc:hexanes); .sup.1H NMR (400 MHz CDCl.sub.3) 7.09 (s, 1H), 6.95
(s, 1H), 6.89 (s, 1H), 4.36 (t, 2H, J=4.4), 3.88 (q, 2H, J=8.9),
3.66 (s, 3H), 3.57 (t, 2H, J=4.4).
EXAMPLE 9A
7-Chloro-2,3-dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]-
oxazino[3,2-g]quinoline (Compound 109A, Structure 7A of Scheme I,
where R.sup.1.dbd.H, R.sup.2=trifluoromethyl. R.sup.6.dbd.H,
R.sup.x.dbd.CF.sub.3, R.sup.A.dbd.Cl)
[0178] A solution of Compound 105 (EXAMPLE 5) (25 mg, 0.07 mmol) in
3 mL POCl.sub.3 was heated at 80.degree. C. for 2 h. The reaction
was quenched with NaHCO.sub.3 (sat'd) in ice and neutralized to
pH=7. The mixture was extracted with CH.sub.2Cl.sub.2, and the
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated. Flash chromatography (95:5. CH.sub.2Cl :MeOH)
afforded 20 mg (77%) of Compound 109A, a yellow solid. Data for
Compound 109A: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (s, 1H),7.46
(s, 1H), 7.16 (s, 1H), 4.38 (t, 2H, J=4.6), 4.00 (q, 2H, J=8.8),
3.66 (t, 2H, J=4.4).
EXAMPLE 10
1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-trifluoromethyl)-7H-[1,4]oxa-
zino[3,2-g]quinolin-7-thione (Compound 110, Structure 8 of Scheme
I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl. R.sup.6.dbd.H,
R.sup.x.dbd.CF.sub.3)
[0179] General Method 8: Conversion of a pyridone to a
thiopyridone. To a solution of a pyridone of Structure 6 (1.0
equiv) in benzene (0.6 mL/mmol) was added Lawesson's reagent (1.0
equiv) and heated to 60.degree. C. for 12-16 hours. The reaction
mixture was allowed to cool to room temperature, partitioned with
H.sub.2O/ether (200 mL/100 mL), extracted with ether (2.times.30
mL), and washed with brine (50 mL/mmol). The organic solution was
dried (MgSO.sub.4) and concentrated under reduced pressure to give
the desired product as an orange solid, which was purified on
silica gel as indicated.
[0180]
1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-
-[1,4]oxazino[3,2-g]quinolin-7-thione (Compound 110, Structure 8 of
Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.H, R.sup.x.dbd.CF.sub.3). This compound was prepared by
General Method 8 from Compound 105 (EXAMPLE 5) (50.0 mg, 0.15 mmol)
and Lawesson's reagent (57.0 mg, 0.15 mmol) and purified by flash
chromatography (19:1 CH.sub.2Cl.sub.2:MeOH) to afford 12 mg (23%)
of Compound 110. Data for: Compound 110: .sup.1H NMR (400 MHz,
CDCl.sub.3) 11.47 (br s, 1H), 7.04 (s, 2H), 6.91 (s, 1H), 4.35 (t,
2H, J=4.6), 3.97 (q, 2H, J=8.8), 3.63 (t, 2H, J=4.6).
EXAMPLE 11
1,2,3,6-Tetrahydro-1-propyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quin-
olin-7-one (Compound 111, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.CH.sub.3CH.sub.2)
[0181] 7-Nitro-4-propyl-2H-1,4-benzoxazine (Structure 4 of Scheme
I, where R.sup.6.dbd.H, R.sup.x.dbd.CH.sub.3CH.sub.2)
[0182] This compound was prepared by General Method 3 (EXAMPLE 1)
from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (530 mg,
2.9 mmol), propionaldehyde (1.61 g, 28 mmol) and NaBH.sub.3CN (872
mg, 14 mmol) to afford 450 mg (69%) of
3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine, an orange oil.
Data for 3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine:
R.sub.f0.57 (2:1 EtOAc:hex ); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.80 (dd, 1H, J=9.1, 2.6), 7.66 (d, 1H, J=2.6), 6.56 (d,
1H, J=9.0), 4.22 (t, 2H, J=4.5), 3.49 (t, 2H, J=4.5), 3.33 (t, 2H,
J=7.5), 1.67 (sext, 2H, J=7.4), 0.98 (t, 3H, J=7.4).
[0183] 7-Amino-3,4-dihydro-4-propyl-2H-1,4-benzoxazine (Structure 5
of Scheme I, where R.sup.6.dbd.H, R.sup.x.dbd.CH.sub.3CH.sub.2).
This compound was prepared by General Method 4 (EXAMPLE 1) from
3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine (50 mg, 0.2 mmol)
and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH, 20:1)
to afford 36 mg (84%) of 7-amino-3
,4-dihydro-4-propyl-2H-1,4-benzoxazine. Data for
7-amimo-3,4-dihydro-4-propyl-2H-1,4-benzoxazine: R.sub.f0.43 (2:1
EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.53 (d,
1H, J=8.9), 6.25-6.20 (m, 2H), 4.21 (t, 2H, J=4.4), 3.28 (br s,
2H), 3.21 (t, 2H, J=4.4), 3.08 (t, 2H, J=7.5), 1.60 (sext, 2H,
J=7.4), 0.94 (t, 3H, J=7.4).
[0184]
1,2,3,6-Tetrahydro-1-propyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,-
2-g]quinolin-7-one (Compound 111, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x=CH.sub.3CH.sub.2). This compound was prepared by General
Method 5 (EXAMPLE 1) from
7-amino-3,4-dihydro-4-propyl-2H-1,4-benzoxazine (395 mg, 2.0 mmol),
and ethyl 4,4,4-trifluoroacetoacetate (0.36 mL, 2.5 mmol) and
purified by flash chromatography (3:2 EtOAc:hexanes) and
recrystallized from MeOH to afford 100 mg (16%) of Compound 111.
Data for Compound 111: R.sub.f 0.24 (3:2 EtOAc:hexanes); .sup.1H
NMR (400 MHz, CDCl.sub.3) 11.79 (br s, 1H), 6.88 (s, 1H), 6.87 (s,
1H), 6.83 (s, 1H), 4,32 (t, 2H, J=4.5), 3.37 (t, 2H, J=4.5), 3.26
(t, 2H,J=7.4),1.66 (sext, 2H, J=7.4), 0.99 (t, 3H, J=7.4).
EXAMPLE 12
1,2,3,6-Tetrahydro-1-isobutyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]qu-
inolin-7-one (Compound 112, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.(CH.sub.3).sub.2CH)
[0185] 3,4-Dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine (Structure
4 of Scheme I, where R.sup.6.dbd.H,
R.sup.x.dbd.(CH.sub.3).sub.2CH). This compound was prepared by
General Method 3 (EXAMPLE 1) from
3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1)(550 mg, 3.0
mmol), isobutyraldehyde (1.65 g, 22.8 mmol) and NaBH.sub.3CN (959
mg, 15 mmol) to afford 713 mg (99%) of
3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine, an yellow solid.
Data for 3,4-dihydro-4-isobutyl-7-nitro-H-1,4-benzoxazine: R.sub.f
0.75 (3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.78 (dd, 1H, J=9.0, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H,
J=9.2), 4.21 (t, 2H, J=4.5), 3.52 (t, 2H, J=4.6), 3.16 (d, 2H,
J=7.4), 3.12 (hept, 1H, J=6.9), 0.97 (d, 6H, J=6.7).
[0186] 7-Amino-3,4-dihydro-4-isobutyl-2H-1,4-benzoxazine (Structure
5 of Scheme I, where R.sup.6.dbd.H,
R.sup.x.dbd.(CH.sub.3).sub.2CH). This compound was prepared by
General Method 4 (EXAMPLE 1) from
3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine (712 mg, 3.0
mmol) and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH,
20:1) to afford 621 mg (99%) of
7-amino-4-isobutyl-2H-1,4-benzoxazine. Data for
7-amino-3,4-dihydro-4-isobutyl-2H-1,4-benzoxazine: R.sub.f0.43 (3:2
EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.49 (d,
1H, J=9.1), 6.23 (m, 2H), 4.20 (t, 2H, J=4.4), 3.28 (br s, 2H),
3.23 (t, 2H, J=4.4), 2.85 (d, 2H, J=7.2), 2.04-1.92 (m, 1H) 0.94
(d, 6H, J=6.5).
[0187]
1,2,3,6-Tetrahydro-1-isobutyl-9-(trifluoromethyl)-7H-[1,4]oxazino[-
3,2-g]quinolin-7-one (Compound 112, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl. R.sup.6=H,
R.sup.x=(CH.sub.3).sub.2CH). This compound was prepared by General
Method 5 (EXAMPLE 1) from
7-amino-3,4-dihydro-4-isobutyl-2H-1,4-benzoxazine (620 mg, 3.0
mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.527 mL, 3.6 mmol)
and purified by flash chromatography (3:2 EtOAc:hexanes) and
recrystallized from MeOH to afford 241 mg (25%) of Compound 112.
Data for Compound 112: R.sub.f0.2 (3:2 EtOAc:hexanes); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 10.62 (br s, 1H), 6.87 (s, 2H), 6.74
(s, 1H), 4.31 .(t, 2H, J=4.5), 3.41 (t, 2H, J=4.5), 3.05 (d, 2H,
J=7.0), 2.05-1.95 (m, 1H), 0.98 (d, 6H, J=6.5).
EXAMPLE 13
1,2,3,6-Tetrahydro-1-isobutyl-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino-
[3,2-g]quinolin-7-one (Compound 113, Structure 7 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6.dbd.H,
R.sup.x.dbd.(CH.sub.3).sub.2CH)
[0188] This compound was prepared by General Method 6 (EXAMPLE 2)
from Compound 112 (10.0 mg, 0.03 mmol), iodomethane (3.0 .mu.L,0.03
mmol) and sodium hydride (1.5 mg, 0.03 mmol) and purified by flash
chromatography (19:1 CH.sub.2Cl.sub.2:MeOH) to afford 8.3 mg (80%)
of Compound 113. Data for Compound 113: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.93 (s, 2H), 6.85 (s, 1H), 4.34 (t, 2H,
J=4.5), 3.65 (s, 3H), 3.43 (t, 2H, J p 4.5), 3.06(d, 2H, J=7.2),
2.09 (m, 1H), 0.99 (d, 6H, J=6.6).
EXAMPLE 14
(.+-.)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-trifluoromet-
hyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 114, Structure
6 of Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6=Me, R.sup.x.dbd.CF.sub.3)
[0189] (.+-.)-2-Methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one
(Structure 2 of Scheme I, where R.sup.6=Me). This compound was
prepared by General Method 1 (EXAMPLE 1) from 2-amino-5-nitrophenol
(3.0 g, 20 mmol), NaHCO (3.9 e, 46 mmol), and 2-chloropropionyl
chloride (2.2 mL, 22 mmol) to afford 3.1 g (77%) of
(.+-.)-2-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)one. Data for
(.+-.)-2-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one: R.sub.f0.45
(11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, DMSO) .delta.
11.28 (br s, 1H),7.92 (dd, 1H, J=8.6, 2.2), 7.77 (d, 1H, J=2.6),
7.07 (d, 1H, J=8.7), 4.85 (q, 1H, J=6.7), 1.46 (d, 3H, J=6.8).
[0190] (.+-.)-3,4-Dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine
(Structure 3 of Scheme I, where R.sup.6=Me). This compound was
prepared by General Method 2 (EXAMPLE 1) from
(.+-.)-2-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (1.8 g, 8.6
mmol) and borane dimethylsulfide (10.0-10.2 M in THF, 3.5 mL,35
mmol) and purified on silica gel (20:1 CH.sub.2Cl.sub.2:MeOH) to
afford 1.57 g (94%) of
3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine, an orange solid.
Data for 3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine:
R.sub.f0.75 (1.1.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.73 (dd, 1H, J=8.7, 2.6), 7.69 (d, 1H, J=2.2),
6.52 (d, 1H, 8.7), 4.56 (br s, 1H), 4.20 (m, 1H), 3.47 (ddd, 1H,
J=12.1, 3.8, 2.7), 3.21 (ddd, 1H, J=12.0, 8.1, 1.2), 1.40 (d, 3H,
J=6.1).
[0191]
(.+-.)-3,4-Dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,-
4-benzoxazine (Structure 4 of Scheme I, where R.sup.6=Me,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
7 (EXAMPLE 5) from
(.+-.)-3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine (400 mg, 2.0
mmol), 2,2,2-trifluoroacetaldehyde monohydrate (2.4 g, 20.6 mmol)
and NaBH.sub.3CN (628 mg, 10.0 mmol) to afford 550 mg (96%) of
(.+-.)-3,4
dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,
a yellow solid. Data for
(.+-.)-3,4-dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzo-
xazine: R.sub.f0.85 (3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.81 (dd, 1H, J=9.2, 2.6), 7.72 (d, 1H, J=2.6),
6.72 (d, 1H, J=9.1), 4.23 (m, 1H), 4.23-3.82 (m, 2H), 3.47 (dd, 1H,
J=12.1, 2.6), 3.37 (dd, 1H, J=12.2, 8.2), 1.41 (d, 3H, J=6.1).
[0192]
(.+-.)-7-Amino-3,4-dihydro-2-methyl-4-(2,2,2-trifluoroethyl)-2H-1,-
4-benzoxazine (Structure 5 of Scheme I, where R.sup.6=Me,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
4 (EXAMPLE 1) from
(.+-.)-3,4-dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzo-
xazine (394 mg, 1.4 mmol) and purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH, 20:1) to afford 345 mg (98%) of
(.+-.)-7-amino-3,4-dihydro-2-methyl-4-(2,2,2-trifuoroethyl)-2H-1,4-benzox-
azine. Data for
(.+-.)-7-amino-3,4-dihydro-2-methyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzo-
xazine: R.sub.f0.60(11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400
MHz CDCl.sub.3) .delta. 6.57 (d, 1H, J=9.2), 6.27-6.22 (m, 2H),
6.24 (s, 1H),4.18 (m, 1H), 3.75-3.62 (m, 3H), 3.27 (dd, 1H,J=12.0,
9.8), 3.10 (dd, 1H, J=12.0, 8.5), 1.34 (d, 3H, J=6.3).
[0193]
(.+-.)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-trif-
luoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 114,
Structure 6 of Scheme I, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl, R.sup.6=Me, R.sup.x.dbd.CF.sub.3). This
compound was prepared by General Method 5 (EXAMPLE 1) from
(.+-.)-7-amino-3,4-dihydro-2-methyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzo-
xazine (345 mg, 1.4 mmol), and ethyl 4,4,4-trifluoroacetoacetate
(0.24 mL, 1.6-mmol) and purified by flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH) to afford 52 mg (34%) of Compound 114. Data
for Compound 114: R.sub.f 0.26 (11.5:1 CH.sub.2Cl.sub.2:MeOH); H
NMR (400 MHz, CDCl.sub.3) .delta. 10. 84br s, 1H), 7.05 (s, 1H),
6.90 (s, 1H), 6.82 (s, 1H), 4.35 (m, 1H), 3.91 (m, 1H), 3.83
(m,1H), 3.44 (dd, 1H J=12.1, 2.0), 3.21 (dd, 1H, J=11.7, 7.8), 1.42
(d, 3H, J=6.2). Anal. Calcd for
C.sub.15H.sub.12F.sub.6N.sub.2O.sub.2: C, 49.19; H, 3.30; N, 7.65.
Found: C, 49.19; H, 3.23; N, 7.54.
EXAMPLE 15
(-)-1,2,3,6-Tetrahydro-3-methyl-1-2,2,2-trifluoroethyl)-9-(trifluoromethyl-
)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 115, Structure 6
of Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6=Me, R.sup.x.dbd.CF.sub.3) and
(+)-1,2,3,6-tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluorometh-
yl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 116, Structure 6
of Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6=Me, R.sup.x.dbd.CF.sub.3)
[0194] General Method 9: Resolution of Compounds of Structure 6,
18, or 23 to their corresponding enantiomers via chiral HPLC. A
preparative Chiralpak AD column (10 .mu.m particle size,
20.times.250 mm OR 10.times.250 mm, Daicel Chemical Industries,
Ltd.) on a Beckman Gold HPLC was equilibrated with an eluent of
hexanes:isopropanol at a flow rate of 4.5-5 mL/min. A solution of
the racemic compound in MeOH, EtOH, or acetone was prepared and
injections were monitored to insure that baseline separation is
achieved. Compound elution was monitored by absorbance detection at
254 nM. Sequential injections were performed until the specified
amounts were obtained. The solvents of the separated enantiomers
were removed in vacuo. Purity of the collected fractions were
verified by injection of analytical amounts and in each case only a
single enantiomer was detected.
[0195]
(-)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(triflu-
oromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 115,
Structure 6 of Scheme I, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl. R.sup.6=Me, R.sup.x=CF.sub.3) and
(+)-1,2,3,6-tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluorometh-
yl)-7H-[1,4]oxazino [3,2-g]quinolin-7-one (Compound 116, Structure
6 of Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6=Me, R.sup.x.dbd.CF.sub.3).
[0196] This compound was prepared according to General Method 9
from Compound 114 (10 mg, 0.03 mmol) on a semiprep Chiralpak AD
column (10.times.250 mm) and eluted with hexanes/isopropanol
(95:5), to afford 3 mg of Compound 115, a yellow solid, and 2.0 mg
of Compound 116, a yellow solid. Data for Compound 115: HPLC
(Chiralpak AD, 4.times.250 mm, 95:5 hexanes:isopropanol, 0.8
mL/min) t.sub.R 16.9 min; [.alpha.].sub.D=-78 (c=0.18). Data for
Compound 116: HPLC (Chiralpak AD, 4.times.250 mm, 95.5
hexanes:isopropanol, 0.8 mL/min) t.sub.R 20.0 mm;
[.alpha.].sub.D=+70 (c=0.12).
EXAMPLE 16
(.+-.)-1,2,3,6-Tetrahydro-1,3-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino-
[3,2-g]quinolin-7-one (Compound 117, Structure 6 of Scheme I, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6=Me,
R.sup.x.dbd.H).
[0197] (.+-.)-3,4-Dihydro-2,4-dimethyl-7-nitro-2H-1,4-benzoxazine
(Structure 4 of Scheme I, where R.sup.6=Mem R.sup.x.dbd.H). This
compound was prepared from General Method 3 (EXAMPLE 1) from
(.+-.)-3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine (150 mg,
0.77 mmol), paraformaldehyde (233 mg, 7.8 mmol) and NaBH.sub.3CN
(235 mg, 3.7 mmol) to afford 160 mg (99%) of
(.+-.)-3,4-dihydro-2,4-dimethyl-7-nitro-2H-1,4-benzoxazine. Data
for (.+-.)-3,4-dihydro-2,4-dimethyl-7-nitro-2H-1,4-benzoxazine:
R.sub.f0.77 (3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.81 (dd, 1H, J=9.1, 2.5), 7.66 (d, 1H, J=2.5), 6.55 (d,
1H, J=8.9), 4.26-4.23 (m, 1H), 3.32 (dd, 1H, J=12.1, 2.7), 3.22
(dd, 1H, J=12.0, 8.2), 3.03 (s, 3H), 1.39 (d, 3H, J=6.5).
[0198] (.+-.)-7-Amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine
(Structure 5 of Scheme I, where R.sup.6=Me, R.sup.x.dbd.H). This
compound was prepared from General Method 4 EXAMPLE 1) from
(.+-.)-3,4-dihydro-2,4dimethyl-7-nitro-2H-1,4-benzoxazine (160 mg,
0.77 mmol) and purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH, 20:1) to afford 134 mg (97%) of
(.+-.)-7-amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine. Data
for (.+-.)-7-amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine:
R.sub.f0.35 (11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.54 (d, 1H, J=8.0), 625-6.20 (m, 2H),
4.36-4.33 (m, 1H), 3.31 (br s, 2H), 3.08 (dd, 1H, J=11.4, 2.3),
2.82 (dd, 1H, 11.4, 8.2), 2.78 (s, 3H), 1.33 (d, 3H, J=6.2).
[0199]
(.+-.)-1,2,3,6-Tetrahydro-1,3-dimethyl-9-(trifluoromethyl)-7H-[1.4-
]oxazino[3,2-g]quinolin-7-one (Compound 117, Structure 6 of Scheme
I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6=Me,
R.sup.x.dbd.H). This compound was prepared by General Method 5
(EXAMPLE 1) from
(.+-.)-7-amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine (75 mg,
0.42 mmol), and ethyl 4,4,4-trifluoroacetoacetate (6.07.mL, 0.48
mmol) and purified by flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH) to afford 50 mg (40%) of Compound 117. Data
for Compound 117: R.sub.f 0.42 (11.5:1 CH.sub.2Cl.sub.2:MeOH);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.17 (br s, 1H), 6.88
(s, 1H), 6.87 (s, 1H), 6.78 (s, 1H), 4.45 (m, 1H), 3.24 (dd, 1H,
J=11.7, 2.5), 3.02 (dd, 1H, J=11.5, 8.2), 2.93 (s, 3H), 1.40 (d,
3H, J=6.5).
EXAMPLE 17
(.+-.)-3-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromet-
hyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 118, Structure
6 of Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl.
R.sup.6=Et, R.sup.x.dbd.CF.sub.3)
[0200] (.+-.)-2-Ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one
(Structure 2 of Scheme I, where R.sup.6=Et). This compound was
prepared by General Method 1 (EXAMPLE 1) from 2-amino-5-nitrophenol
(3.0 g, 19.5 mmol), NaHCO.sub.3 (3.9 g, 46.5 mmol), and
2-chlorobutyryl chloride (3.1 g, 22.4 mmol) to afford 1.2 g (28%)
of (.+-.)-2-ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one. Data for
(.+-.)-2-ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one: R.sub.f0.48
(19:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.29 (br s, 1H), 7.91 (dd, 1H, J=8.7, 2.6), 7.79 (d, 1H,
J=2.4), 7.06 (d, 1H, J=8.7), 4.71-4.68 (m, 1H), 1.88-1.76 (m, 2H),
1.00 (t, 3H, J=7.2).
[0201] (.+-.)-2-Ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine
(Structure 3 of Scheme I, where R.sup.6=Et). This compound was
prepared by General Method 2 (EXAMPLE 1) from
(.+-.)-2-ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (1.2 g, 5.4
mmol) and borane dimethylsulfide (10.0-10.2 M in THF, 2.2 mL, 22
mmol) and purified on silica gel (1.8:1 hexanes:EtOAc) to afford
723 mg (65%) of
(.+-.)-2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, an orange
solid. Data for
(.+-.)-2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: R.sub.f0.85
(11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.73 (dd, 1H, J=8.5, 2.4), 7.71 (d, 1H, J=2.3), 6.50 (d,
1H, J=8.6), 4.53 (br s, 1H), 3.99-3.94 (m, 1H), 3.48 (dd, 1H ,
J=8.9, 3.0), 3.23 (dd, 1H,J=10.9, 8.0), 1.75-1.61 (m, 2H), 1.07 (t,
3H, J=7.5).
[0202]
(.+-.)-2-Ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-
-benzoxazine (Structure 4 of Scheme I, where R.sup.6=Et,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
7 (EXAMPLE 5) from
(.+-.)-2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (250 mg, 1.2
mmol), 2,2,2-trifluoroacetaldehyde monohydrate (1.4 g, 12 mmol) and
NaBH.sub.3CN (366 mg, 5.8 mmol) to afford 346 mg (99%) of
(.+-.)-2-ethyl-3,4-dihydro-7-nitro-4(2,2,2-trifluoroethyl)-2H-1,4-benzoxa-
zine. Data for
(.+-.)-2-ethyl-3,4-dihydro-7-nitro-4(2,2,2-trifluoroethyl)-2H-1,4-benzoxa-
zine: R.sub.f 0.75(3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.80 (dd, 1H, J=8.9, 2.6), 7.73 (d, 1H, J=2.5),
6.70 (d, 1H, J=9.0), 4.03-3.81 (m, 3H), 3.48 (dd, 1H, J=12.1, 2.6),
3.39 (dd, 1H, J=12.1, 8.0), 1.80-1.62 (m, 2H), 1.08 (t, 3H,
J=7.4).
[0203]
(.+-.)-7-Amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-
-benzoxazine (Structure 5 of Scheme I, where R.sup.6=Et,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
4 (EXAMPLE 1) from
(.+-.)-2-ethyl-3,4-dihydro-7-nitro-4(2,2,2-trifluoroethyl)-2H-1,4-benzoxa-
zine (170 mg, 0.6 mmol) and purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH, 20:1) to afford 151 mg (99%) of
(.+-.)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzox-
azine. Data for
(.+-.)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzox-
azine: R.sub.f 0.62(3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.56 (d, 1H, J=8.0), 6.25-6.20 (m, 2H), 3.93
(m, 1H), 3.70-3.64 (m, 3H), 3.43 (br s, 1H), 3.31 (m, 1H), 3.12
(dd, 1H, J=11.9, 8.1), 1.74-1.59 (m, 2H), 1.04 (t, 3H, J=7.5).
[0204]
(.+-.)-3-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trif-
luoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Comnound 118,
Structure 6 of Scheme I, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl, R.sup.6=Et, R.sup.x.dbd.CF.sub.3). This
compound was prepared by General Method 5 (EXAMPLE 1) from
(.+-.)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzox-
azine (100 mg, 0.38 mmol), and ethyl 4,4,4-trifluoroacetoacetate
(0.81 mg, 0.44 mmol) and purified by flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH).to afford 75 mg (51%) of Compound 114. Data
for Compound 114: R.sub.f0.18 (19:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 12.05 (br s, 1H), 7.03 (s, 1H),
6.95 (s, 1H), 6.92 (s, 1H), 4.15-4.05 (m, 1H), 3.98-3.88 (m, 1H),
3.88-3.75 (m, 1H), 3.44 (dd, 1H, J=11.8, 2.5), 3.32 (dd, 1H,
J=11.9, 8.1), 1.76 (m, 1H), 1.68 (m, 1H), 1.09 (t, 3H, J=7.6).
EXAMPLE 18
(.+-.)-3-Ethyl-1,2,3,6-tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1.4]oxa-
zino[3,2-g]quinolin-7-one (Compound 119, Structure 6 of Scheme I,
where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.6=Et,
R.sup.x.dbd.H)
[0205]
(.+-.)-2-Ethyl-3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine
(Structure 4 of Scheme I, where R.sup.6=Et, R.sup.x.dbd.H). This
compound was prepared by General Method 3 (EXAMPLE 1) from
2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 17) (120
mg, 0.57 mmol), paraformaldehyde (174 mg, 5.8 mmol) and
NaBH.sub.3CN (176 mg, 2.8 mmol) to afford 127 mg (99%) of
2-ethyl-3,4-dihydro-4-methyl-7-nitro-2-1,4-benzoxazine. Data for
2-ethyl-3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine: R.sub.f
0.89(11.5:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.81. (dd, 1H, J=9.0, 2.5), 7.67 (d, 1H,
J=2.5), 6.54 (d, 1H, J 9.0), 4.01 (m, 1H), 3.34 (dd, 1H, J=12.0,
2.7), 3.23 (dd, 1H, =12.0, 8.1), 3.03 (s, 3H), 1.79-1.72 (m, 1H),
1.67-1.60 (m, 1H), 1.07 (t, 3H, J=7.5).
[0206]
(.+-.)-7-Amino-2-ethyl-3,4-dihydro-4-methyl-2H-1,4-benzoxazine
(Structure 4 of Scheme I, where R.sup.6=Et, R.sup.x.dbd.H). This
compound was prepared by General Method 4 (EXAMPLE 1) from
(.+-.)-2-ethyl-3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine (130
mg, 0.6 mmol) and purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH, 19:1) to afford 80 mg (71%) of
(.+-.)-7-amino-2-ethyl-3,4dihydro-4-methyl-2H-1,4-benzoxazine. Data
for (.+-.)-7-amino-2-ethyl-3,4-dihydro-4-methyl-2H-1,4-benzoxazine:
R.sub.f 0.5 (19:1 CH.sub.2Cl.sub.2/MeOH); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.53 (dd, 1H, J=9.1, 2.7), 625-6.20 (m, 2H),
4.11 (m, 1H), 3.10 (dd, 1H, J=11.4, 2.1), 2.84 (dd 1H, J=11.3,
8.1), 2.78 (s, 3H), 1.75-1.70 (band, 1H), 1.64-1.58 (m, 1H), 1.03
(t, 2H, J=7.5).
[0207]
(.+-.)-3-Ethyl-1,2,3,6-tetrahydro-1-methyl-9-(trifluoromethyl)-7H--
[1,4]oxazino[3,2-g]quinolin-7-one (Compound 119, Structure 6 of
Scheme I, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl. R.sup.6=Et,
R.sup.x.dbd.H). This compound was prepared by General Method 5
(EXAMPLE 1) from
(.+-.)-7-amino-2-ethyl-3,4-dihydro-4-methyl-2H-1,4-benzoxazine (80
mg, 0.4 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.92 mg, 0.5
mmol) and purified by flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH) to afford 26 mg (20%) of Compound 119. Data
for Compound 119: R.sub.f0.19 (19:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 11.5 (br s, 1H), 6.89 (s, 2H),
6.83 (s, 1H), 4.22 (m, 1H), 3.26 (dd, 1H, J=11.6, 2.4), 3.05 (dd,
1H, J=11.6, 8.2), 2.94 (s, 3H), 1.76 (m, 1H), 1.67 (m, 1H), 1.08
(t, 3H, J=7.5).
EXAMPLE 19
1,2,3,6-Tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-on-
e (Compound 120, Structure 10 of Scheme II, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl)
[0208] 3,4-Dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine
(Structure 4 of Scheme 1, where R.sup.6.dbd.H, R.sup.x=4-anisyl).
This compound-was prepared by General Method 3 (EXAMPLE 1) from
3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (305 mg, 1.7
mmol), p-anisaldehyde (2.3 g, 17 mmol) and NaBH.sub.3CN (532 mg,
8.4 mmol) to afford 361 mg (70%) of
3,4-dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine, an
yellow solid. Data for
3,4-dihydro-4-(p-methoxyblenzy)-7-nitro-2H-1,4-benzoxazine: R.sub.f
0.79 (3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.76 (dd, 1H, J=9.0, 2.6), 7.70 (d, 1H, J=2.5), 7.14 (d, 2H,
J=8.6), 6.88 (d, 2H, J=8.6), 6.63 (d, 1H, J=9.1), 4.54 (s, 2H),
4.26 (t, 2H, J=4.5), 3.80 (s, 3H), 3.51 (t, 2H, J=4.6).
[0209] General Method 10: Reduction of a nitrobenzene derivative to
an aniline with zinc/calcium chloride dihydrate. To a solution of
the nitrobenzene derivative (1.0 equiv) in ethanol:water (95:5) was
added zinc dust (4.30 equiv) and calcium chloride dihydrate (2.15
equiv) at room temperature, whereupon the mixture was then heated
to reflux. Color change of the solution from yellow to colorless
indicated that the reaction was complete, with a reaction time of
approximately 4-5 hours. The reaction mixture was filtered hot
through a pad of celite and washed with hot EtOAc (100 mL). The
solvent was removed under reduced pressure and partitioned with
water (150 mL) and EtOAc (150 mL). The aqueous layer was then
adjusted to a pH of 34 with 20% HCl, extracted with EtOAc
(3.times.100 mL), washed with brine (100 mL), dried (MgSO.sub.4)
and concentrated under reduced pressure. Purification by flash
chromatography (silica gel, 20:1, CH.sub.2Cl.sub.2:MeOH) gave the
desired product.
[0210] 7-Amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine
(Structure 5 of Scheme I, where R.sup.6.dbd.H, R.sup.x=4-anisyl).
This compound was prepared by General Method 10 from
3,4-dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine (1.0 g,
3.3 mmol) and purified by flash chromatography.
(CH.sub.2Cl.sub.2/MeOH, 20:1) to afford 900 mg (99%) of
7-amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine. Data
for 7-amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine:
R.sub.f0.60 (24:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.22 (d, 2H, J=8.6), 6.86 (d, 2H, J=8.6), 6.60
(d, 1H, J=8.4), 6.34 (d, 1H, J=2.5), 6.30 (dd, 1H, J=8.5, 2.4),
4.25 (s, 2H), 4.21 (t, 2H, J=4.5), 3.80 (s, 3H), 3.17 (t, 2H,
J=4.3).
[0211]
(.+-.)-1,2,3,6-Tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2--
g]quinolin-7-one (Compound 120, Structure 10 of Scheme II, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl). This compound was prepared
by General Method 5 (EXAMPLE 1) from
7-amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine (1.78 g,
6.58 mmol) and ethyl 4,4,4,-trifluoroacetoacetate (1.15 mL, 7.9
mmol), and purified by flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH) to afford 533 mg (30%) of Compound 120. Data
Compound 120: R.sub.f 0.17 (3:2 EtOAc:hexanes); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 10.73 (br s, H), 6.94 (s, 1H), 6.87 (s,
1H), 6.75 (s, 1H), 4.35 (t, 2H, J=4.4), 3.99 (br s, 1H), 3.50-3.42
(m, 1H).
EXAMPLE 20
1-Cyclopropylmethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino-
[3,2-g]quinolin-7-one (Compound 121, Structure 11 of Scheme II,
where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.x=cyclopropyl)
[0212] This compound was prepared by-!General Method 3 (EXAMPLE 1)
from Compound 120 (EXAMPLE 19) (55 mg, 0.21 mmol),
cyclopropanecarboxaldehyde (100 mg, 1.5 mmol) and NaBH.sub.3CN (65
mg, 1.01 mmol to afford 64 mg (98%) of Compound 121. Data for
Compound 121: R.sub.f0.29(19:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 11.04 (brs, 1H), 7.00 (s, 1H), 6.88
(s, 1H), 6.78 (s, 1H), 4.36 (t, 2H, J=4.4), 3.46 (t, 2H), J=4.4),
3.19 (d, 2H, J=6.3), 1.05 (m, 1H), 0.62-0.58 (m, 2H), 0.27 (m,
2H).
EXAMPLE 21
1,2,3,6-Tetrahydro-1-(2-pvyidylmethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino-
[3,2-g]quinolin-7-one (Compound 122, Structure 11 of Scheme II,
where R.sup.1.dbd.H. R.sup.2=trifluoromethyl R.sup.x=2-pyridyl).
This compound was prepared by General Method 3 (EXAMPLE 1) Compound
120 (EXAMPLE 19) (19 mg, 0.07 mmol), 2-pyridinecarboxaldehyde (75.6
mg, 0.7 mmol) and NaBH.sub.3CN (22 mg, 0.3 mmol) to afford 9 mg
(36%) of Compound 122. Data for Compound 122: R.sub.f0.17 (19:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
11.48 (br s, 1H), 8.61 (d, 1H, J=5.5), 7.64 (t, 1H, J=6.9), 7.29(d,
1H, J=7.8), 7.19(dd, 1H, J=7.2, 5.5), 6.84 (s, 1H), 6.82 (s, 2H),
4.60 (s, 2H), 4.42 (t, 2H, J=4.4), 3.60 (t, 2H, J=4.5).
EXAMPLE 22
(.+-.)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluorome-
thyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 123, Structure
18 of Scheme III, where R.sup.2.dbd.CF.sub.3,
R.sup.x=trifluoromethyl, R.sup.1, R.sup.6, R.sup.7.dbd.H)
[0213] (2-Methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine. This
compound was prepared according to General Method 7 (EXAMPLE 5)
from 2-amino-5-nitroanisole (5.38 g, 32.0 mmol),
trifluoroacetaldehyde hydrate (26.5 mL, 37.1 g, 0.320 mol),
NaBH.sub.3CN (10.0 g, 0.160 mol) in 107 mL trifluoroacetic acid to
afford 7.6 g (95%) or
(2-methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine, a light
brown crystalline solid, after recrystallization 1:1 EtOAc:hexanes,
30 mL). Data for
(2-methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine: R.sub.f0.552
(2:1 hexanes:EtOAc); .sup.1H NMR acetone-d.sub.6) .delta. 7.87 (dd,
1H, J=8.9, 2.4), 7.69 (d, 1H, J=2.4), 6.96 (d, 1H, J=8.9), 6.38
(broad s, 3H), 4.20 (qd, 2H, J=9.3, 7.1), 4.00 (s, 3H).
[0214] (4-Amino-2-methoxyphenyl)-2,2,2-(trifluoroethyl)amine
(Structure 13 of Scheme III, where R.sup.x.dbd.CF.sub.3). This
compound was prepared according to General Method 10 (EXAMPLE 19)
from (2-methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine (8.40 g,
33.6 mmol), zinc dust (9.66 g, 0.148 mmol), and calcium chloride
dehydrate (10.9 g, 73.9 mmol) in 300 mL 95% EtOH/water to afford to
6.7 g (90%) of
4-amino-2-methoxyphenyl)-2,2,2-(trifluoroethyl)amine, a deep purple
oil. Data. for
(4-amino-2-methoxyphenyl)-2,2,2-(trifuoroethyl)amine: R.sub.f0.25
(1:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.54
(d, 1H, J=8.1), 6.20-6.30 (m, 2H), 4.15 (broad s, 1H), 3.81 (s,
3H), 3.68 (qd, 2H, J=9.0, 7.4), 3.38 (broad s, 2H).
[0215]
7-Methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-qui-
nolin-2-one (Structure 14 of Scheme III, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl . R.sup.x=trifluoromethyl).
[0216] General Method 11: Condensation of an aniline with an
acetoacetate derivative in benzene or toluene followed by a Knorr
reaction in sulfuric acid. A solution of an aniline (1.0 equiv) in
benzene or toluene (10 mL/mmol) and an acetoacetate derivative (1.2
equiv) was heated at reflux for 12-16 hrs. The resulting mixture
was cooled to room temperature and concentrated under reduced
pressure. The crude reaction mixture was diluted in concentrated
sulfuric acid (8 mL/mmol) and heated to 100.degree. C. for 6-16
hrs. The resulting mixture was poured over ice and neutralized with
6M NaOH solution to pH 7.0, extracted with CH.sub.2Cl.sub.2
(3.times.30 mL/mmol), washed with pH 7 phosphate buffer (50
mL/mmol) and brine (50 mL/mmol). The organic solution was dried
(MgSO.sub.4) and concentrated under reduced pressure. Purification
was performed either by flash chromatography (silica gel, 20:1,
CH.sub.2Cl.sub.2/MeOH) or by another specified method to afford the
desired quinolone as a fluorescent-yellow solid.
[0217]
7-Methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-qui-
nolin-2-one (Structure 14 of Scheme III, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl, R.sup.x=trifluoromethyl).
[0218] This compound was prepared according to General Method 11
from (5.72 g, 26.0 mmol) and ethyl 4,4,4-trifluoroacetoacetate
(4.56 mL, 5.74 g, 31.2 mmol) in 87 mL toluene, followed by
treatment with 65 mL concentrated H.sub.2SO.sub.4 to afford 2.72 g
(30.7%) of
7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-
-one, a fluffy yellow solid, after rinsing the crude material with
a 1:1 mixture of EtOAc:hexanes (60 mL). Data for
7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-
-one: R.sub.f0.19 (4:1 EtOAc:CH.sub.2Cl.sub.2); .sup.1H NMR (400
MHz, acetone-d.sub.6) .delta. 10.87 (broad s, 1H), 7.04 (s, 1H),
6.99 (broad s, 1H), 6.73 (s, 1H), 5.54 (broad m, 1H), 4.07 (app
quint, 2H, J=8.4), 3.98 (s, 3H).
[0219] General Method 12: Transformation of a pyridone to an
isopropyl imino ether with isopropyl iodide and cesium fluoride. To
a suspension of pyridone (1 equiv) and CsF (4 equiv) in DMF (0.25
M) was added 2-iodopropane (4 equiv). The suspension was stirred
for 18 h, whereupon it was poured into cold water (25 mL/mmol) and
extracted with EtOAc (2.times.25 mL/mmol). The organic layers were
washed sequentially with water (2.times.15 mL/mmol) and brine (15
mL/mmol), dried over MgSO.sub.4, filtered, and concentrated to
afford a yellow brown solid, which was used without further
purification.
2-Isopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline: This compound was prepared by General Method 12 from
7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-
-one (2.42 g, 7.11 mmol), CsF (4.32 g, 28.5 mmol), and
2-iodopropane (2.84 mL, 4.84 g, 28.5 mmol) in 28 mL DMF to afford
2.47 g (90.6%) of
2-isopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline, a yellow brown solid, which was used without further
purification. Data for
2-isopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline: R.sub.f0.24 (9:1 hexanes:EtOAc); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.18 (s, 1H), 7.02 (s, 1H), 7.01 (broad s,
1H), 5.48 (heptet, 1H, J=6.3), 4.87 (broad t, 1H, J=6.7), 4.02 (s,
3H), 3.88 (app quint, 2H, J=8.8), 1.39 (d, 6H, J=6.3).
[0220]
7-Hydroxy-2-isopropyloxy-6-[2,2,2-(trifluoroethyl)amino]-4-(triflu-
oromethyl)quinoline (Structure 15 of Scheme III, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.x=trifluoromethyl):
To a suspension of sodium hydride (60% mineral oil dispersion, 1.72
g, 6.13 mmol) in 20.6 mL DMF was added thiophenol (4.53 mL, 4.86 g,
44.1 mmol) at 0.degree. C. After the bubbling subsided, a solution
of
isopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl-
)quinoline (2.34 g, 6.13 mmol) in 10 mL DMF was added and the
mixture was heated to 110.degree. C. After 5 h, the mixture was
poured into cold water and neutralized with 21 mL 2 M NaHSO.sub.4,
and the aqueous layer was extracted with ethyl acetate (2.times.200
mL). The organic layers were washed sequentially with water
(2.times.100 mL) and brine (100 mL), dried over MgSO.sub.4,
filtered and concentrated. Flash chromatography (hexanes:EtOAc,
2:1) afforded 1.71 g (75.8%) of
2-isopropyloxy-7-hydroxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline, a yellow solid. Data for
7-hydroxy-2-isopropyloxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline: R.sub.f0.21 (4:1 hexanes:EtOAc); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.18 (s, 1H), 7.05 (broad s, 1H), 7.01 (s,
1H), 6.0 (v broad s, 1H), 5.42 (hept, 1H, J=6.1), 4.69 (broad t,
1H, J=6.9), 3.88 (m, 2H), 1.37 (d, 6H, J=6.1).
[0221] General Method 13: Cyclization of an .alpha.-bromoester onto
an o-aminophenol to form a compound of Structure 16. To a
suspension of an aminophenol of Structure 15 (1 equiv) and
K.sub.2CO.sub.3 (2.05 equiv) in DMF (0.25 M) was added the
.alpha.-bromoester (1.05 equiv). The mixture was heated to
80.degree. C. for 1 h, then heated to 110.degree. C. for 4 h, then
the reaction was partitioned between EtOAc (50 mL/mmol), water (25
mL/mmol) and sat'd NH.sub.4C (25 mL/mmol). The aqueous layer was
extracted with EtOAc (25 mL/mmol), and the combined organic layers
were washed sequentially with water (2.times.25 mL/mmol), brine (25
mL/mmol), dried over MgSO.sub.4, filtered and concentrated. This
material was used without purification, or was purified as
indicated.
[0222]
7-Isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]-
oxazino[3,2-g]quinolin-2(3H)-one (Structure 16 of Scheme III, where
R.sup.2.dbd.CF.sub.3, R.sup.x=trifluoromethyl, R.sup.1, R.sup.6,
R.sup.7.dbd.H): This compound was prepared by General Method 13
from
2-isopropyloxy-7-hydroxy-6-[(2,2,2-trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline (1.51 g, 4.10 mmol), K.sub.2CO.sub.3 (1.16 g, 8.40
mmol) and ethyl bromoacetate (0.719 g, 4.30 mmol) in 16.4 mL DMF to
afford-1.57 g (94%) of
7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,-
4]oxazino[3,2-g]quinolin-2(3H)-one, a light yellow-brown solid,
R.sub.f0.50 (4:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.57 (broad s, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 5.53 (hept,
1H, J=6.2), 4.79 (s, 2H), 4.71 (q, 2H, J=8.4), 1.41 (d, 6H).
[0223] General Method 14: Methenylation of a tertiary amide of
Structure 16 and subsequent reduction with NaBH.sub.3CN. To a
solution of a substituted
7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino-
[3,2-g]quinolin-2(3H)-one derivative (1 equiv) in THF (0.15 M) was
added Tebbe reagent (0.5 M in toluene, 1.1 equiv) at 0.degree. C.
After 1 h, ether (50 mL/mmol) and methanol (0.7 mL/mmol) were added
sequentially, and the brown solution was allowed to warm to rt.
After 30 min, the mixture was filtered through Celite, rinsed with
ether, and concentrated to a deep orange-brown solid. The solid was
passed quickly through a plug of silica gel or basic alumina to
afford an orange solid which was carried on directly. To a
suspension of the above solid and NaBH.sub.3CN (5 equiv) in
dichloroethane (0.2 M) was added acetic acid (2.5 mmol) dropwise at
0.degree. C. The mixture bubbled vigorously, and was allowed to
warm to rt. After 1 d the orange solution was poured into
NaHCO.sub.3 (40 mL/mmol) and extracted with EtOAc (2.times.40
mL/mmol). The organic layers were washed with brine (30 mL/mmol),
dried over MgSO.sub.4, filtered, and concentrated. The material was
purified as indicated.
[0224]
(.+-.)-2,3-Dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)--
9-(trifluoromethyl)-1H-[1,4]oxazino[3.2-g]quinoline (Structure 17
of Scheme III, where R.sup.2.dbd.CF.sub.3, R.sup.x=trifluoromethyl.
R.sup.1, R.sup.6, R.sup.7.dbd.H). This compound was made from
General Method 14 from
7-isopropoxy-1-2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxa-
zino[3,2-g]quinolin-2(3H)-one (0.689 g, 1.69 mmol), Tebbe's reagent
(3.7 mL, 1.9 mmol) in 11 mL THF to afford 0.728 g of
(.+-.)-2,3-dihydro-7-isopropoxy-2-methylene-1-(2,2,2-trifluoroethyl)-9-(t-
rifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, an orange solid
after filtration through silica gel. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.4 (broad s, 1H), 7.49 (s, 1 H), 7.29 (s, 1H),
5.59 (hept, 1H, J=6.2), 4.95 (s, 2H), 4.91 (q, 2H, J=9.1), 1.58 (d,
6H, J=6.2). Subsequent treatment of the above solid (0.728 g) as
described in General Method 14 with NaBH.sub.3CN (0.531 g, 8.45
mmol) and 4.2 mL acetic acid in 8.4 mL dichloroethane afforded
0.366 g (53%) of
(.+-.)-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trif-
luoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow solid, after
flash chromatography (hexanes:EtOAc, 9:1). R.sub.f0.28 (9:1
hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.29 (s,
1H), 7.12 (s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.26 (dd,
ABX, 1H, J=10.7, 2.4), 4.16 (dd, ABX, 1H, J=10.7, 2.8), 3.97-4.07
(m, 1H), 3.77-3.87 (m, 1H), 3.61-3.68 (m, 1H), 1.38 (d, 6H, J=6.2).
General Method 15: Hydrolysis of an isopropyl imino ether to a
pyridone. A solution of the imino ether in a 3:1 acetic
acid:concentrated HCl (0.1-0.2 M) solution was heated at
60-110.degree. C. for 4-16 h. The solution was poured into sat'd
NaHCO.sub.3 (80 mL/mmol), extracted with EtOAc (2.times.80
mL/mmol), washed with brine (60 mL/mmol), dried over MgSO.sub.4,
filtered, concentrated, and purified as indicated.
[0225]
(.+-.)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-trif-
luoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 123,
Structure 18 of Scheme III, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.x=trifluoromethyl). This compound was
prepared according to General Method 15 from
(.+-.)-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trif-
luoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (0.362 g, 0.887 mmol)
in 1.6 mL conc. HCl and 4.8 mL acetic acid heated to 10.degree. C.
for 5 h. The product was isolated by purification by flash
chromatography (92:8 CH.sub.2Cl.sub.2:MeOH), followed by
recrystallization from methanol to afford 0.164 g (50%) of Compound
123, a yellow solid. Data for Compound 123: HPLC (ODS, 7:3
MeOH:water, 3.0 mL/min) t.sub.R 13.56 min; .sup.1H NMR (400 MHz
CDCl.sub.3) 11.07 (broad s, 1H), 7.08 (broad s, 1H), 6.96 (s, 1H),
6.75 (s, 1H), 4.25-4.30 (m, 2H), 4.05-4.25 (m, 2H), 3.72-3.82 (m,
1H), 1.28 (d, 3H, J=6.6); .sup.13C (100 MHz, DMSO-d.sub.6) 160.0,
147.7, 135.6 (q, J=30.4), 134.3 (m), 129.9, 125.8 (q, J=282), 122.7
(q, J=275), 118.4 (broad s), 108.1, 106.0, 102.8, 68.8, 51.7, 50.9
(q, J=32.2), 15.0.
EXAMPLE 23
(+)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethy-
l)-7H-[1,4oxazino[3,2-g]quinolin-7-one (Compound 124, Structure
(+)-18 of Scheme III, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.x=trifluoromethyl), and
(-)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluorometh-
yl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 125, Structure
(-)-18 of Scheme III, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.x=trifluoromethyl)
[0226] This compound was prepared according to General Method 9.
(EXAMPLE 15) from Compound 123 (EXAMPLE 22) (10 mg, 0.03 mmol) on a
semiprep Chiralpak AD column (20.times.250 mm) eluted
hexanes/isopropanol (93:7), to afford 3.3 mg of Compound 124, a
yellow solid, and 3.0 mg of Compound 125, a yellow solid. Data for
Compound 124: HPLC (Chiralpak AD, 93:7 hexanes:isopropanol, 5.0
mL/min) t.sub.R 35.4 min; [.alpha.].sub.D=+39.3.
[0227] Data for Compound 125: HPLC (Chiralpak AD, 93:7
hexanes:isopropanol, 5.0 mL/min) t.sub.R 40.9 min;
[.alpha.].sub.D=-41.3.
EXAMPLE 24
(.+-.)-trans-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(t-
rifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 126,
Structure 18 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6.dbd.H, R.sup.7=Me,
R.sup.x=trifluoromethyl)
[0228]
7-Isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-
-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one (Structure 16 of Scheme
III, where R.sup.1.dbd.H, R.sup.2.dbd.CF.sub.3, R.sup.6.dbd.H,
R.sup.7=Me, R.sup.x=trifluoromethyl). This compound was prepared
according to General Method 13 (EXAMPLE 22) from
2-isopropyloxy-7-hydroxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline (EXAMPLE 22) (55 mg, 0.15 mmol), ethyl
2-bromopropionate (29 mg, 0.16 mmol) and K.sub.2CO.sub.3 (46 mg,
0.33 mmol) in 1.5 mL DMF to afford 61 mg (96%) of
7-isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,-
4]oxazino[3,2-g]quinolin-2(3H)-one. Data for
7-isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,-
4]oxazino[3,2-g]quinolin-2(3H)-one: R.sub.f0.31 (9:1
hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.55
(broad s, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 5.53 (hept, 1H, J=6.2),
4.81 (q, 2H, J=6.8), 4.60-4.76 (m, 2H), 1.64 (d, 3H, J=6.8), 1.41
(d, 6H, J=6.2).
[0229]
(.+-.)-trans-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-triflu-
oroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(Structure 17 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6.dbd.H, R.sup.7=Me,
R.sup.x=trifluoromethyl) and
(.+-.)-cis-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-
-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (Structure 17
of Scheme III, where R.sup.1.dbd.H, R.sup.2.dbd.CF.sub.3,
R.sup.6=Me, R.sup.7.dbd.H, R.sup.x=trifluoromethyl). This compound
was prepared according to General Method 14 (EXAMPLE 22) from
7-isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,-
4]oxazino[3,2-g]quinolin-2(3H)-one (19 mg, 0.046 mmol), Tebbe
reagent (0.10 mL, 0.050 mmol) in 0.5 mL THF followed by reduction
with NaBH.sub.3CN (17 mg, 0.27 mmol) in 0.23 mL HOAc and 0.46 mL
dichloroethane to afford 15 mg (78%) of a 3:1 mixture of
diastereomers after flash chromatography (4:1 hexanes:EtOAc). The
diastereomers were separated on a Beckman HPLC (ODS Ultrasphere
semi-prep column, 5 .mu.m, 10.times.250 mm, 3.0 mL/min, 80%
MeOH/water) to afford 3.5 mg (18%) of
(.+-.)-trans-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethy-
l)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow
solid, and 6.5 mg (34%) of
(.+-.)-cis-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-
-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline. Data for
(.+-.)-trans-(.+-.)-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-triflu-
oroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: HPLC
(ODS, 10.times.250 mm, 80% MeOH/water, 3 mL/min) t.sub.R 50 min;
R.sub.f0.54 (4:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.26 (s, 1H), 7.09 (broad s, 1H), 6.98 (s, 1H), 5.48 (hept,
1H, J=6.2), 4.40 (qd, 1H, J=6.5, 2.2), 3.96-4.09 (m, 1H), 3.72-3.85
(m, 1H), 3.42 (qd, J=6.5, 2.0, 1H), 1.35-1.42 (m, 9H), 1.14 9d, 3H,
J=6.5).
[0230] Data for
(.+-.)-cis-2,3-dihydro-7-isopropoxy-2,3dimethyl-1-(2,2,2-trifluoroethyl)--
9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: HPLC (ODS,
10.times.250 mm, 80% MeOH/water, 3 mL/min) t.sub.R 57 min;
R.sub.f0.51 (4:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.27 (s, 1H), 7.09 (broad s, 1H), 6.99 (s, 1H), 5.48 hept,
1H, J=6.2), 4.33 (qd, 1H, J=6.5, 1.8), 4.03-4.16 (m, 1H), 3.72-3.84
(m, 1H), 3.36 (qd, J=6.7, 1.5), 1.38 (d, 6H, J=6.2), 1.36 (d, 3H,
J=6.5), 1.27 (d, 3H,J=6.6).
[0231]
(.+-.)-trans-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroeth-
yl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one
(Compound 126 Structure 18 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6.dbd.H, R.sup.7=Me,
R.sup.x=trifluoromethyl). This compound was prepared according to
General Method 15 (EXAMPLE 22) from
(.+-.)-trans-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethy-
l)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (3.5 mg,
0.0083 mmol) in 0.2 mL cone. HCl and 0.5 mL acetic acid heated to
110.degree. C. for 3 h, affording 2.5 mg (78%) of Compound 126
after flash chromatography (92:8 CH.sub.2Cl.sub.2:MeOH). Data for
Compound 126: R.sub.f0.20 (92:8 CH.sub.2Cl.sub.2:MeOH): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 11.50 (broad s, 1H), 7.01 (broad s,
1H), 6.90 (s, 1H), 6.87 (s, 1H), 4.32 (qd, 1H, J=6.3, 1.9),
3.93-4.08 (m, 1H), 3.67-3.82 (m, 1H), 3.32 (qd, 1H, J=6.5, 1.3),
1.34 (d, 3H, J=6.4), 1.23 (d, 3H, J=6.5).
EXAMPLE 25
(.+-.)-cis-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(tri-
fluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 127,
Structure 18 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6=Me, R.sup.7.dbd.H,
R.sup.x=trifluoromethyl)
[0232] This compound was prepared according to General Method 15
(EXAMPLE 22) from
(.+-.)-cis-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-triflu-
oroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(EXAMPLE 24) (6.0 mg, 0.014 mmol) in 0.2 mL conc. HCl and 0.5 mL
acetic acid heated to 110.degree. C. for 3 h, affording 4.5 mg
(85%) of Compound 127 after flash chromatography (92:8
CH.sub.2Cl.sub.2:MeOH). Data for Compound 127: R.sub.f0.20 (92:8
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) 67 12.06
(broad s, 1H), 7.02 (broad s, 1H), 6.92 (s, 1H), 6.90 (s, 1H), 4.37
(qd, 1H, J=6.4, 1.8), 3.83-3.98 (m, 1H), 3.68-3.82 (m, 1H), 3.38
(qd, 1H, J=6.7, 1.6), 1.37 (d, 3H, J=6.4), 1.11 (d, 3H, J=6.6).
EXAMPLE 26
(.+-.)-trans-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)--
9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound
128, Structure 18 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6.dbd.H, R.sup.7=Et,
R.sup.x=trifluoromethyl)
[0233]
(.+-.)-3-Ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluorom-
ethyl)-1H-[1,4]oxazino[3-2-g]quinolin-2(3H)-one (Structure 16 of
Scheme III, where R.sup.1.dbd.H, R.sup.2.dbd.CF.sub.3,
R.sup.6.dbd.H, R.sup.7=Et. R.sup.x=trifluoromethyl). This compound
was prepared according to General Method 13 (EXAMPLE 22) from
2-isopropyloxy-7-hydroxy-6-(2,2,2-(trifluoroethyl)amino]-4-(trifluorometh-
yl)quinoline (EXAMPLE 22) (70 mg, 0.19 mmol), ethyl
2-bromobutanoate (41 mg, 0.21 mmol) and K.sub.2CO.sub.3 (58 mg,
0.42 mmol) in 1.9 mL. DMF to afford 63 mg (76%) of
(.+-.)-3-ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)--
1H-[1,4]oxazino [3,2-g]quinolin-2(3H)-one. Data for
(.+-.)-3-ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)--
1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one: R.sub.f0.47 (5.7:1
hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (broad s,
1H), 7.49 (s, 1H), 7.11 (s, 1 H), 5.53 (hept, 1H, J=6.2), 4.72-4.83
(m, 1 H), 4.66 (dd, 1 H, J=8.5, 4.8), 4.55-4.65 (m, I H), 1.85-2.10
(m, 2 H), 1.41 (d, 6H, J=6.2), 1.11 (t, 3H, J=7.4).
[0234]
(.+-.)-trans-3-Ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-tr-
ifluoroethyl-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(Structure 17 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6.dbd.H, R.sup.7=Et,
R.sup.x=trifluoromethyl) and
(.+-.)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroet-
hyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3.2-g]quinoline (Structure
17 of Scheme III, where R.sup.1.dbd.H, R.sup.2.dbd.CF.sub.3,
R.sup.6=Et, R.sup.7.dbd.H, R.sup.x=trifluoromethyl). This compound
was prepared according to General Method 14 (EXAMPLE 22) from
3-ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4-
]oxazino[3,2-g]quinolin-2(3H)-one (39 mg, 0.089 mmol), Tebbe
reagent (0.20 mL, 0.098 mmol) in 0.9 mL THF followed by reduction
with NaBH.sub.3CN (34 mg, 0.53 mmol) in 0.45 mL HOAc and 0.90 mL
dichloroethane to afford 9 mg (23%) of
(.+-.)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-tr-
ifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,
a yellow solid, and 7 mg of a 1:1 mixture of diastereomers after
flash chromatography (9:1 hexanes:EtOAc). The diastereomers were
separated on a Beckman HPLC (ODS Ultrasphere semi-prep column, 5
.mu.m, 10.times.250 mm, 3.0 mL/min, 90% MeOH/water) to afford 3 mg
(8%) of
(.+-.)-trans-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoro-
ethyl) 9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a
yellow solid. Data for
(.+-.)-trans-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoro-
ethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: HPLC
(ODS, 10.times.250 mm, 90% MeOH/water, 3 mL/min) t.sub.R 16.2 min;
R.sub.f0.25 (9:1 hexanes:EtOAc); .sup.1H NMR (400 MHz,
benzene-d.sub.6) .delta. 7.70 (s, 1H), 7.28 (broad s, 1H), 7.02 (s,
1H), 5.55 (hept, 1H, J=6.2), 3.41-3.52 (m, 2H), 2.90-3.01 (m, 1H),
2.63 (broad q, 1H, J=6.3), 1.48-1.57 (m, 1H), 1.30 (d, 3H, J=6.5),
1.28 (d, 3H, J=6.5), 1.11-1.20 (m, 1H), 0.78 (t, 3H, J=7.5), 0.76
(d,.3H, J=6.5). Data for
(.+-.)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroet-
hyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: HPLC
(ODS, 10.times.250 mm, 90% MeOH/water, 3 mL/min) t.sub.R 19.4 min;
R.sub.f0.28 (9:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.29 (s, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 5.47 (hept, 1H,
J=6.2), 4.09 (ddd, 1H, J=7.9, 5.5, 2.0), 3.96-4.06 (m, 1H),
3.74-3.84 (m, 1H), 3.47 (qd, 1H, J=6.5, 2.0), 1.65-1.88 (m, 1H),
1.50-1.62 (m, 1H), 1.37 (d, 6H, J=6.2), 1.12 (d, 3H, J=6.6), 1.10
(t, 3H, J=7.4).
[0235]
(.+-.)-trans-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluor-
oethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one
(Compound 128, Structure 18 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6.dbd.H, R.sup.7=Et,
R.sup.x=trifluoromethyl). This compound was prepared according to
General Method 15 from
(.+-.)-trans-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoro-
ethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (3 mg,
0.007 mmol) in 0.1 mL conc. HCl and 1.5 mL acetic acid heated at
100.degree. C. for 18 h to afford 1.7 mg (63%) of Compound 128, a
yellow solid. Data for Compound 128: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 11.83 (broad s, 1H), 6.99 (broad s, 1H), 6.91
(s, 2H), 3.92-4.05 (m, 2H), 3.68-3.79 (m, 1H), 3.41 (qd, 1H, J=6.7,
1.4), 1.66-1.75 (m, 1H), 1.53-1.62 (m, 1H), 1.24 (d, 3H, J=6.6),
1.01 (t, 3H, J=7.5).
EXAMPLE 27
(.+-.)-cis-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9--
(trifluoromethyl)-7H-[1,4]oxazin[3,2-g]quinolin-7-one (Compound
129, Structure 18 of Scheme III, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.6=Et, R.sup.7.dbd.H,
R.sup.x=trifluoromethyl)
[0236] This compound was prepared according to General Method 15
(EXAMPLE 22) from
(.+-.)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-tr-
ifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(EXAMPLE 26) (8 mg, 0.018 mmol) in 0.1 mL conc. HCl and 1.5 mL
acetic acid heated at 100.degree. C. for 18 h to afford 5 mg (71%)
of Compound 129, a yellow solid. Data for Compound 129: R.sub.f0.19
(19:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 12.48 (broad s, 1H), 7.02 (broad s, 1H), 6.97 (s, 1H),
6.93.(s, 1H), 4.04-4.10 (m, 1H), 3.86-3.97 (m, 1H), 3.69-3.80(m,
1H), 3.42 (dq, 1H, J=6.5, 1.9), 1.73-1.83 (m, 1H), 1.50-1.60(m,
1H), 1.07-1.11 (m, 6H).
EXAMPLE 28
(.+-.)-1,2,3,6-Tetrahydro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-9-(tr-
ifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 130,
Structure 20 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl)
[0237]
(.+-.)-2,3-Dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluo-
roethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(Structure 19 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl): To a solution of
7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino-
[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (0.183 g, 0.448 mmol) in 4.8
mL THF was added Tebbe reagent (0.99 mL, 0.49 mmol) at 0.degree. C.
After 1 h, ether (22 mL) and MeOH (0.32 mL) were added sequentially
and the mixture was allowed to warm to rt. The slurry was filtered
through Celite and concentrated, and the resultant residues was
filtered through a short plug of basic alumina (4:1 hexanes:EtOAc)
to afford 0.20 g of
(.+-.)-2,3-dihydro-7-isopropoxy-2-methylene-1-(2,2,2-trifluoroethyl)-9-(t-
rifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline. This residue was
dissolved in 2.2 mL THF, and BH.sub.3 THF solution (1M, 0.49 mL,
0.49 mmol) was added dropwise at 0.degree. C. After 15 min, the
mixture was allowed to warm to rt, whereupon 0.1 mL MeOH was added
and the solution allowed to stir for 16 h. The solvent was removed
in vacuo, and the residue was redissolved in 2.2 mL THF and 0.45 mL
MeOH, whereupon 0.10 mL 6N NaOH and a 35% H.sub.2O.sub.2 solution
(0.055.mL, 60.9 mg, 0.63 mmol) was added. A precipitate was formed
which was filtered with 20 mL THF. The filtrate was concentrated,
and the resultant solid was dissolved in 1 mL MeOH, acidified with
0.05 mL conc. HCl, and the solution concentrated in vacuo. The
residue was treated with 0.1 mL 6N NaOH, and partitioned between
water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted
with EtOAc (2.times.20 mL), and the combined organic layers were
washed with brine (20 mL), dried over MgSO.sub.4, filtered, and
concentrated. Flash chromatography (2:1 hexanes:EtOAc) afforded 91
mg (48%) of
(.+-.)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl-
)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a light
amber oil. Data for
(.+-.)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifl-
uoroethyl)-9-trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:
R.sub.f0.34 (2:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.30 (s, 1H), 7.17 (broad s, 1H), 7.01 (s, 1H), 5.48 (hept,
1H, J=6.2), 4.50 (dd, 1H, J=11.1, 1.6), 4.12-4.25 (m, 1H),
3.96-4.09 (m, 1H), 3.78-3.90 (m, 2H), 3.61-3.67 (m, 1H), 1.71 (t,
1H, J=5.1), 1.38 (d, 6H, J=6.2).
[0238]
(.+-.)-1,2,3,6-Tetrahydro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethy-
l)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one
(Compound 130, Structure 20 of Scheme IV, where R.sup.1, R.sup.6,
R.sup.7.dbd.H, R.sup.2=trifluoromethyl). A solution of
(.+-.)2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-
-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (20 mg, 0.047
mmol) in 1.0 mL conc. HCl was heated at 90.degree. C. for 4 h,
whereupon the solution was poured into cold sat'd NaHCO.sub.3 (20
mL) and extracted with EtOAc (2.times.20 mL). The combined organic
layers were washed with brine (20 mL), dried over MgSO.sub.4,
filtered, and concentrated. Flash chromatography (2:1
hexanes:EtOAc) afforded 12 mg (67%) of Compound 130, a yellow
solid. Data for Compound 130: R.sub.f0.21 (3:2 EtOAc:
CH.sub.2Cl.sub.2); .sup.1H NMR(400 MHz acetone-d.sub.6) .delta.
10.95 broad s, 1H), 7.10 (broad s, 1H), 6.95 (s, 1H), 6.74 (s, 1H),
4.58 (dd, 1H, J=10.9, 1.5), 4.20-4.42 (m. 3H), 4.17 (dd, 1H,
J=10.9, 2.2), 3.72-3.81 (m, 1H), 3.59-3.73 (m, 2H).
EXAMPLE 29
(.+-.)-1,2,3,6-Tetrahydro-2-(acetoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(tr-
ifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 131,
Structure 21 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl). This compound was prepared by General
Method 15 (EXAMPLE 22) from
(.+-.)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl-
)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28)
(4.6 mg, 0.011 mmol) in 0.1 mL conc. HCl and 0.5 mL HOAc heated at
100.degree. C. for 3 h to afford 1.6 mg (35%) of Compound 131, a
yellow solid. Data for Compound 131: R.sub.f0.21 (3:2
EtOAc:CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.25 (broad s, 1H), 7.10 (broad s, 1H), 6.93 (s, 1H), 6.89 (s,
1H), 4.44 (dd, 1H, J=11.0, 1.3), 4.26 (dd, 1H, ABX, J=11.3,
6.0),4.15 (dd, 1H, J=11.0, 2.5), 4.10 (dd, ABX, J=11.4, 7.9),
4.02-4.14 (m, 1H), 3.84-3.96 (m, 1H), 3.68-3.74 (m, 1H), 2.09 (s,
3H).
EXAMPLE 30
(.+-.)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(tr-
ifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 132,
Structure 23 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl, R.sup.5=Me)
[0239] General Method 16: Alkylation of an alcohol of Structure 19
to compound of Structure 22 with an alkyl halide. To a solution of
a compound of Structure 19 (1 equiv) and sodium hydride (60%
mineral oil dispersion, 4 equiv) in THF (0.03-0.04 M) was added the
specified alkyl halide (4 equiv). After TLC analysis show the
consumption of starting material (6-18 h), the reaction mixture was
quenched with 1 M phosphate buffer (50 mL/mmol), extracted with
EtOAc (2.times.500 mL/mmol). The organic layers were washed with
brine, dried over MgSO.sub.4, filtered, and concentrated, and
purified as indicated.
[0240]
(.+-.)-2,3-Dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluo-
roethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(Structure 22 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl, R.sup.5=Me). This compound was prepared by
General Method 16 from
(.+-.)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl-
)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28)
(10 mg, 0.024 mmol), NaH (4.7 mg, 0.12 mmol) and iodomethane (17
mg, 0.12 mmol) in 0.6 mL THF to afford 8.3 mg (81%) of
(.+-.)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl-
)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow
solid, after flash chromatography (5:1 hexanes:EtOAc). Data for
(.+-.)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl-
)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: R.sub.f0.21
(3:1 hexanes: EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.29 (s, 1H), 7.14 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H,
J=6.2), 4.43 (dd, 1H, J=11.0, 1.6), 4.16 (dd, J=11.0, 2.6),
3.98-4.21 (m, 2 H), 3.67-3.73 (m, 1 H), 3.50-3.60 (m, 2 H), 3.37
(s, 3 H), 1.38 (d, 6H, J=6.2).
[0241]
(.+-.)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethy-
l)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one
(Compound 132, Structure 23 of Scheme IV, where R.sup.1, R.sup.6,
R.sup.7.dbd.H, R.sup.2=trifluoromethyl, R.sup.5=Me). This compound
was prepared according to General Method 15 (EXAMPLE 22) from
(.+-.)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl-
)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (8.3 mg,
0.019 mmol) in 0.1 mL conc. HCl and 0.5 mL acetic acid heated at
100.degree. C. for 4.5 h to afford 6.0 mg (80%) of Compound 132, a
yellow solid. Data for Compound 132: R.sub.f0.48 (2:1
EtOAc:CH.sub.2C12); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.09
(broad s, 1H), 7.06 (broad s, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 4.43
(dd, 1H, J=10.9, 1.2), 4.14 (dd, J=10.9, 2.3), 3.93-4.12 (m, 2H),
3.63-3.70 (m, 1 H), 3.44-3.56 (m, 2,2H), 3.36 (s, 3H).
EXAMPLE 31
(+)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-triflu-
oromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 133,
Structure (+)-23 of Scheme IV, where R.sup.1, R.sup.6,
R.sup.7.dbd.H, R.sup.2=trifluoromethyl. R.sup.5 =Me) and
(-)-1,2,3,6-tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trif-
luoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 134,
Structure (-)-23 of Scheme IV, where R.sup.1, R.sup.6,
R.sup.7.dbd.H, R.sup.2=trifluoromethyl, R.sup.5=Me)
[0242] This compound was-prepared according to General Method 9
(EXAMPLE 1-5) from Compound 132 (5 mg, 0.013 mmol) on a semiprep
Chiralpak AD column (20.times.250 mm), hexanes/isopropanol (95:5),
to afford 1.8 mg of Compound 133, a yellow solid, and 1.8 mg of
Compound 134, a yellow solid. Data for Compound 133: HPLC
(Chiralpak AD, 95:5 hexanes:isopropanol, 5.0 mL/min) t.sub.R 35.7
min; [.alpha.].sub.D=+40.0.
[0243] Data for Compound 134: HPLC (Chiralpak AD, 93:7
hexanes:isopropanol, 5.0 mL/min) t.sub.R 40.9 min;
[.alpha.].sub.D=-43.8.
EXAMPLE 32
(.+-.)-2-(Ethoxymethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(tri-
fluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 135,
Structure 23 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl, R.sup.5=Et)
[0244]
(.+-.)-2-(Ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluor-
oethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(Structure 22 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl. R.sup.5=Et). This compound was prepared
according to General Method 16 (EXAMPLE 30) from
(.+-.)-2,3-dihydro-2-hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-
-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28)
(10 mg, 0.024 mmol), NaH (4.7 mg, 0.12 mmol) and iodoethane (17 mg,
0.12 mmol) in 1.0 mL THF to afford 9.8 mg (89%) of
(.+-.)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-
-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow oil,
after flash chromatography (5:1 hexanes:EtOAc). Data for
(.+-.)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-
-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: R.sub.f0.60
(5:1 hexanes: EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.29 (s, 1H), 7.14 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H,
J=6.2), (dd, 1H, J=10.9, 1.5), 4.16 (dd, J=10.9, 2.5), 4.00-4.20
(m, 2H), 3.70 (broad t, 1H, J=6.8), 3.54-3.63 (m, 2H), 3.50 (q, 2H,
J=6.9), 1.38 (d, 6H, J=6.2), 1.20 (t, 3H, J=7.0
[0245]
(.+-.)-2-(Ethoxymethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl-
-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound
135, Structure 23 of Scheme IV, where R.sup.1, R.sup.6,
R.sup.7.dbd.H, R.sup.2=trifluoromethyl. R.sup.5=Et).
[0246] This compound was prepared according to General Method 15
(EXAMPLE 22) from
2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethy-
l)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (9.8 mg,
0.022 mmol) in 0.1 mL conc. HCl and 0.5 mL acetic acid heated at
100.degree. C. for 4 h to afford 6.0 mg (67%) of Compound 135, a
yellow solid. Data for Compound 135: R.sub.f0.25 (11.5:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
12.3 (broad s, 1H), 7.06 (broad s, 1H), 6.95 (s, 1H), 6.92 (s, 1H),
4.44 (broad d, 1H, J=11.0), 4.14 (dd, 1H, J=10.9, 2.2), 3.95-4.10
(m, 2H), 3.67 (broad t, 1H, J=6.9), 3.45-3.60 (m, 4H), 1.19 (t, 3H,
J=7.0).
EXAMPLE 33
(.+-.)-1,2,3,6-Tetrahydro-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(-
trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound
136, Structure 23 of Scheme IV, where R.sup.1, R.sup.6,
R.sup.7.dbd.H, R.sup.2=trifluoromethyl, R.sup.5=n-Pr)
[0247]
(.+-.)-2,3-Dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifl-
uoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(Structure 22 of Scheme IV, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl. R.sup.5=n-Pr).
[0248] This compound was prepared according to General Method 16
(EXAMPLE 30) from
(.+-.)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifl-
uoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline
(EXAMPLE 28) (11 mg, 0.026 mmol), NaH (5.0 mg, 0.12 mmol) and
1-iodopropane (21 mg, 0.12 mmol) in 1.0 mL THF to afford 6 mg (50%)
of
(.+-.)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroeth-
yl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow
oil, after flash chromatography (5:1 hexanes:EtOAc). Data for
(.+-.)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroeth-
yl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:
R.sub.f0.57 (5:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.28 (s, 1H), 7.13 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept,
1H, J=6.2), 4.44 (dd, 1H, J=10.9, 1.8), 4.17 (dd, 1H, J=11.0, 2.5),
4.00-4.20 (m, 2H), 3.71 (broad t, 1H, J=6.8), 3.54-3.64 (m, 2H),
3.40 (broad t, 2H, J=6.6), 1.52-1.62 (m, 2H), 1.38 (d, 6H, J=6.2),
0.91 (t, 3H, J=7.4).
[0249]
(.+-.)-1,2,3,6-Tetrahydro-2-(1-propoxymethyl)-1-(2,2,2-trifluoroet-
hyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one
(Compound 136, Structure 23 of Scheme IV, where R.sup.1, R.sup.6,
R.sup.7.dbd.H, R.sup.2=trifluoromethyl. R.sup.5=n-Pr). This
compound was prepared according to General Method 15 (EXAMPLE 22)
from
(.+-.)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroeth-
yl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (6.0 mg,
0.013 mmol) in 0.1 mL conc. HCl and 0.5 mL acetic acid heated at
100.degree. C. for 4 h to afford 3.1 mg (56%) of Compound 136, a
yellow solid. Data for Compound 136: R.sub.f0.25 (11.5:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.75 (broad s, 1H), 7.06 (broad s, 1H), 6.92 (s, 1H), 6.90 (s,
1H), 4.44 (dd, 1H, J=10.9, 1.7), 4.14 (dd, 1H, J=10.9, 2.5),
3.94-4.08 (m, 2H), 3.65-3.70 (m, 1H), 3.47-3.59 (m, 2H), 3.39 (t,
2H, J=6.6), 1.50-1.62 (m, 2 H), 0.91 (t, 3H, J=7.4).
EXAMPLE 34
1,6-Dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]oxazino[3-
,2-g]-quinolin-2,7-dione (Compound 137, Structure 24 of Scheme V,
where R.sup.1, R.sup.6, R.sup.7.dbd.H, R.sup.2=trifluoromethyl)
[0250] This Compound was prepared according to General Method 15
(EXAMPLE 22) from
7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,-
4]oxazino[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (72 mg, 0.18 mmol),
in 0.5 mL conc. HCl and 2.0 mL acetic acid heated at 60.degree. C.
for 16 h to afford 42 mg (65%) of Compound 137, an off-white solid,
after flash chromatography (92:8 CH.sub.2Cl.sub.2:MeOH). Data for
Compound 137: R.sub.f0.34 (92:8 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR
(400 MHz, acetone-d.sub.6) .delta. 11.11 (broad s, 1H), 7.52 (s,
1H), 7.18 (s, 1H); 6.86 (s, 1H), 4.95 (q, 2H, J=9.0), 4.90 (s,
2H).
EXAMPLE 35
(.+-.)-1,2,3,6-Tetrahydro-2-hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(t-
rifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 138,
Structure 25 of Scheme V, where, R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.4=Me, R.sup.2=trifluoromethyl). To a solution of Compound 137
(EXAMPLE 34) (0.012 g, 0.033 mmol) in 1 mL THF and 0.1 mL HMPA and
was added MeLi solution (1.4 M in ether, 0.12 mL, 0.16 mmol) at
-78.degree. C. for 0.5 h. The reaction was quenched with 20 mL
phosphate buffer (pH=7) and extracted with EtOAc (2.times.20 mL).
The organic fractions were dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Flash chromatography (5%
methanol/CH.sub.2Cl.sub.2) gave 8 mg (62% yield) of Compound 138, a
yellow solid. .sup.1H NMR (400MHz, acetone-d.sub.6) 10.92 (br s,
1H), 7.13 (br s, 1H), 6.96 (s, 1H), 6.75 (s, 1H), 4.34-4.24 (m,
1H), 4.23 (d, 1H, J=11.6), 4.19 (f, 1H, J=10.8), 4.07-3.96 (m, 1H),
1.49 (s, 3H).
EXAMPLE 36
1,6-Dihydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]-
oxazino[3,2-g]quinolin-2,7-dione (Compound 139, Structure 24 of
Scheme V, where R.sup.1, R.sup.6.dbd.H, R.sup.2=trifluoromethyl,
R.sup.7=Me ): A mixture of
7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino-
[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (7.0 mg, 0.017 mmol) in 0.5
mL 57% HI was heated to 65.degree. C. for 16 h, whereupon it was
poured onto cold NaHCO.sub.3 (25 mL). The mixture was extracted
with EtOAc (25 mL), and the organic layer was washed sequentially
with 1 M phosphate buffer (10 mL) and brine (10 mL), dried over
MgSO.sub.4, filtered, and concentrated. Flash chromatography (92:8
CH.sub.2Cl.sub.2:MeOH) afforded 1.4 mg (22%) of Compound 139, an
off-white solid. Data for Compound 139: R.sub.f0.37 (92:8
CH.sub.2Cl.sub.2:MeOH; .sup.1H NMR (400 MHz, acetone-d.sub.6)
.delta. 11.09 (broad s, 1H), 7.52 (s, 1H), 7.19 (s, 1H), 6.86 (s,
1H), 4.80-5.05 (m, 3H), 1.59 (d, 3H, J=6.7).
EXAMPLE 37
1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-2-thioxo-7-
H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 140, Structure 27 of
Scheme V, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl)
[0251]
7-Isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]-
oxazino[3,2-g]quinolin-2(3H)-thione (Structure 26 of Scheme V,
where R.sup.1, R.sup.6, R.sup.7.dbd.H, R.sup.2=trifluoromethyl). A
mixture of
7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino-
[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (48.4 mg, 0.119 mmol) and
Lawesson's reagent (0.144 g, 0.356 mmol) in 2.4 mL toluene was
heated at reflux for 6 h, whereupon the mixture was partitioned
between EtOAc (40 mL) and water (20 mL). The aqueous layer was
extracted with EtOAc (20 mL), and the combined organic layers were
washed with brine (20 mL), dried over MgSO.sub.4, filtered, and
concentrated. Flash chromatography (9:1 hexanes:EtOAc) afforded 41
mg of
7-isopropoxy-1-2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[-
3,2-g]quinolin-2(3H)-thione, a yellow oil. Data for
7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino-
[3,2-g]quinolin-2(3H)-thione: R.sub.f0.36 (9:1 hexanes:EtOAc);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.72 (broad s, 1H), 7.48
(s, 1H), 7.13 (s, 1H), 5.54 (hept, H, J=6.2), 5.32-5.42 (m, 2H),
5.05 (s, 2H), 1.41 (d, 6H, J=6.2).
[0252]
1,2,3,6-Tetrahydro-1-(2,2,2-trfluoroethyl)-9-(trifluoromethyl)2-th-
ioxo-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 140, Structure
27 of Scheme V, where R.sup.1, R.sup.6, R.sup.7.dbd.H,
R.sup.2=trifluoromethyl. To a solution of
7-isopropoxy-1-2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[-
3,2-g]quinolin-2(3H)-thione (30 mg, 0.071 mmol) in 1.4 mL
CH.sub.2Cl.sub.2 was added BCl.sub.3 (1 M in CH.sub.2Cl.sub.2, 1.2
mL, 1.2 mmol). After 8 h, the mixture was quenched with saturated
NaHCO.sub.3 (15 mL) and extracted with EtOAc (2.times.15 mL). The
organic layers were washed with brine (15 mL), dried over
MgSO.sub.4, filtered, and concentrated. Flash chromatography (3:2
CH.sub.2Cl.sub.2:EtOAc) afforded 17 mg (63%) of Compound 140, an
off-white solid. Data for Compound 140: R.sub.f0.36 (3:2
CH.sub.2Cl.sub.2:EtOAc); .sup.1H NMR (400 MHz, acetone-d.sub.6)
.delta. 11.22 (broad s, 1H), 7.72 (broad s, 1H), 7.19 (s, 1H), 6.90
(s, 1H), 5.62-5.75 (m, 2H), 5.16 (s, 2H).
EXAMPLE 38
(.+-.)-1,2,3,6-Tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-
-g]quinolin-7-one (Compound 141, Structure 30 of Scheme VI, where
R.sup.4=Me)
[0253] (2-Methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine. This
compound was prepared according to General Method 3 (EXAMPLE 1)
from 2-amino-5-nitroanisole (1.00 g, 5.95 mmol), p-anisaldehyde
(1.62 g, 11.9 mmol), NaBH.sub.3CN (0.373 g, 5.95 mmol) in 100 mL
acetic acid to afford 1.25 g (75%) of
(2-methoxy-4-nitrophenyl)-4-methoxybenzyl)amine, an orange solid,
after washing the crude product with 4:1 hexanes:EtOAc. Data for
(2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine: R.sub.f0.80 (3:2
EtOAc:hexanes); .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.88 (dd,
1H, J=8.8, 2.4), 7.64 (d, 1H, J=2.4), 7.22-7.28 (m, 2H), 6.85-6.90
(m, 2H), 6.51 (d, 1H, J=9.0), 5.31 (broad s, 1H), 4.38 (d, 2H,
J=5.4), 3.93 (s, 3H), 3.82 (s, 3H).
[0254] (4-Amino-2-methoxyphenyl)-(4-methoxybenzyl)amine (Structure
13 of Scheme III, where R.sup.x=4-anisyl). This compound was
prepared by General Method 10 (EXAMPLE 19) from
(2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine (1.92 g, 6.65
mmol), zinc dust (1.87 g, 28.6 mmol), and calcium chloride
dihydrate (2.10.g, 14.3 mmol) in 350 mL 95:5 EtOH:water to afford
1.23 g (70%) of (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine, a
light purple solid, after flash chromatography
(CH.sub.2Cl.sub.2:MeOH 19:1). Data for
(4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine: R.sub.f0.80 (19:1
CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (400 MH, CDCl.sub.3) .delta.
7.30 (d, 2H, J=8.6), 6.87 (d, 2H, J=8.6), 6.47 (d, 1H, J=8.1), 6.28
(d, 1H, J=2.4), 6.23 (dd, 1H, J=8.1, 2.4), 4.20 (s, 2H), 4.10 (v
broad s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.31 (broad s, 2H).
[0255] 6-Amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one.
This compound was prepared according to General Method 11 (EXAMPLE
22) from (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine (1.23 g,
4.76 mmol) and ethyl 4,4,4-trifluoroacetoacetate (1.05 g, 5.71
mmol) in 60 mL benzene followed by treatment with 10 mL
concentrated H.sub.2SO.sub.4 to afford 0.734 (60%) of
6-amino-7-methoxy-4-(trfluoromethyl)-1H-quinolin-2-one, a yellow
solid, after rinsing with MeOH:ether:hexanes. Data for
6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one:
R.sub.f0.28 (19:1 CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 12.2 (v broad s, 1H), 7.06 (broad s, 1H), 6.93
(s, 1H), 6.79 (s, 1H), 4.01 (s, 3H), 3.94 (broad s, 2H).
[0256] 6-Amino-2-isopropoxy-7-methoxy-4-(trifluoromethyl)quinoline.
This compound was prepared according to General Method 12 (EXAMPLE
22) from 6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one
(500 mg, 1.9 mmol), CsF (1.18 g, 7.7 mmol), isopropyl iodide (1.31
g, 7.7 mmol) in 8 mL DMF to afford 308 mg (53%) of
6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline, a
light yellow oil, and 190 mg (29%) of
2-isopropyloxy-7-methoxy-6N-(isopropyl)amino-4-(trifluoromethyl)quinoline-
, after flash chromatography (7:3 hexares:EtOAc). Data for
6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline:
R.sub.f0.5 1 (4:1 hexanes:EtOAc); .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.18 (s, 1H), 7.13 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept,
1H, J=6.3), 4.11 (broad s, 2H), 4.01 (s, 3H), 1.40 (d, 6H,
J=6.3).
[0257] 6-Amino-7-hydroxy-2-isopropyloxy-4-(trifluoromethyl)quinolin
(Structure 28 of Scheme VI). To a suspension of sodium hydride (60%
mineral oil dispersion, 180 mg, 4.6 mmol, rinsed with hexanes) in
3.5 mL DMF was added thiophenol (550 mg, 5.0 mmol) at 0.degree. C.,
whereupon a solution of
6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline (200
mg, 0.67 mmol) in 2 mL DMF was added. The mixture was heated at
110.degree. C. for 6 h, then poured into ice, and the pH was
adjusted to 5 by the addition of 2N NaHSO.sub.4. The mixture was
extracted with EtOAc (2.times.30 mL), washed sequentially with
water (30 mL) and brine (30 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Flash chromatography (4:1
hexanes:EtOAc) afforded 147 mg (77%) of
6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline, a
tan solid. Data for
6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline:
R.sub.f0.14 (4:1 hexanes:EtOAc); .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.19 (broad s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 5.60 (v.
broad s, 1H), 5.45 (hept, 1H, J=6.2), 4.00 (v. broad s, 2H), 1.38
(d, 6H, J=6.3).
[0258] General Method 17. Alkylation of an .alpha.-halo-ketone to
an o-aminophenol and subsequent reductive cyclization to a
1,4-oxazine derivative. To a solution of 2-amino-5-nitrophenol (1.0
equiv) in acetone (0.6 mL/mmol) was added an .alpha.-halo ketone
(1.1 equiv) and K.sub.2CO.sub.3 (1.1 equiv) at 0.degree. C. under
N.sub.2. The reaction mixture was allowed to warm to room
temperature and stirred for 6-8 hours. The crude reaction mixture
was then evaporated under reduced pressure and washed with water
(3.times.100 mL) and the resulting solid was dried under high
vacuum. To this crude solid (1.0 equiv) in trifluoroacetic acid
(0.26 M) was added portionwise NaBH.sub.3CN (1.0 equiv) and stirred
at room temperature under N.sub.2 overnight. The resulting mixture
was poured over ice and neutralized with 6M NaOH to pH 7.0,
extracted with EtOAc (3.times.30 mL/mmol), washed with brine (50
mL/mmol). The organic solution was dried (MgSO.sub.4) and
concentrated under reduced pressure. Purification by flash
chromatography (silica gel, 19:1, CH.sub.2Cl.sub.2/MeOH) afforded
the desired 1,4-oxazine derivative.
[0259]
(.+-.)-2,3-Dihydro-7-isopropoxy-2-methyl-9-(trifluoromethyl)-1H-[1-
,4]oxazino[3,2-g]quinoline (Structure 29 of Scheme VI, where
R.sup.4=Me). This compound was prepared by General Method 17 from
6-amino-3,4-dihydro-7-hydroxy-2-isopropoxy-4-(trifluoromethyl)quinoline
(15 mg, 0.05 mmol), chloroacetone (5.0 .mu.L, 0.06 mmol), and
K.sub.2CO.sub.3 (8.0 mg, 0.06 mmol) to afford 13 mg of crude solid.
The crude solid (13 mg, 0.04 mmol), NaBH.sub.3CN (2.5 mg, 0.04
mmol) and trifluoroacetic acid afforded 10.0 mg (77%) of
(.+-.)-2,3-dihydro-7-isopropoxy-2-methyl-9-trifluoromethyl)-1H-[1,4]oxazi-
no[3,2-g]quinoline. Data for
(.+-.)-2,3-dihydro-7-isopropoxy-2-methyl-9-(trifluoromethyl)-1H-[1,4]oxaz-
ino[3,2-g]quinoline: R.sub.f0.84 (2:3, EtOAc:hexanes); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.24 (s, 1 H), 7.02 (d, 1H, J=2.0),
6.97 (s, 1H), 5.48 (m, 1H), 4.30 (dd, 1H, J=10.6, 2.7), 4.12 (br s,
1H), 3.88 (dd, 1H, J=10.7, 8.3), 3.64 (m, 1H), 1.38 (d, 6H, J=6.3),
1.24 (d, 3H, J=6.8).
[0260]
(.+-.)-1,2,3,6-Tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxa-
zino[3,2-g]quinolin-7-one (Compound 141, Structure 30 of Scheme VI,
where R.sup.4=Me). This compound was prepared by General Method 15
(EXAMPLE 22) from
(.+-.)-2,3-dihydro-7-isopropoxy-2-methyl-9-(trifluoromethyl)-1H-[1,4-
]oxazino[3,2-g]quinoline (10.0 mg, 0.03 mmol) in 0.2 mL HCl and 1
mL HOAc heated at 80.degree. C. for 6 h to afford 7.0 mg (77%) of
Compound 141, a yellow solid, after purification by flash
chromatography (3:2, EtOAc/hexanes). Data for Compound 14.1:
R.sub.f0.31(3:2, EtOAc:hexanes), .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 12.14 (br s, 1H), 6.94 (s, 1H), 6.89 (s, 2H), 4.29 (dd, 1H,
J=8.3, 2.0), 3.94 (br s, 1H), 3.86 (dd, 1H, J=10.5, 8.5), 3.58 (m,
1H), 1.23 (d, 3H, J=6.3).
EXAMPLE 39
(.+-.)-1-Cyclopropylmethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-
-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 142, Structure 31
of Scheme VI, where R.sup.4=Me, R.sup.x=cyclopropyl)
[0261] This compound was prepared by General Method 3 (EXAMPLE 1)
from Compound 141 (7.0 mg, 0.02 mmol), cyclopropane carboxaldehyde
(17.3 mg, 0.2 mmol) and NaBH.sub.3CN (7.7 mg, 0.1 mmol) to afford
6.6 mg (82%) of Compound 142. Data for Compound 142: R.sub.f0.36
(3:2, EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.58 (brs, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 6.85(s, 1H), 4.26 (dd,
1H, J=10.7, 2.4), 4.14 (dd, 1H, J=10.5, 2.7), 3.72 (m, 1H), 3.32
(dd, 1H, J=14.6, 5.8), 3.02 (dd, 1H, J=14.6, 4.3), 1.22 (d, 3H,
J=6.3), 1.05 (m, 1H), 0.63 (m, 2H), 0.3 (m, 2H).
EXAMPLE 40
(.+-.)-2-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3
2-g]quinolin-7-one (Comnound 143, Structure 30 of Scheme VI, where
R.sup.4=Et)
[0262]
(.+-.)-2-Ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,-
4]oxazino[3,2-g]quinoline (Structure 29 of Scheme VI, where
R.sup.4=Et). This compound was prepared by General Method 17
(EXAMPLE 38) from
6-amino-7-hydroxy-2-isopropoxy-4-(trifluoromethyl)quinoline
(EXAMPLE 36) (15 mg, 0.05 mmol), 1-bromo-2-butanone (6.0 .mu.L,
0.06 mmol), and K.sub.2CO.sub.3 (8.0 mg, 0.06 mmol) to afford 16 mg
of crude solid. The crude solid (16 mg, 0.05 mmol), NaBH.sub.3CN
(3.0 mg, 0.05 mmol) and trifluoroacetic acid afforded 13 mg (81%)
of
(.+-.)-2-ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]oxazi-
no[3,2-g]quinoline. Data for
(.+-.)-2-ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]oxazi-
no[3,2-g]quinoline: R.sub.f0.78 (2:3, EtOAc:hexanes) .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.22 (s, 1H), 7.01 (s, 1H), 6.96 (s,
1H), 5.47 (m, 1H), 4.33 (dd, 1H, J=10.6, 2.5), 4.20 (br s, 1H),
3.95 (dd, 1H, J=10.6, 7.9), 3.40 (m, 1H), 1.58 (m, 2H), 1.37 (d,
6H, J=6.1), 1.06 (t, 3H, J=7.5).
[0263]
(.+-.)-2-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxaz-
ino[3,2-g]quinolin-7-one (Compound 143, Structure 30 of Scheme VI,
where R.sup.4=Et. This compound was prepared by General Method 15
(EXAMPLE 22) from
(.+-.)-2-ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]-
oxazino[3,2-g]quinoline (13.0 mg, 0.04 mmol) and was purified by
flash chromatography (3:2, EtOAc/hexanes) to yield 8.1 mg (72%) of
Compound 143. Data Compound 143: R.sub.f0.34 (3:2, EtOAc:hexanes);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.11 (br s, 1H), 6.95
(s, 1H), 6.89 (s, 1H), 6.88 (s, 1H), 4.34 (dd, 1H, J=10.2, 2.5),
4.02 (br s, 1H), 3.93 (dd, 1H, J=10.7, 7.8), 3.35 (m, 1H), 1.56 (m,
2H), 1.06 (t, 3H, J=7.5).
EXAMPLE41
(.+-.)-1-(Cyclopropylmethyl)-2-ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl-
-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 144. Structure 31
of Scheme VI, where R.sup.4=Et, R.sup.x=cyclopropyl)
[0264] This compound was prepared by General Method 3 (EXAMPLE 1)
from Compound 143 (8.1 mg, 0.03 mmol), cyclopropane carboxaldehyde
(19.1 mg, 0.2 mmol) and NaBH.sub.3CN (8.5 mg, 0.1 mmol) and
purified by HPLC (75:25 MeOH:water, semi-prep ODS column @3 mL/min)
to afford 4.0 mg (44%) of Compound 144. Data for Compound 144:
R.sub.f0.30 (3:2, EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 11.72 (brs, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 6.85 (s, 1H),
4.34 (dd, 1H, J=10.7, 1.9), 4.15 (dd, 1H, J=10.7, 2.4), 3.39 (m,
2H), 3.0 (m, 1H), 1.59 (m, 2H), 1.06 (m, 1H), 0.98 (t, 3H, J=7.8),
0.62 (m, 2H), 0.29 (m, 2H).
EXAMPLE 41A
1,2,3,6-Tetrahydro-1-isopropyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]q-
uinolin-7-one (Compound 144A, Structure 31D of Scheme VIA, where
R.sup.1.dbd.R.sup.4.dbd.R.sup.6.dbd.H, R.sup.2=trifluoromethyl,
R.sup.13=isopropyl)
[0265]
2-Isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quino-
line (Structure 31B of Scheme VIA, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl. R.sup.13=isopropyl, R.sup.A=isopropyloxy).
A suspension of
6-amino-7-methoxy-4-trifluoromethyl-1H-quinolin-2-one (0.50 g, 1.9
mmol), CsF (1.18 g, 7.7 mmol) and isopropyl iodide (1.31 g (7.7
mmol) in 8 mL DMF was stirred at 30.degree. C. for 18 h, whereupon
the mixture was quenched with pH 7 phosphate buffer and extracted
with EtOAc (2.times.). The combined organic layers were washed
sequentially with water (2.times.) and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. Flash chromatography
(7:3, hexanes:EtOAc) afforded 0.19 g (32%) of
2-isopropyloxy-6-isopropylamino-7-methoxy-4-rfluoromethyl)quinol-
ine, an oil. Data for Compound
2-isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quinoline:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.13 (s, 1H), 6.99 (s,
1H), 6.87 (s, 1H), 5.47 (sept, 1H, J=6.2), 4.37 (d, 1H, J=7.4),
3.99 (s, 3H), 3.70-3.80 (m, 1H), 1.39 (d, 6H, J=6.2), 1.30 (d, 6H,
J=6.2).
[0266]
2-Isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quino-
line (Structure 31C of Scheme VIA, where R.sup.1.dbd.H,
R.sup.1=trifluoromethyl, R.sup.13=isopropyl, R.sup.A=isopropyloxy).
A solution of
2-isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quinoline
(0.10 g, 0.30 mmol), thiophenol (0.24 g, 2.2 mmol), and NaH (60%
dispersion in mineral oil, 78 mg, 2.0 mmol) in 2 ML DMF was heated
at 110.degree. C. for 5 h, whereupon the mixture was poured over
ice, and adjusted to pH 5 with 2M NaHSO.sub.4. The aqueous layer
was extracted with EtOAc (2.times.), and the combined organic
layers were washed sequentially with water (2.times.) and brine,
dried over MgSO.sub.4, filtered and concentrated. Flash
chromatography (4:1 hexanes:EtOAc) afforded 90 mg (95%) of
2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline,
a yellow oil. Data for
2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.16 (s, 1H), 6.98 (s,
1H), 6.92 (s, 1H), 5.37 (sept, 1H, J=6.2), 3.70 (sept, 1H, J=6.3),
1.35 (d, 6H, J=6.2), 1.29 (d, 6H, J=6.3).
[0267]
1,2,3,6-Tetrahydro-1-isopropyl-9-(trifluoromethyl)-7H-[1,4]oxazino-
[3,2-g]quinolin-7-one (Compound 144A, Structure 31D of Scheme VIA,
where R.sup.1.dbd.R.sup.4.dbd.R.sup.6.dbd.H,
R.sup.2=trifluoromethyl, R.sup.13=isopropyl). A suspension of
2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline
(60 mg, 0.18 mmol), 1,2-dibromoethane (62 mg, 0.33 mmol) and
K.sub.2CO.sub.3 (47 mg, 0.34 mmol) in 3 mL acetone and 1.5 mL water
was heated at reflux for 18 h, whereupon the mixture was
partitioned between water and EtOAc. The aqueous layer was
extracted with EtOAc, and the combined organic layers were washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Flash chromatography (4:1 hexanes:EtOAc) afforded 27
mg of a yellow oil which was carried on directly by treatment with
0.05 mL concentrated HCl and 0.5 mL HOAc and heated at 70.degree.
C. for 4 h, whereupon the reaction was poured over ice and adjusted
to pH 7 with 25% aqueous NaOH. The aqueous layer was extracted with
EtOAc (3.times.), and the combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Flash chromatography (3:2 hexanes:EtOAc) afforded 10 mg (30%) of
Compound 144A, a yellow solid. Data for Compound 144A: .sup.1H NMR
(500 M CDCl.sub.3) .delta. 12.0 (broad s, 1H), 6.99 (s, 1H),6.87
(s, 1H), 6.80 (s, 1H), 4.34 (t, 2H, J=4.6, 2H), 4.08 (sept, 1H,
J=6.3), 3.26 (t, 2H, J=4.6), 1.22 (d, 6H, J=6.3).
EXAMPLE 42
(.+-.)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromet-
hyl)7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 145, Structure
35 of Scheme VII, where R.sup.1.dbd.H, R.sup.2.dbd.CF.sub.3,
R.sup.4=Et, R.sup.x=trifluoromethyl)
[0268] (.+-.)-3-Ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine
(Structure 32 of Scheme VII, where R.sup.4=Et. This compound was
prepared by General Method 17 (EXAMPLE 38) from
2-amino-5-nitrophenol (2.0 g, 13.0 mmol), 1-bromo-2-butanone (1.45
mL, 14.2 mmol), and K.sub.2CO.sub.3 (1.97 g, 14.2 mmol) to afford
3.0 g of crude solid. The crude solid (3.0 g, 13.3 mmol),
NaBH.sub.3CN (837 mg, 13.3 mmol) and trifluoroacetic acid afforded
1.96 g (70%) (.+-.)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine
after purification by flash chromatography (19:1,
CH.sub.2Cl.sub.2/MeOH). Data for
(.+-.)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: R.sub.f0.57
(2:3 EtOAc:hexanes); .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.74
(dd, 1H, J=8.7, 2.6), 7.69 (d, 1H, J=2.6), 6.51 (d, 1H, J=8.8),
4.59 (br s, 1H), 4.25 (dd, 1H, J=10.7, 3.2), 3.86 (dd, 1H, J=10.7,
7.1), 3.43 (m, 1H), 1.6 (m, 2H), 1.05 (t, 3H, J=7.4).
[0269]
(.+-.)-3-Ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-
-benzoxazine (Structure 33 of Scheme VII, where R.sup.4=Et,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
7 (EXAMPLE 5) from
(.+-.)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (200 mg, 0.96
mmol), 2,2,2-trifluoroacetaldehyde monohydrate (1.12 g, 9.6 mmol)
and NaBH.sub.3CN (292 mg, 4.6 mmol) to afford 100 mg (36%) of
3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,
a yellow solid. Data for
(.+-.)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzox-
azine: R.sub.f0.69 (2:3 EtOAc:hexanes); .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.80 (dd, 1H, J=8.9, 2.6), 7.71 (d, 1H, J=2.6),
6.72 (d, 1H, J=9.0), 4.34 (dd, 1H, J=10.9, 1.4), 4.19-4.05 (m, 1H),
4.02 (dd, 1H, J=11.0, 2.3), 3.87-3.72 (m, 1H), 1.72-1.62 (m, 2H),
1.00 (t, 3H, J=7.4).
[0270]
(.+-.)-7-Amino-3-ethyl-3,4-dihydro-4-[2,2,2(trifluoroethyl)]-2H-1,-
4-benzoxazine (Structure 34 of Scheme VII, where R.sup.4=Et,
R.sup.x.dbd.CF.sub.3). This compound was prepared by General Method
4 (EXAMPLE 1) from
(.+-.)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzox-
azine (100 mg, 0.34 mmol) and purified by flash chromatography
(EtOAc:hexanes, 3:2) to afford 83 mg (93%) of
(.+-.)-7-amino-3-ethyl-3,4-dihydro-4-2,2,2-trifluoroethyl)-2H-1,4-benzoxa-
zine. Data for
(.+-.)-7-amino-3-ethyl-3,4-dihydro-4-[2,2,2(trifluoroethyl)]-2H-1,4-benzo-
xazine: R.sub.f0.63 (3:2 EtOAc:hexanes); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.64 (d, 1H, J=8.3), 6.28 (dd, 1H, J=8.5, 2.7),
6.23 (d, 1H, J=2.4), 4.15 (d, 1H, J=10.7), 3.96 (dd, 1H, J=10.7,
2.4), 3.65 (m, 1H), 3.40 (br s, 1H), 3.03 (m, 1H), 1.53 (m, 2H),
0.96 (t, 3H, J=7.6).
[0271]
(.+-.)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trif-
luoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 145,
Structure 35 of Scheme VII, where R.sup.1.dbd.H,
R.sup.2.dbd.CF.sub.3, R.sup.4=Et. R.sup.x=trifluoromethyl). This
compound was prepared by General Method 5 (EXAMPLE 1) from
(.+-.)-7-amino-3-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzox-
azine (83 mg, 0.32 mmol) and ethyl 4,4,4-trifluoroacetoacetate (70
mg, 0.38 mmol) and purified by flash chromatography (3:2
EtOAc:hexanes) to yield 54 mg (44%) of Compound 145. Data for
Compound 145: R.sub.f 0.36 (3:2 EtOAc:hexanes); .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 11.67 (br s, 1h), 7.07 (s, 1H), 6.91 (s,
1H), 6.89 (s, 1H), 4.35 (dd, 1H, J=10.7. 2.0), 4.15 (dd, 1H,
J=10.7, 2.4), 4.04-3.97 (m, 1H), 3.75 (m, 1H), 3.28 (m, 1H), 1.64
(m, 2H), 1.00 (t, 3H, J=7.3).
EXAMPLE 43
(.+-.)-1,2-Diethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[-
3,2-g]quinolin-7-one (Compound 146, Structure 35 of Scheme VII,
where R.sup.1.dbd.H, R.sup.2.dbd.CF.sub.3, R.sup.4=Et,
R.sup.x.dbd.CH.sub.3)
[0272] (.+-.)-3,4-Diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine
(Structure 33 of Scheme VII, where R.sup.4=Et,
R.sup.x.dbd.CH.sub.3). This compound was prepared by General Method
3 (EXAMPLE 1) from 3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine
(EXAMPLE 42) (200 mg, 0.96 mmol), acetaldehyde (424 mg, 9.6 mmol)
and NABH.sub.3CN (293 mg, 4.6 mmol) to afford 170 mg (75%) of
(.+-.)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow
solid. Data for
(.+-.)-3,4-diethyl-3,4dihydro-7-nitro-2H-1,4-benzoxazine:
R.sub.f0.80 (3:2 EtOAc:hexanes); .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.80 (dd, 1H, J=8.9, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d,
1H, J=9.2), 4.01 (dd, ABX, 1H, J=10.7, 2.5), 3.96 (dd, ABX, 1H,
J=10.7, 2.6), 3.60 (m, 1H), 3.55-3.35 (m, 2H), 1.29 (d, 3H, J=6.6),
1.24 (t, 3H, J=7.0).
[0273] (.+-.)-7-Amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine
(Structure 34 of Scheme VII, where R.sup.4=Et.
R.sup.x.dbd.CH.sub.3). This compound was prepared by General Method
4 (EXAMPLE 1) from
(.+-.)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (170 mg,
0.72 mmol) and purified by flash chromatography (EtOAc:hexanes,
3:2) to afford 39 mg (25%) of
(.+-.)-7-amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine. Data for
(.+-.)-7-amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine: (3:2
EtOAc:hexanes); .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 6.57 (d,
1H, J=8.3), 6.26-6.20 (m, 2H), 4.12 (dd, ABX, 1H, J=10.3, 2.4),
3.92 (dd, ABX, 1H, J=10.7, 2.4), 3.32-3.28 (m, 3H), 3.15-3.10.(m,
1H), 3.01 (m, 1H), 1.57-1.48 (m, 2H), 1.15 (t, 3H, J=7.0), 0.94 (t,
3H, J=7.3).
[0274]
(.+-.)-1,2-Diethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]-
oxazino[3,2-g]quinolin-7-one (Compound 146, Structure 35 of Scheme
VII, where R.sup.1.dbd.H, R.sup.2.dbd.CF.sub.3, R.sup.4=Et,
R.sup.x.dbd.CH.sub.3). This compound was prepared by General Method
5 (EXAMPLE 1) from
(.+-.)-7-amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine (39 mg,
0.18 mmol) and ethyl 4,4,4-trifluoroacetoacetate (42 mg, 0.22 mmol)
and purified by flash chromatography (19:1, CH.sub.2Cl.sub.2/MeOH)
to yield 15 mg (25%) of Compound 146. Data for Compound 146:
R.sub.f0.28 (19:1, CH.sub.2Cl.sub.2:MeOH); .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 11.50 (br s, 1H), 6.89 (s, 1H), 6.88 (s, 1H),
6.84 (s, 1H), 4.32 (dd, ABX, 1H, J=10.7, 2.0), 4.06 (dd, ABX, 1H,
J=10.7, 2.7), 3.51-3.47 (m, 1H), 3.30-3.23 m, 2H), 1.66-1.60 (m,
2H), 1.25 (t, 3H, J=7.3), 0.98 (t, 3H, J=7.3).
EXAMPLE 43A
(.+-.)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2.9-bis(trifluoromethyl-
)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 146A, Structure 35
of Scheme VII, where R.sup.1.dbd.H, R.sup.2,
R.sup.4=trifluoromethyl, R.sup.x.dbd.CF.sub.1)
[0275] 2-(Trifluoroethyl)amino-5-nitrophenol (Structure 32A of
Scheme VIIA, where R.sup.x=CF.sub.3). This compound was prepared by
General Method 7 (EXAMPLE 5) from 2-amino-5-nitrophenol (5.0 g, 32
mmol), 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (9.4 g, 65
mmol) and NaBH.sub.3CN (4.1 g, 65 mmol) in 90 mL trifluoroacetic
acid to afford 5.5 g (72%) of
2-(trifluoroethyl)amino-5-nitrophenol, a yellow solid, after flash
chromatography (3:1 hexanes:EtOAc). Data for
2-(trifluoroethyl)amino-5-nitrophenol: .sup.1H NMR (400MHz,
acetone-d.sub.6) 9.48 (broad s,. 1H), 7.79 (dd, 1H, J=9.1, 2.4),
7.67 (d, 1H, J=2.4), 6.96 (d, 1H, J=8.8), 6.20 (broad s, 1H),
4.26-4.18 (m, 2H)
[0276]
(.+-.)-3,4-Dihydro-7-nitro-4-(2,2,2-trifluoroethyl-3-(trifluoromet-
hyl)-2H-1,4-benzoxazine (Structure 33 of Scheme VIIA, where
R.sup.4=trifluoromethyl, R.sup.x.dbd.CF.sub.1). This compound was
prepared by General Method 17 (EXAMPLE 38) from
2-(trifluoroethyl)amino-5-nitrophenol (1.00 g, 4.23 mmol),
3-bromo-1,1,1-trifluoroacetone (4.84. g, 25.4 mmol), and
K.sub.2CO.sub.3 (2.34 g, 16.9 mmol) to afford 1.5 g of crude solid.
This was combined with another lot of the same reaction (4.2 mmol)
and purified by flash chromatography (1:1 hexanes:EtOAc) to afford
1.0 g (40%) of a yellow oil. This material (725 mg, 2.47 mmol) was
treated with 20 mL trifluoroacetic acid and NaBH.sub.3CN (776 mg,
12.4 mmol) to afford 0.26 g (38%)
(4)-3,4-dihydro-7-nitro-3-(trifluoromethyl)-2H-1,4-benzoxazine
after purification by flash chromatography (3:1 hexanes:EtOAc).
Data for
(.+-.)-3,4-dihydro-7-nitro-3-(trifluoromethyl)-2H-1,4-benzoxazine:
.sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (dd, 1H, J=9.1, 2.8), 7.81
(d, 1H, J=2.5), 6.92 (d, 1H, J=9.1), 4.73 (d, 1H, J=12.1),
4.48-4.39 (m, 1H), 4.13-4.06 (m, 2H), 3.99-3.88 (m, 1H).
[0277]
(.+-.)-7-Amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluorome-
thyl)-2H-1,4-benzoxazine (Structure 34 of Scheme VII, where
R.sup.4=trifluoromethyl, R.sup.x.dbd.CF.sub.3). This compound was
prepared by General Method 4 (EXAMPLE 1) from
(.+-.)-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2-
H-1,4-benzoxazine (45 mg , 0.16 mmol) and 10% Pd-C (30 mg) and
purified by flash chromatography (EtOAc:hexanes, 1:1) to afford 26
mg (65%) of
(.+-.)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2-
H-1,4-benzoxazine. Data for
(.+-.)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2-
H-1,4-benzoxazine: .sup.1H NMR (400MHz, CDCl.sub.3) 6.68 (d, 1H,
J=8.4), 6.32-6.28 (m, 2H), 4.56 (dd, 1H, J=12.0, 0.96), 4.16-4.00
(m, 2H), 3.84-3.69 (m, 2H), 3.60-3.32 (m, 2H).
[0278]
(.+-.)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluo-
romethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 146A,
Structure 35 of Scheme VII, where R.sup.1.dbd.H, R.sup.2,
R.sup.4=trifluoromethyl R.sup.x.dbd.CF.sub.3). This compound was
prepared by General Method 11 (EXAMPLE 22) from
(.+-.)-7-amino-3,4dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-
-1,4-benzoxazine (26 mg, 0.11 mmol) and ethyl
4,4,4-trifluoroacetoacetate (58 mg, 0.32 mmol) in 1.5 mL toluene
followed by treatment with 1 mL H.sub.2SO.sub.4 afforded 3-5 mg
(90%) of Compound 146A. Data for Compound 146A: .sup.1H NMR
(400MHz, CDCl.sub.3) 12.6 (broad s, 1H), 7.19 (broad s, 1H), 7.04
(s, 1H), 6.96(s, 1H), 4.73 (d, 1H, J=11.7), 4.42-4.31 (m, 1H),
4.23-4.19 (m, 1H), 4.02-3.95 (m, 1H), 3.96-3.84 (m, 1H).
EXAMPLE 43B
(+)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2.9-bis(trifluoromethyl)-7-
H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 146B, Structure
(+)-35 of Scheme VII, where R.sup.1.dbd.H, R.sup.2,
R.sup.4=trifluoromethyl. R.sup.x.dbd.CF.sub.3) and
(.+-.)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethy-
l)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 146C, Structure
(-)-35 of Scheme VIIA, where R.sup.1.dbd.H, R.sup.2,
R.sup.4=trifluoromethyl, R.sup.x.dbd.CF.sub.3)
[0279] This compound was prepared according to General Method 9
(EXAMPLE 15) from Compound 146A (EXAMPLE 42A) (10 mg, 0.03 mmol) on
a semiprep Chiralpak AD column (20.times.250 mm) eluted
hexanes/isopropanol (95:5), to afford 4.5 mg of Compound 146B, an
orange solid, and 4.7 mg of Compound 146C, an orange solid. Data
for Compound 146B: HPLC (Chiralpak AD, 95:5 hexanes:isopropanol,
5.0 mL/min) t.sub.R 54.1 min; [.alpha.].sub.D=+62.7.
[0280] Data for Compound 146C: HPLC (Chiralpak AD, 95:5
hexanes:isopropanol, 5.0 mL/min) t.sub.R 64.3 min;
[.alpha.].sub.D=-60.4.
EXAMPLE 44
(.+-.)-1-Ethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxa-
zino[3,2-g]quinolin-7-one (Compound 147, Structure 35 of Scheme
VII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.4=Me,
R.sup.x.dbd.CH.sub.3)
[0281] (.+-.)-3,4-Dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine
Structure 32 of Scheme VII, where R.sup.4=Me). This compound was
prepared by General Method 17 (EXAMPLE 38) from
2-amino-5-nitrophenol (4.0 g, 25.9 mmol), chloroacetone (2.27 mL,
28.5 mmol), and K.sub.2CO.sub.3 (3.94 g, 28.5 mmol) to afford 3.5 g
of crude solid. The crude solid (3.0 g, 14.2 mmol), NaBH.sub.3CN
(892 mg, 14.2 mmol) and trifluoroacetic acid afforded 2.68 g (97%)
of 3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine. Data for
(.+-.)-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine: R.sub.f
0.51 (2:3, EtOAc hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.74 (dd, 1H, J=8.7, 2.6), 7.70 (d, 1H, J=2.3), 6.50 (d,
1H, J=8.7), 4.46 (br s, 1H), 4.23 (dd, 1 H, J=10.5, 2.8), 3.76 (dd,
1H, J=10.5, 7.8), 3.67 (m, 1H), 1.25 (d, 3H, J=6.4).
[0282]
(.+-.)-4-Ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine
(Structure 33 of Scheme VII, where R.sup.4=Me,
R.sup.x.dbd.CH.sub.3). This compound was prepared by General Method
3 (EXAMPLE 1) from
(.+-.)-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine (200 mg, 1.0
mmol), acetaldehyde (455 mg, 10.3 mmol) and NaBH.sub.3CN (314 mg,
5.0 mmol) to afford 144 mg (63%) of
4ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine. Data for
(.+-.)-4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine:
R.sub.f 0.80 (3:2EtOAc:hexanes); .sup.1H NMR (500 MHz,
CDCl.sub.3).delta. 7.80 (dd, 1H, J=8.9, 2.6), 7.66 (d, 1H, J=2.6),
6.55 (d, 1H, J=9.2), 4.07 (dd, 1H, J=10.7, 2.5), 3.96 (dd, 1H,
J=10.7, 2.6), 3.60 (m, 1H), 3.55-3.35 (m, 2H), 1.29 (d, 3 H,
J=6.6), 1.24 (t, 3H, J=7.0).
[0283]
(.+-.)-7-Amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine
(Structure 34 of Scheme VII, where R.sup.4=Me,
R.sup.x.dbd.CH.sub.3). This compound was prepared by General Method
4 (EXAMPLE 1) from
(.+-.)-4-ethyl-3,4-dihydro-3-methyl-7-nitro2H-1,4-benzoxazine (140
mg, 0.62 mmol) and purified by flash chromatography (EtOAc:hexanes,
3:2) to afford 90 mg (74%) of
(.+-.)-7-amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine.
Data for
(.+-.)-7-amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine:
R.sub.f0.48,(3:2 EtOAc:hexanes) .sup.1 H NMR (400 MHz, CDCl.sub.3)
.delta. 6.53 (d, 1H, J=8.0), 6.26-6.20 (m, 2H), 4.04 (dd, 1H,
J=10.5, 2.6), 3.94 (dd, 1H, J=10.4, 4.3), 3.37-3.26 (m, 4H),
3.17-3.07 (m, 1H), 1.13 (m, 6H).
[0284]
(.+-.)-1-Ethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H--
[1,4 oxazino[3,2-g]quinolin-7-one (Compound 147, Structure 35 of
Scheme VII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl.
R.sup.4=Me, R.sup.x.dbd.CH.sub.3). This compound was prepared by
General Method 5 (EXAMPLE 1) from
(.+-.)-7-amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine (90
mg, 0.47 mmol) and ethyl 4,4,4-trifluoroacetoacetate (103 mg, 0.56
mmol) and purified by flash chromatography (3:2 EtOAc:hexanes) to
yield 46 mg (30%) of Compound 147. Data for Compound 147: R.sub.f
0.37 (3:2, EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 12.07 (br s, 1H), 6.89 (s, 1H), 6.88 (s, 2H), 4.18 (dd, 1H,
J=10.5, 2.5), 4.09 (dd, 1H, J=10.6, 3.4), 3.54-3.51 (m, 1H),
3.47-3.40 (m, 1H), 3.31-3.24 (m, 1H), 1.23 (m, 6H).
EXAMPLE 45
(2R-)-(.+-.)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifl-
uoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one benzoxazine
(Compound 148, Structure 41 of Scheme VIII, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl R.sup.4=Me. R.sup.x.dbd.CF.sub.3)
[0285] General Method 18: Displacement of a halonitroaromatic
compound with an amino alcohol. A mixture of the halonitrobenzene
(1.2 equiv) and the amino alcohol (1 equiv) was dissolved in
absolute ethanol (3.3 M) or DMF. To this solution was added sodium
bicarbonate (1 equiv). The suspension was heated at reflux
temperature for 12 h when TLC indicated complete conversion of the
amino alcohol. After cooling to room temperature, the reaction
mixture was filtered with the aid of additional ethanol and the
filtrate was concentrated under reduced pressure, which was then
purified as indicated.
[0286] (2R)-(+)-2-(2-Fluoro-4-nitrophenyl)amino-1-propanol
(Structure 36 of Scheme VIII, where R.sup.4=Me). This compound was
prepared according to General Method 18 from
3,4-difluoronitrobenzene (76.2 g 0.48 mol),
R-(+)-2-amino-1-propanol (30 g, 0.40 mol) and sodium bicarbonate
(33.6 g, 0.40 mol) in 120 mL ethanol to afford 68.4 g (80%) of
(2R)-(+)-2-(2-fluoro4-nitrophenyl)amino-1-propanol, a yellow solid,
after recrystallization from ethanol. Data for
(2R)-(+)-2-(2-fluoro-4-nitrophenyl)amino-1-propanol: mp
128.2-129.7.degree. C.; [.alpha.].sub.D=+22.6 (EtOH, c 3.1);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.99 (1H, dd, J=11.4),
7.89 (1H, dd, J=2.5, 11.6), 6.72 (1H, dd, J=8.7), 4.75(1H, bs), 3.8
(2H, m), 3.69 (1H, m), 1.31 (3H, d, J=6.4).
[0287] General Method 19: Formation of an oxazolidine from an
aminoalcohol and a carbonyl derivative, or its corresponding
hydrate or hemiacetal. A r.b. flask equipped with a Dean-Stark
condenser was charged sequentially with the amino alcohol (1
equiv), benzene (0.3-0.5 M), trifluoroacetaldehyde ethyl hemiacetal
(5 equiv), and p-toluenesulfonic acid (catalytic). The reaction
mixture was refluxed with azeotropic removal of water for 10-12 h.
After cooling to room temperature the reaction mixture was
concentrated under reduced pressure. The residue was dissolved in
ethyl acetate and washed with aqueous sodium bicarbonate, brine and
dried over anhydrous MgSO.sub.4. After filtration, the solvents
were removed under reduced pressure to afford the desired
oxazolidine.
cis-(2S,4R)-(-)-3-(2-Fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxaz-
olidine and
trans-(2R,4R)-(+)-3-(2-Fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethylox-
azolidine (Structure 37 of Scheme VIII, where R.sup.4=Me.
R.sup.x.dbd.CF.sub.3). These compounds were: prepared according to
General Method 19 from
(2R)-(+)-2-(2-fluoro-4-nitrophenyl)amino-1-propanol (68 g, 0.317
mole), 750 mL of benzene, trifluoroacetaldehyde ethyl hemiacetal
(229 g, 1.58 mole), and 100 mg of p-toluenesulfonic acid (100 mg,
0.53 mmol) to afford
cis-(2S,4R)-(-)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxaz-
olidine and
trans-(2R,4R)-(+)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethylox-
azolidine as a low melting solid. The product was found to be a
mixture of two diastereoisomers (cis/trans 4:1). Crystallization
from ethyl acetate-hexanes furnished the major (cis) isomer as pale
yellow needles and the minor (trans) isomer as a glassy solid. The
combined yield of both compounds was 93.2 g (100%).
[0288] Data for
cis-(2S,4R)-(-)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxaz-
olidine: mp 46-50.degree. C.; [.alpha.].sub.D=-60.9 (CHCl.sub.3, c
10.3); .sup.1H NMR (CDCl.sub.3) .delta. 8.01 (1H, m), 7.98 (1H, dd,
J=2.5, 12.3), 6.96 (1H, dd, J=9.0), 5.75 (1H, q, J=4.7), 4.33 (1H,
m), 4.19 (1H, m), 3.99 (1H, m), 1.45 (3H, d, J=6.26). Data for
trans-(2R,4R)-(+)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethylox-
azolidine: [.alpha.].sub.D=+258.9 (CHCl.sub.3, c 8.25); .sup.1H NMR
(CDCl.sub.3) .delta. 8.02 (1H, dd), 7.98 (1H, dd, J=2.5,-12.9 ).
6.96 (1H, dd, J=8.5), 5.83 (1H, q, J=4.7), 4.48(1H, m), 4.40 (1H,
m), 3.95 (1H, m), 1.23 (3H, d, J=6.0).
[0289] (2R
)-(-)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol
(Structure 38 of Scheme VIII, where R.sup.4=Me.
R.sup.x.dbd.CF.sub.3). A 1-L three-necked RB flask equipped with an
addition funnel and mechanical stirrer was charged sequentially
with
cis-(2S,4R)-(+)-3-(2-fluoro-4-nitrophenyl)4-methyl-2-trifluoromethyloxazo-
lidine and
trans-(2R,4R)-(+)-3-(2-fluoro-4-nitrophenyl)4-methyl-2-trifluor-
omethyloxaiolidine (93 g, 0.36 mole), 600 mL of dry chloroform, and
triethylsilane (183.7 g, 1.58 mol). The solution was cooled to
-78.degree. C. and TiCl.sub.4 (90 g, 0.474 mol) was added dropwise
via addition funnel. After the addition was complete, the reaction
mixture was allowed to warm to room temperature and stirred for
another 24 h. The reaction mixture was quenched with ice and then
neutralized with aqueous Na.sub.2CO.sub.3. The organic layers were
washed with water, brine and dried over MgSO.sub.4. After
filtration, the solvents were evaporated under reduced pressure and
the residue was purified by silica gel column chromatography (ethyl
acetate: hexanes 1:9) to afford 57 g (61%) of (2R
)-(-)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol,
as a glassy solid. Data for (2R
)-(-)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol
[.alpha.].sub.D=-205.9 (EtOH, c 10.15 ) .sup.1H NMR (CDCl.sub.3)
.delta. 7.99 (1H, dd, J=2.5, 9.0), 7.95 (1H, dd, J=2.6, 14,7), 7.32
(1H, dd, J=8.6), 3.94 (1H, m), 3.74 (2H, m), 3.65 (1H, m), 1.86(1H,
bs), 1.19 (3H, d, J=6.7).
[0290] General Method 20: Intramolecular cyclization of an alcohol
of Structure 38 or 42 on a haloaromatic to form a benzoxazine. A
solution of the aminoalcohol (1 equiv) in dry THF (1M) was added to
a suspension of NaH (1.5 equiv) in dry THF (2M) and the mixture was
heated at reflux. After cooling, methanol (50 mL/mol) was added to
consume excess sodium hydride. The reaction mixture was poured into
ice-cold water and extracted with ethyl acetate. The organic
portions were combined, washed with brine and dried over
MgSO.sub.4. After filtration, the solvents were evaporated under
reduced pressure and purified as indicated.
(3R)-(+)-3,4-Dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benz-
oxazine (Structure 39 of Scheme VIII, where R.sup.4=Me.
R.sup.x.dbd.CF.sub.3)
[0291] This compound was prepared according to General Method 20
from (2R
)-(-)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol
(57 g, 0.193 mol) in 200 mL and NaH (6.93 g, 0.289 mole) in 400 mL
of dry THF heated at reflux for 3 h to afford 36.5 g (68%) of
(3R)-(+)-2,3-dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-ben-
zoxazine, a yellow crystalline solid, after flash chromatography.
Data for
(3R)-(+)-2,3-dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-ben-
zoxazine: mp 95.5-96.4.degree. C.; [.alpha.].sub.D=+57.8 (EtOH, c
2.25); .sup.1H NMR (CDCl.sub.3) 3 7.80 (1H, dd, J=2.5, 9.1 ), 7.73
(1H, d, J=2.6), 6.71 (1H, d, J=9.1), 4.13 (2H, m ), 4.03 (1H, m),
3.84 (1H, m), 3.69 (1H, m), 1.31 (3H, d J=6.6).
[0292]
(3R)-(-)-7-Amino-3.4-dihydro-3-methyl4-(2,2,2-trifluoroethyl)-2H-1-
,4-benzoxazine (Structure 40 of Scheme VIII, where R.sup.4=Me.
R.sup.x.dbd.CF.sub.3). This compound was prepared according to
General Method 4 (EXAMPLE 1) from
(3R)-(+)-2,3-dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-ben-
zoxazine (35.5 g, 0.128 mol) and 10% palladium on carbon (3 g) in
400 mL of ethyl acetate to afford 31 g (98%) of
(3R)-(-)-7-amino-2,3-dihydro-3-methyl-4-trifluoroethyl-2H-1,4-benzoxazine-
, an off-white solid, after purification by silica gel column
chromatography (ethyl acetate-hexanes). Data for
(3R)-(-)-7-amino-2,3-dihydro-3-methyl4-trifluoroethyl-2H-1,4-benzoxazine:
[.alpha.].sub.D=-39.4 (EtOH, c 1.7) .sup.1H NMR (CDCl.sub.3)
.delta. 6.58 (1H, d, J=8.2 ), 6.40 (1H, m ), 6.37 (1H, m), 4.05
(1H, dd, J=2.3, 11.0) 3.98 (1H, dd, J=2.9, 10.6), 3.66 (2H, m),
3.38 (1H, m) 3.40(NH2), 1.18 (3H, d, J=6.6).
(2R-)-(-)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluor-
omethyl)-7H-[1,4]oxazino[3 2-g]quinolin-7-one benzoxazine (Compound
148, Structure 41 of Scheme VIII, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl. R.sup.4=Me. R.sup.x.dbd.CF.sub.3)
[0293] A mixture of
(3R)-(-)-7-amino-3,4-dihydro-3-methyl-4-trifluoroethyl-2H-1,4-benzoxazine
(4.14 g, 16.8 mmol) and of ethyl 4,4,4-trifluoroacetoacetate (4.64
g, 25 mmol) were taken up in 85 mL of wet toluene (5% H.sub.20).
The reaction mixture was refluxed for 24 h. After cooling to room
temperature, the solvents were evaporated under reduced pressure.
The crude anilide obtained as a glassy solid was then treated with
50 mL of concentrated H.sub.2SO.sub.4. The reaction mixture was
then slowly warmed to 70.degree. C. and then to 98.degree. C. After
45 min, the heating bath was removed and the reaction mixture was
allowed to cool to room temperature and then poured on to crushed
ice with vigorous stirring. The yellow precipitate formed was
filtered, washed with distilled water, and dried under vacuum. The
crude product thus obtained was purified by silica gel column
chromatography (ethyl-acetate:hexanes), followed by
recrystallization from ethyl acetate-hexanes to afford 2.6 g
(42.3%) of Compound 148, a bright-yellow crystalline solid. Data
for Compound 148: mp 219-223.1.degree. C.; [.alpha.].sub.D=-81.7
(EtOH, c 2.4 ); .sup.1H NMR (CDCl.sub.3) .delta. 7.05 (1H, s), 6.91
(1H, s), 6.89 (1H, s), 4.23 (1H, dd, J=2.4, 10.8), 4.14 (1H, dd,
J=2.7, 10.7), 3.92 (1H, m), 3.78 (1H, m), 3.61 (1H,m) 1.27 (3H, d
J=6.6).
EXAMPLE 46
(2R-)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluorometh-
yl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 149. Structure
41 of Scheme VIII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl.
R.sup.4=Et R.sup.x.dbd.CF.sub.3)
[0294] (2R)-2-(2-Fluoro-4-nitrophenyl)amino-1-butanol (Structure 36
of Scheme VIII, where R.sup.4=Et). This compound was prepared
according to General Method 18 (EXAMPLE 45) from
3,4-difluoronitrobenzene (5.34 mL, 0.048 mol), R-(-)-2
amino-1-butanol (4.14 mL, 0.044 mol) and sodium bicarbonate (3.68
g, 0.044 mol) in 133 mL anhydrous DMF heated at 90.degree. C. for
12 hrs to afford 9.9 g (99%) of
(2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol, a yellow oil, after
flash chromatography (gradient elution, hexanes:ethyl acetate 95:5
to 50:50). Data for (2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.98 (dd, J=8.8, 1.5,
1H), 7.89 (dd, J=11.7, 2.4, 1H), 6.71 (dd, J=8.8, 8.8, 1H), 4.72
(bs, 1H), 3.81 (m, 1H), 3.73 (m, 1H), 3.55 (m, 1H), 1.76 (m, 1H),
1.63 (m, 1H), 1.02 (t, J=7.8, 3H).
[0295]
(4R)-3-(2-Fluoro-4-nitrophenyl)-4-ethyl-2-(trifluoromethyl)-1,3-ox-
azolidine (Structure 37 of Scheme VIII, where R.sup.4=Et.
R.sup.x.dbd.CF.sub.3). This compound was prepared according to
General Method 19 (EXAMPLE 45) from
(2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol (1.6 g, 70 mmol),
trifluoroacetaldehyde ethyl hemiacetal (4.9 g, 34 mmol) and
p-toluenesulfonic acid (0.13 g, 0.68 mmol) in 70 mL anhydrous
benzene to afford 1.8 g (85%) of
(4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine,
after flash chromatography (gradient elution, hexanes:ethyl acetate
90:10 to 50:50). Data for
(4R)-3-(2-fluoro-1-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.01 (m, 1H), 7.98 (m,
1H), 6.95 (dd, J=8.8, 8.8, 1H), 5.68 (m, 1H), 4.30 (m, 1H), 4.08
(m, 1H), 3.92 (m, 1H), 2.00 (m, 1H), 1.67 (m, 1H), 0.97 (t, J=7.8,
3H).
[0296] (2R
)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol
(Structure 38 of Scheme VIII, where R.sup.4=Et.
R.sup.4.dbd.CF.sub.3). To a solution of
(4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine
(9.2 g, 29.8 mmol) and Et.sub.3SiH (19.1 mL, 119 mmol) in 100 mL
chloroform was added BF.sub.3OEt.sub.2 (7.56 mL, 60 mmol). The
reaction was heated to reflux for 12 hrs, whereupon additional
BF.sub.3OEt.sub.2 (7.56 mL, 60 mmol) was added, and the mixture
heated at reflux for an additional 12 hrs. After cooling, MeOH (5
mL) was added and the reaction was allowed to stir at r.t. for an
hour. The reaction was poured in water (250 mL) and extracted with
ethyl acetate (3.times.250 mL). The organic layers were combined,
washed sequentially with water (250 mL) and brine (250 mL), dried
(MgSO.sub.4), filtered, and concentrated under reduced pressure to
a brown oil. Flash chromatography (gradient elution, hexanes:ethyl
acetate 95:5 to 50:50) afforded 5.4 g (59%) of (2R
)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol. Data
for (2R
)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.98 (dd, J=8.8, 2.4,
1H), 7.94.(dd, J=13.2, 12.9, 1H), 7.37 (dd, J=8.8, 8.8, 1H), 4.12
(m, 1H), 3.87 (m, 1H), 3.77 (m, 1H), 3.70 (m, 1H), 3.57 (me 1H),
1.78 (dd, J=6.8, 4.4, 1H),1.58(dq, J=7.8, 2.9, 2H), 0.95 (t, J=7.3,
1H).
[0297]
(3R-3-Ethyl-3,4-dihydro-7-nitro-4-(2.2,2-trifluoroethyl)-2H-1,4-be-
nzoxazine (Structure 39 of Scheme VIII, where R.sup.4=Et,
R.sup.x.dbd.CF.sub.3). This compound was prepared according to
General Method 20 from (2R
)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol (5.4
g, 17.3 mmol) in 45 mL THF and NaH (1.4 g, 35 mmol) in 10 mL THF
heated at reflux for 1 hr to afford 3.78g (75%) of
(3R)-3ethyl-3,4-dihydro-7-nitro-4-2,2,2-trifluoroethyl)-2H-1,4-benzoxazin-
e, after flash chromatography (gradient elution, hexanes:ethyl
acetate 95:5 to 50:50). Data for
(3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxaz-
ine: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.81 (dd, J=8.8,
2.4, 1H), 7.73 (d, J=2.9, 1H), 6.72 (d, J=8.8, 1H), 4.34 (dd,
J=11.2, 1.5, 1H), 4.13 (m, 1H), 4.03 (dd, J=11.2, 2.4, 1H), 3.8 (m,
1H), 3.37 (m, 1H), 1.67 (m, 1H), 1.01 (t, J=7.3, 3H).
[0298] (3R)-7-Amino-3-ethyl-3
4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4benzoxazine (Structure 40
of Scheme VIII, where R.sup.4=Me. R.sup.x.dbd.CF.sub.3). This
compound was prepared according to General Method 4 (EXAMPLE 1)
from
(3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxaz-
ine (5.6 g, 19.3 mmol) and 10% Pd/C (cat.) in 60 mL ethyl acetate
to afford 4.8 g (95%) of
(3R)-7-aniino-3,4-dihydro-3-ethyl-4-trifluoroethyl-2H-1,4-benzoxazine
as a tan solid, which was carried on directly to the next step.
[0299]
(2R)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(triflu-
oromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 149,
Structure 41 of Scheme VIII, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl. R.sup.4=Et. R.sup.x.dbd.CF.sub.3). This
compound was prepared by General Method II (EXAMPLE 22) from
(3R)-7-amino-3-ethyl-3,4dihydro-4-trifluoroethyl-2H-1,4-benzoxazine
(4.8 g, 18.4 mmol) and ethyl-4,4,4-trifluoroacetoacetate (8.1 mL,
55.2 mmol) in 58 mL toluene heated at reflux for 3d, followed by
workup and treatment with 35 mL concentrated H.sub.2SO.sub.4 heated
to 90.degree. C. for 0.5 h to afford 1.5 g (21%) of Compound 149, a
yellow solid, after flash chromatography (gradient elution,
hexanes:ethyl acetate 95:5 to 50:50) followed by additional
purification using reverse phase HPLC (Kromasil C18, 50.times.250
mm; 65:35 MeOH:water; flow rate of 80 mL/min.). Data for Compound
149:. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 11.75 (bs, 1H),
7.06 (s, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.89 (s, 1H), 4.34 (dd,
J=10.7, 1.5, 1H), 4.14 (dd, J=112, 2.4, 1H), 3.99 (m, 1H), 3.75 (m,
1H), 3.28 (m, 1H), 1.64 (dq, J=7.6, 7.3, 2H), 1.00 (t, J=7.3,
3H).
EXAMPLE 47
(2R)
1,2,3,6-Tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluorome-
thyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 150, Structure
41 of Scheme VIII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl.
R.sup.4=isobutyl, R.sup.x.dbd.CF.sub.3).
[0300] (2R)-2-(2-Fluoro-4-nitrothenyl)amino-4-methyl-1-Rentanol
(Structure 36 of Scheme VIII, where R.sup.4=isobutyl). This
compound was prepared according to General Method 18 (EXAMPLE 45)
from 3,4-difluoronitrobenzene (8.73 g, 54.9 mmol),
R-2-amino-4-methyl-1-pentanol (5.00 g, 42.7 mmol) in EtOH heated at
reflux for 16 h to afford 6.0 g (55%) of
(2R)-2-(2-fluoro-4-nitrophenyl)amino-4-methyl-1-pentanol, a yellow
solid, after flash chromatography (gradient elution, hexanes:EtOAc
9:1 to 1:1). Data for
(2R)-2-(2-fluoro-4-nitrophenyl)amino-4-methyl-1-pentanol: R.sub.f
0.3 (3:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.01-7.97 (m, 1H), 7.90 (dd, 1H, J=11.7, 2.7), 6.74 (dd, 1H, J=8.6,
8.6), 4.62-4.57 (m, 1H), 3.82-3.74 (m, 1H), 3.75-3.62 (m, 2H),
1.77-1.65 (m, 1H), 1.61-1.45 (m, 2H), 0.99 (d, 3H, J=6.6), 0.93 (d,
3H, J=6.6).
[0301]
(4R)-3-(2-Fluoro-4-nitrophenyl)4-isobutyl-2-(trifluoromethyl)-1,3--
oxazolidin (Structure 37 of Scheme VIII, where R.sup.4=isobutyl,
R.sup.x.dbd.CF.sub.3. This compound was prepared according to
General Method 19 (EXAMPLE 45) from
(2R)-2-(2-fluoro-4-nitrophenyl)amino-4-methyl-1-pentanol (6.0 g, 23
mmol) trifluoroacetaldehyde ethyl hemiacetal (30.4 g, 211 mmol) and
p-toluenesulfonic acid (0.020 g, 0.10 mmol) in 250 mL benzene to
afford 5.15 g (65%) of
(4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxazolidine.
Data for
(4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxaz-
olidine as a mixture of diastereomers: R.sub.f 0.8 (3:1
hexates:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.03-7.94
(m, 2H), 6.96-6.88 (m, 1H), 5.81 (q, 1H, minor diast., J=4.7), 5.69
(q, 1H, major diast., J=4.7), 4.45-4.40 (m, 1H, minor diast.),
4.36-4.28 (m, 1H, major diast), 4.11-4.01 (m, 2H), 1.82-1.74 (m,
1H), 1.66-1.52 (m, 2H), 1.02 (d, 3H, major diast., J=6.4),
0.99-0.95 (m, 3H), 0.91 (d, 3H, minor diast, J=6.6).
[0302]
(2R)-2-[2-Fluoro-4-nitro(2,2.2-trifluoroethyl)anilino]-4-methyl-1--
pentanol (Structure 38 of Scheme VIII, where R.sup.4=isobutyl.
R.sup.x.dbd.CF.sub.3. To a solution of
(4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxazolidine
(4.8 g, 14.3 mmol) and Et.sub.3SiH (21.6 g, 186 mmol) in 60 mL
chloroform was added BF.sub.3OEt.sub.2 (14.2, 60 mmol, added in
portions) The reaction was heated at reflux for 1 d After cooling,
the reaction was poured in water (200 mL) and extracted with
chloroform (3.times.1 50 mL). The organic layers were combined,
washed sequentially with water (200 mL) and brine (200 mL), dried
(MgSO.sub.4); filtered, and concentrated under reduced pressure to
a brown oil. Flash chromatography (gradient elution, hexanes:ethyl
acetate 95:5 to 3:1) afforded 2.1 g. (44%) of
(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentano-
l, an orange oil. Data for
(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino-4-methyl-1-pentanol-
: R.sub.f0.8.(3:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.98 (dd, 1H, J=9.3, 2.4), 7.94 (dd, 1H, J=12.9, 2.5), 7.40
(dd, 1H, J=8.7, 8.7), 4.21-4.10 (m, 1H), 3.89-3.78 (m, 1H),
3.79-3.65 (m, 3H), 1.96-1.89 (m, 1H), 1.67-1.54 (m, 1H), 1.55-1.44
(m, 1H), 1.32-1.22 (m, 1H), 0.91 (d, 3H, J=6.6), 0.77 (d, 3H,
J=6.6).
[0303]
(3R)-3.4-Dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,-
4-benzoxazine (Structure 39 of Scheme VIII, where R.sup.4=isobutyl,
R.sup.x.dbd.CF.sub.3. This compound was prepared according to
General Method 20 (EXAMPLE 45) from
(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentano-
l (1.95 g, 5.76 mmol) in 30 mL THF and NaH (1.4 g, 35 mmol) in 25
mL THF heated at reflux for 1 hr. to afford 0.87 g (50%) of
(3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzo-
xazine, yellow oil. Data for
(3R)-3,4-dihydro-3-isobutyl-7-nitro-4(2,2,2-trifluoroethyl)-2H-1,4-benzox-
azine: R.sub.f 0.6 (3:1 hexanes:EtOAc); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.79 (dd, 1H, J=9.1, 2.7), 7.71 (d, 1H, J=2.5),
6.72 (d, 1H, J=9.1), 4.30 (dd, 1H, ABx, J=11.0, 1.5), 4.19-4.06 (m,
1H), 4.06-4.01 (m, 11), 3.82-3.73 (m, 1H), 3.53-3.47 (m, 1H),
1.71-1.61 (m,2H), 1.38-1.29 (m, 1H), 0.99 (d, 3H, J=6.5), 0.96 (d,
3H, J=6.5).
[0304]
(3R)-7-Amino-3,4-dihydro-3-isobutyl-4-(2,2,2-trifluoroethyl)-2H-1,-
4-benzoxazine (Structure 40 of Scheme VIII, where R.sup.4=isobutyl,
R.sup.x.dbd.CF.sub.3). This compound was prepared according to
General Method 4 (EXAMPLE 1) from
(3R)-4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxa-
zine (0.22 g, 0.69 mmol) and 10% Pd/C (0.075 g) in 5 mi ethyl
acetate to afford 0.13 g (65%) of (3R
-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine.
Data for
(3R)-7-amino-3,4-dihydro-3-isobutyl4-trifuoroethyl-21-l,4-benzoxazine-
: R.sub.f03 (3:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.63 (d, 1H, J=8.5), 6.27 (dd, 1H, J=8.5, 2.6), 6.23 (d,
1H, J=2.5), 4.10 (dd, 1H, ABx, J=10.6, 1.8), 3.97 (dd, 1H, ABx,
J=10.6, 2.3), 3.70-3.51 (m, 2H), 3.38 (broad s, 2H), 3.19-3.13 (m,
1H), 1.75-1.63 (m, 1H), 1.47-1.25 (m, 2H), 0.93 (d, 3.H, J=6.6),
0.89 (d, 3H, J=6.6).
[0305]
(2R)-1,2,3,6-Tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(tri-
fluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 150,
Structure 41 of Scheme VIII, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl. R.sup.4=isobutyl. R.sup.x.dbd.CF). This
compound was prepared by General Method 11 (EXAMPLE 22) from
(3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine
(0.13 g, 0.45 mmol) and ethyl-4,4,4-trifluoroacetoacetate (0.25 g,
1.4 mmol) in 6 mL toluene heated at reflux for 3 h, followed by
workup and treatment with 3 mL concentrated H.sub.2SO.sub.4 heated
to 9.5.degree. C. for 1 h to afford 17 mg (9%) of Compound 150, a
yellow solid, after purification by flash chromatography (95:5
CH.sub.2Cl.sub.2:MeOH) and recrystallization from EtOAc:hexanes.
Data for Compound 150: R.sub.f0.2 (19:1 CH.sub.2Cl.sub.2;MeOH);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.58 (broad s, 1H), 7.05
(broad s, 1H), 6.97 (s, 1H), 6.91 (s, 1H), 4.30 (dd, 1H, ABX,
J=11.0, 1.1), 4.16 (dd, 1H, ABX, J=11.0, 1.3), 4.01-3.91 (m, 1H),
3.75-3.65 (m, 1H), 3.42-3.37 (m, 1H), 1.71-1.62 (m, 1H), 1.62-1.54
(m, 1H), 1.35-1.27 (m, 1H), 0.96 (d, ;H, J=6.9), 0.93 (d, 3H,
J=7.5).
EXAMPLE 48
(2R)-1,2,3,6-Tetrahydro-2-isopropyl-1-(2,2,2-trifluoroethyl)-9-(trifluorom-
ethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 151,
Structure 41 of Scheme VIII, where R.sup.1.dbd.H,
R.sup.2=trnfluoromethyl, R.sup.4=isopropyl.
R.sup.x.dbd.CF.sub.3)
[0306] (2R)-2-(2-Fluoro 4-nitrothenyl)amino-3-methyl-1-butanol
(Structure 36 of Scheme VIII, where R.sup.4=isopropyl). This
compound was prepared according to General Method 18 (EXAMPLE 45)
from 3,4-difluoronitrobenzene (9.9 g, 62 mmol),
R-2-amino-3-methyl-1-butanol (5.00 g, 48.5 mmol) in 6 mL EtOH
heated at reflux for 22 h to afford 8.3 g (71%) of
(2R)-2-(2-fluoro-4-nitrophenyl)amino-3-methyl-1-butanol, a yellow
solid, after flash chromatography. Data for
(2R)-2-(2-fluoro-4-nitrophenyl)amino-3-methyl-1-butanol: R.sub.f
0.8 (1:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.00-7.96 (m, 1H), 7.90 (dd, 1H, J=11.6, 2.4), 6.73 (dd, 1H J=8.5,
8.5), 4.75-4.69 (m, 1H),3.87-3.79 (m, 1H), 3.79-3.70 (m, 1 H),
3.47-3.39 (m, 1H), 2.06-1.97 (m, 1H), 1.03 (d, 3H, J=3.6), 1.01 (d,
3H, J=3.6).
[0307]
(4R)-3-(2-Fluoro-4-nitrophenyl-4-isopropyl-2-(trifluoromethyl)-1,3-
-oxazolidine (Structure 37 of Scheme VIII, where R.sup.4=isotropyl,
R.sup.x.dbd.CF.sub.3. This compound was prepared according to
General Method 19 (EXAMPLE 45) from
(2R)-2-(2-fluoro-4-nitrophenyl)amino-3-methyl-1-butanol (8.3 g, 34
mmol) trifluoroacetaldehyde ethyl hemiacetal (86.4 g, 0.600 mol)
and p-toluenesulfonic acid (20 mg, 0.10 mmol) in 220 mL benzene to
afford 5.2 g (47%) of
(4R-3-(2-fluoro-4-nitrophenyl)4-isopropyl-2-trifluoromethyloxazolidine.
Data for
(4R)-3-(2-fluoro-4-nitrophenyl)-4-isopropyl-2-trifluoromethyloxa-
zolidine: R.sub.f0.7 (3:1 hexanes:EtOAc); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.04-7.97 (m, 2H), 7.22 (dd, 1H, J=8.7, 8.7),
5.34 (quartet, 1 H, J=4.6), 4.27 (dd, 1H, J=8.0, 8.0), 4.11 (dd,
1H, J=7.4, 7.4), 3.81 (quartet, 1H, J=7.1), 2.02-1.93 (m, 1H), 0.96
(d, 6H, J=6.8).
[0308]
(2R)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1--
butanol (Structure 38 of Scheme VIII, where R.sup.4=isopropyl,
R.sup.x.dbd.CF.sub.1. To a solution of
(4R)-3-(2-fluoro-4-nitrophenyl)-4-isopropyl-2-trifluoromethyloxazolidine
(1.8 g, 5.6 mmol) and Et.sub.3SiH (1.88 g, 16.1 mmol) in 15 mL
CHCl.sub.3 was added TiCl.sub.4 (6. mL of a 1M solution in
CH.sub.2Cl.sub.2, 6 mmol) at -78.degree. C. The solution was
stirred for 2 h, then allowed to warm to 0.degree. C. and stirred
for 2 h. The mixture was poured into 150 mL water and neutralized
with 6N NaOH. The aqueous layer was extracted with CHCl.sub.3
(3.times.100 mL), and the combined organic layers washed with brine
(150 mL), dried over MgSO.sub.4, filtered and concentrated. Flash
chromatography (gradient elution, hexanes:EtOAc 9:1 to 3:1)
afforded 1.6 g (88%) of
(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol-
, an orange oil. Data for
(2R-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol:
R.sub.f0.3 (3:1 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.96 (dd, 1H, J=8.8, 2.3), 7.92 (dd, 1H, J=13.4,2.5), 7.37
(dd, 1H, J=8.8, 8.8), 4.334.23 (m, 1H), 4.03-3.86 (m, 2H),
3.81-3.74 (m, 1H), 3.36-3.27 (m, 1H), 1.97-1.88 (m, 1H), 1.85
(broads, 1H), 0.99 (d, 3H, J=6.6), 0.94 (d, 3H, J=6.6).
[0309]
(3R)-3,4-Dihydro-3-isopropyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1-
,4-benzoxazine (Structure 39 of Scheme VIII, where
R.sup.4=isopropyl, R.sup.x.dbd.CF.sub.3. This compound was prepared
according to General Method 20 (EXAMPLE 45) from
(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol
(1.58 g, 4.87 mmol) in 30 mL THF and NaH (0.351 g, 14.6 mmol) in 10
mL THF heated at reflux for 0.5 hr to afford 0.80 g (54%) of (3R)3
,4-dihydro-3-isopropyl-7-nnitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazi-
ne, a yellow oil, after purification by flash chromatography
(gradient elution, hexanes:EtOAc 9:1 to 3:1). Data for
(3R)-3,4-dihydro-3-isopropyl-7-nitro
(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: R.sub.f0.5 (3:1
hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.81 (dd,
1H, J=9.1, 2.5), 7.72 (d, 1H, J=2.6), 6.79 (d, 1H, J=9.1), 4.49
(dd, 1H, ABX, J=11.1, 0.92), 4.37-4.26 (m, 1H), 3.95 (dd, 1H,
J=11.1, 2.4), 3.80-3.69 (m, 1H), 3.14 (d, 1H, J=8.5), 2.08-1.98 (r,
1H), 1.0 1 (d, 3H, J=6.9), 0.99 (d, 3H, J=6.9).
[0310]
(3R)-7-Amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1-
,4-benzoxazine (Structure 40 of Scheme VIII, where
R.sup.4=isopropyl R.sup.x'CF.sub.3). This compound was prepared
according to General Method 4 (EXAMPLE 1) from
(3R)-3,4-dihydro-3-isopropyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benz-
oxazine (0.350 g, 1.15 mmol) and 10% Pd/C (0.14 g) in 7 mL EtOAc to
afford 0.284 g (90%) of
(3R)-7-amino-3,4-dihydro-3-isopropyl-4-(2,2,2)-trifluoroethyl)-2H-1,4-ben-
zoxazine after purification by flash chromatography (gradient
elution, hexanes:EtOAc 9:1 to 3:1). Data for
(3R)-7-amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benz-
oxazine: R.sub.f0.2 (3:1 hexanes:EtOAc); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.71 (d, 1H, J=8.5), 6.27 (dd, 1H, J=8.5, 2.6),
6.20 (d, 1H, J=2.5), 4.34 (dd, 1H, ABX, J=11.0, 1.5), 3.84 (dd, 1H,
ABX, J=11.3, 2.2), 3.71-3.47 (m, 2H), 3.41 (broad s, 2H), 2.62 (d,
1H, J=9.8), 1.81-1.70 (m, 1H), 0.98 (d, 3H, J=6.7), 0.96 (d, 3H,
J=6.7).
[0311]
(2R)-1,2,3,6-Tetrahydro-2-isopropyl-1-(2,2,2-trifluoroethyl)-9-(tr-
ifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 151.
Structure 41 of Scheme VIII, where R.sup.1.dbd.H,
R.sup.2=trifluoromethyl. R.sup.4=isopropyl. R.sup.x.dbd.CF.sub.3).
This compound was prepared according to General Method 11 (EXAMPLE
22) from
(3R)-7-amino-3,4-dihydro-3-isopropyl4-(2,2,2-trifluoroethyl)-2H-1,4-benzo-
xazine (0.284 g, 1.04 mmol) and ethyl 4,4,4-trifluoroacetoacetate
(0.573 g, 3.11 mmol) in 8 mL toluene followed by workup and
treatment with 6 mL conc. sulfuric acid to afford 0.15 g (38/o) of
Compound 151, a yellow solid, after flash chromatography (19:1
CH.sub.2Cl.sub.2:MeOH). Further purification was performed by
reverse phase HPLC (ODS, 5 micron, 10.times.250 mm), 80%
MeOH:water, 2.6 mL/min). Data for Compound 151: R.sub.f0.2 (19:1
CH.sub.2Cl.sub.2; MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
12.52 (broad s, 1H), 7.14 (broad s, 1H), 6.95 (s, 1H), 6.92 (s,
1H), 4.50 (d, 1H, J=11.0), 4.18-4.06 (m, 1H), 4.05 (dd, 1H, ABX,
J=11.0, 2.5), 3.75-3.60 (m, 1H), 2.98 (d, 1H, J=8.7), 1.98-1.88 (m,
1H), 1.00 (d, 3H, J=7.3), 0.98 (d, 3H, J=7.3).
EXAMPLE 49
(.+-.)-1,2,3,4,4a,5-Hexahydro-11-(trifluoromethyl)-pyrido[1',2',4,5][1,4]o-
xazino[3,2-g]quinolin-9(8H)-one (Compound 152, Structure 41 of
Scheme VIII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.4,
R.sup.x.dbd.--(CH.sub.2).sub.3)
[0312] (.+-.)-[1-(2-Fluoro-4-nitrophenyl)-2-piperidinyl]-methanol]
(Structure 42 of Scheme IX, where R.sup.4,
R.sup.x.dbd.--(CH.sub.2).sub.4--). A solution of
3,4-difluoronitrobenzene (1.00 g, 6.28 nmuol) and
(.+-.)-2-piperidinemethanol (0.724 g, 6.28 mmol) in 1.5 mL EtOH was
heated at 50.degree. C. for 18 h, then heated at reflux for 24 h.
The solvent was concentrated and the crude reaction purified by
flash chromatography (7:3 hexanes:EtOAc) to afford 0.85 g (53%) of
(.+-.)-[1-(2-fluoro-4-nitrophenyl)-2-piperidinyl]-methanol], an
orange oil. Data for
(.+-.)-[1-(2-fluoro-4-nitrophenyl)-2-piperidinyl]-methanol]:
R.sub.f0.36 (3:7, EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.95 (dd, 1H, J=8.8,2.4), 7.88 (dd, 1H, J=13.2, 2.4), 7.01
(t, 1H, J=8.8), 4.04-3.97 (m, 2H), 3.74-3.68 (m, 1H), 3.45-3.42 (m,
1H), 3.34-3.28 (m, 1H), 1.89-1.82 (m, 1H), 1.77-1.61 (m, 6H).
[0313]
(.+-.)-3-Nitro-6,6a7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine
(Structure 39 of Scheme IX, where R.sup.4,
R.sup.x.dbd.(CH.sub.2).sub.4--). A suspension of
(+)[1-(2-fluoro-4-nitrophenyl)-2-piperidinyl]-methanol (0.586 g,
2.30 mmol) and sodium hydride (60% mineral oil suspension, 0.101 g,
2.54 mmol) in 10 mL THF was heated at reflux for 16 h. The mixture
was neutralized with phosphate buffer (pH 7), and the resultant
solution was extracted twice with EtOAc. The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Flash chromatography (7:3
hexanes:EtOAc) afforded 0.410 g (76%) of
(.+-.)-3-nitro-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine,
a yellow-orange solid. Data for
(.+-.)-3-nitro-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine:
R.sub.f0.71 (2:3, EtOAc:hexanes) .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.78 (dd7, 1H, J=9.3, 2.9), 7.64 (d, 1H, J=2.9), 6.75 (dc,
1H, J=9.3), 4.23 (dd, 1H, J=10.7, 2.9), 3.96 (dd, 1H, J=10.7, 7.8),
3.93 (m, 1H), 3.22-3.17 (m, 1H), 2.78 (td, 1H, J=12.8, 3.0),
1.95-1.92 (m, 1H), 1.88-1.84 (m, 1H), 1.75-1.71 (m, 1H), 1.66-1.60
(m, 1H), 1.58-1.48 (m, 1H), 1.35-1.27 (m, 1H).
[0314]
(.+-.)-3-Amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazin-
e, Structure 40 of Scheme VIII, where R.sup.4,
R.sup.x.dbd.--(CH.sub.2).sub.3--). This compound was prepared
according to General Method 4 (EXAMPLE 1) from
(.+-.)-3-nitro-6,6a,7,8,9,10-hexahydropyrido]2,1-c][1,4]benzoxazine
(0.300 g, 1.30 mmol) to afford 0.232 g (88%) of
(.+-.)-amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine,
a colorless oil, after flash chromatography (gradient elution 3:7
EtOAc:hexanes, then 3:2 EtOAc: hexanes). Data for
(.+-.)-3-amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine:
R.sub.f0.5 (2:3, EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.66 (d, 1H, J=8.3), 6.24 (dd, 1H, J=8.5, 2.7), 6.21 (d,
1H, J=2.4), 4.11 (dd, 1H, J=10.7, 2.4), 3.97 (dd, 1H, J=10.7, 9.0),
3.69 (dd, 1H, J=13.7, 11.2),3.33 (br s, 2H), 2.85-2.80 (m, 1H),
2.43 (td, 1H, J=11.7, 2.9), 1.87-1.78 (m, 2H), 1.69-1.60 (m, 2H),
1.45-1.36 (m, 1H), 1.28-1.19 (mt 1H).
[0315]
(.+-.)-1,2,3,4,4a,5-Hexahydro-11-(trifluoromethyl)-pyrido[1',2':4,-
5][1,4]oxazino[3,2-g]quinolin-9(8H)-one (Compound 152, Structure 41
of Scheme VIII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.4, R.sup.x=--(CH.sub.2).sub.3--). This compound was prepared
according to General Method 11 (EXAMPLE 22) from
(.+-.)3-amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine
(0.232 g, 1.13 mmol), ethyl 4,4,4-trifluoroacetoacetate (0.250 g,
1.36 mmol) in 11 mL benzene followed by treatment with conc.
H.sub.2SO.sub.4 to afford 0.110 g (30%) of Compound 152, a yellow
fluffy solid. Data for Compound 152: R.sub.f0.15 (2:3,
EtOAc:hexanes); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.73 (br
s, 1 H), 7.09 (s, 1H), 6.87 (s, 1H), 6.73 (s, 1H), 4.26 (dd, 1H,
J=10.5, 2.6), 4.06 (dd, 1H, J=10.5, 9.0), 3.80 (m, 1H), 3.02-2.97
(m, 1H), 2.60 (td, 1H, J=12.2, 2.9), 1.92 (m, 2H), 1.74-1.65 (m,
2H), 1.50-1.42.(m, 1H), 1.29-1.21 (m, 1H).
EXAMPLE 50
(R)-2,3,3a,4-Tetrahydro-10-(trifluoromethyl)-1H-pyrrolo[1',2':4,5][1,4]oxa-
zino[3,2-g]quinolin-8(7H)-one (Compound 153, Structure 41 of Scheme
VIII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.4,
R.sup.x.dbd.--CH.sub.2).sub.2--)
[0316] (R)-[1-(2-Fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol
(Structure 42 of Scheme IX, where R.sup.4,
R.sup.x.dbd.--(CH.sub.2).sub.2--). A suspension of
3,4-difluoronitrobenzene (1.57 g, 9.8 mmol),
(R)-2-pyrrolidinemethanol (1.0 g, 9. 8 mmol) and K.sub.2CO.sub.3
(1.36 g, 9.8 mmol) in 30 mL DMF was heated at 75.degree. C. for 20
h, whereupon the mixture was partitioned between water (100 mL) and
EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100
mL), and the combined organic layers washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Flash chromatography
(19:1 CH.sub.2Cl.sub.2 :MeOH) afforded 2.27 g (96%) of
(R)-[1-(2-fluoro-4-nitrophenyl)-2-pyriolidinyl]-methanol, an orange
solid. Data for
(R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol:
R.sub.f0.17 (7:3 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.94 (dd, 1H, J=9.1, 2.6), 7.89 (dd, 1H, J=14.4, 2.6), 6.68
(t, 1H, J=9.0), 4.25-4.32 (m, 1H), 3.60-3.75 (m, 3H), 3.40-3.50 (m,
1H), 1.95-2.15 (m, 4H), 1.43 (t, 1H, J=5.8).
[0317]
(R)-2,3,3a,4-Tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine
(Structure 42 of Scheme IX, where R.sup.4,
R.sup.x.dbd.--(CH.sub.2).sub.2--). A suspension
of(R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol (2.27 g,
9.4 mmol) and NaH (60% mineral oil suspension, 0.737 g, 18.9 mmol)
in 35 mL THF was heated at reflux for 1 h. The reaction was
quenched with phosphate buffer, and the aqueous layer was extracted
with EtOAc. The solution was filtered through Celite, and the
organic layer was washed with brine, dried over MgSO.sub.4,
filtered, and concentrated. Flash chromatography (3:2
EtOAc:hexanes) afforded 476 mg (22%) of
(R)-2,3,3a,4-tetaahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine,
an orange solid. Data for
(R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine:
R.sub.f0.55 (3:2hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.87 (dd, 1H, J=9.2, 2.4), 7.74 (d, 1H, J=2.4), 6.44 (d,
1H, J=8.8), 4.56 (dd, 1H, J=10.3, 3.4), 3.65-3.72 (m, 1H), 3.60
(broad t, 1H, J=8.6), 3.44 (t, 1H, J=10.0), 3.36 (td, 1H, J=9.8,
7.3), 2.15-2.25 (m, 2H), 2.05-2.15 (m, 1H), 1.45-1.55 (m, 1H).
[0318]
(R)-7-Amino-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine
(Structure 40 of Scheme VIII, where R.sup.4,
R.sup.x.dbd.--(CH.sub.2).sub.2--). This compound was prepared
according to General Method 4 (EXAMPLE 1) from
(R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine
(0.470 g, 2.10 mmol) to afford 0.39 g (98%) of
(R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine.
Data for
(R)-7-amino-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine:
R.sub.f0.55 (3:2 hexanes:EtOAc); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.50 (d, 1H, J=8.3), 6.32 (d, 1H, J=2.4), 6.29 (dd, 1H,
J=8.3, 2.4), 4.31 (dd, 1H, J=8.3, 1.5), 3.37-3.50 (m, 3H), 3.31
(broad s, 2H), 3.13 (broad q, 1H, J=8.3), 2.07-2.15 (m, 1H),
1.90-2.05 (m, 2H), 1.40-1.50 (m, 1H).
[0319]
(R)-2,3,3a,4-Tetrahydro-10-(trifluoromethyl)-1H-pyrrolo[1',2':4,5]-
[1,4]oxazino[3,2-g]quinolin-8(7H-one (Compound 153, Structure 41 of
Scheme VIII, where R.sup.1.dbd.H, R.sup.2=trifluoromethyl, R.sup.4,
R.sup.x.dbd.--(CH.sub.2).sub.2. This compound was prepared
according to General Method 11 (EXAMPLE 22) from (R)-7-amino-2,3
,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine (0.390 g, 2.05
mmol) and ethyl 4,4,4-trifluoroacetoacetate (0.378 g, 2.05 mmol) in
14 mL benzene, followed by workup and treatment with 7 mL
concentrated sulfuric acid to afford 120 mg (20%) of Compound 153,
a yellow solid after flash chromatography (92:8
CH.sub.2Cl.sub.2:MeOH). Further purification was performed by
reverse phase HPLC (ODS, 5 micron, 10.times.250 mm, 3 mL/min). Data
for Compound 153: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.42
(broad s, 1H), 6.91 (s, 1H), 6.89 (s, 1 H), 6.76 (broad s, 1H),
4.54 (dd, 1H, J=9.6, 2.7), 3.61 (t, 1H, J=9.6), 3.50-3.60 (m, 1H),
3.40-3.50 (m, 1H), 3.30-3.40 (m, 1H), 2.12-2.22 (m, 2H), 2.00-2.10
(m, 1 H), 1.40-1.50 (m, 1 H).
EXAMPLE 51
1,3,4,6-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quino-
lin-2,7-dione (Compound 154, Structure 47 of Scheme X, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.R.sup.7.dbd.R.sup.13=Me)
[0320] 3,4-Dihydro-3,3-dimethylquinoxalin-2(1H)-one (Structure 44
of Scheme X, where R.sup.6.dbd.R.sup.7=Me). In a 200-mL r.b. flask,
a solution of 1,2-phenylenediamine (2.12 g, 19.6 mmol),
diisopropylethylamine (4.55 ml, 25.5 mmol, 1.3 equiv),
ethyl-2-bromoisobutyrate (4.97 mL, 25.5 mmol, 1.3 equiv) in DMF (20
mL) was heated to 110.degree. C. overnight, cooled, partitioned
between EtOAc (100 mL) and H.sub.2O (30 mL). The aqueous layer was
extracted with EtOAc (2.times.50 mL). The combined organic layers
were washed sequentially with 1 M HCl (40 mL), H.sub.2O (40 mL),
saturated NaHCO.sub.3 (40 ml), H.sub.2O (40 mL) and brine (30 mL),
dried (MgSO.sub.4), filtered, and concentrated. The crude product
was purified by recrystallization (CH.sub.2Cl.sub.2/hexane) to give
2.09 g (60%) of 3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one as
white crystals. Data for
3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.84 (bs, 1H), 6.89 (dd, J=7.3, 7.3, 1H), 6.76
(dd, J=7.2, 7.3, 1H), 6.70 (d, J=7.6, 1H), 6.67 (d, J=6.9, 1H),
3.69 (bs, 1H), 1.41 (s, 6H).
[0321] 3,4-Dihydro-1,3,3-trimethylquinoxalin-2(1h)-one. In a 200-mL
r.b. flask, a solution of
3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one (1.00 g,5.66 mmol) in
dry THF was treated with NaH (0.28 g, 7.09 mmol, 1.25 equiv). The
reaction mixture was stirred at room temperature for 30 minutes
before iodomethane (0.39 mL, 6.24 mmol, 1.1 equiv) was added to the
reaction flask. The reaction was then stirred at room temperature
overnight then partitioned between EtOAc (100 mL) and H.sub.2O (20
mL). The aqueous layer was extracted with EtOAc (2.times.30 mL).
The combined organic layers were then washed with brine (20 mL),
dried (MgSO.sub.4), filtered, and concentrated to a thick oil.
Purification by flash chromatography (25% EtOAc/hexane) afforded
830 mg (78%) of 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one as
a white solid. Data for
3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 6.90 (m, 3H), 6.67 (d, J=7.7, 1H), 3.69
(bs, 1H), 3.36 (s 3H), 1.37 (s, 6H).
[0322] 3,4-Dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)one
(Structure 45 of Scheme X, where
R.sup.6.dbd.R.sup.7.dbd.R.sup.13=Me). In a 50-mL r.b. flask, a
solution of 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one (830
mg, 4.36 mmol) in 20 mL of conc. HiSO.sub.4 was cooled to
-15.degree. C. A solution of HNO.sub.3 (336 mg, 4.80 mmol, 1.1
equiv) dissolved in conc. H.sub.2SO.sub.4 (1 mL) was then added
dropwise via syringe in order to maintain a temperature below
-5.degree. C. After complete addition the reaction was allowed to
stir at -15.degree. C. for 15 min, warmed to rt, poured over NaOH
(15 g) pellets and ice. After complete solution of the NaOH
pellets, the red precipitate was filtered, redissolved in EtOAc
(150 mL), washed with H.sub.2O (20 mL), brine (20 mL), dried
(MgSO.sub.4), filtered, and concentrated to give a orange solid. No
further purification is required to obtain 960 mg (94%) of
3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one as an
orange solid. Data for
3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.76 (dd, J=8.8,2.5, 1H), 7.55
(d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 4.04 (bs, 1H), 3.42 (s, 3H),
1.41 (s, 6H).
[0323] 6-Amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one
(Structure 46 of Scheme X, where
R.sup.6.dbd.R.sup.7.dbd.R.sup.13=Me). In a Parr shaker apparatus, a
solution 3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one
(96.0 mg, 4.08 mmol) in 50 mL of EtOAc:EtOH (1:1) and a catalytic
amount of 10% Pd on activated carbon (96 mg, 10 wt-%) were shaken
under an atmosphere of hydrogen gas at 45 psi overnight. The
reaction mixture was filtered through a pad of celite. The filtrate
and EtOH washings were combined and concentrated to give 838 mg
(100%) of 6-amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one,
purple brown solid. Data for
6-amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 6.69 (d, J=8.42, 1H), 6.19 (dd,
J=8.5, 2.4, 1H), 6.05 (d, J=2.4, 1H), 3.55 (bs, 1H), 3.31 (s, 3H),
1.35 (s, 6H).
[0324]
1,3,4,6-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-
-g]quinolin-2,7-dione (Compound 154, Structure 47 of Scheme X,
where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.R.sup.7.dbd.R.sup.13=R =Me). In a 100-mL r.b. flask, a
solution of 6-amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one
(500 mg, 2.44 mmol) and ethyl-4,4,4-trifluoroacetoacetate (0.46 mL,
3.16 mmol, 1.3 equiv) in toluene (40 mL) was heated to reflux with
stirring overnight. Removal of solvent followed be treatment of the
crude product with conc H.sub.2SO.sub.4 (10 mL) at 100.degree. C.
for 10 h, cooled to rt, poured onto ice and the pH adjusted to 7
with NaOH pellets. The aqueous phase was extracted with EtOAc
(4.times.50 mL), combined, washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to a brown oil. Purification by flash
chromatography (EtOAc/hexane, 25% to 50%, gradient elution)
afforded 80 mg (10%) of Compound 154 as a yellow solid. Data for
Compound 154: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.07 (s,
1H), 7.22 (s, 1H), 7.01 (s, 1H), 6.73 (s, 1H), 6.61 (s, 1H), 3.30
(s, 3H), 1.29 (s, 6H).
EXAMPLE 52
1,2,3,4-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quino-
lin-7(6H)-one (Compound 155, Structure 49 of Scheme X, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.R.sup.7.dbd.R.sup.13=Me)
[0325]
1,2,3,4-Tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl-
)pyrazino[3,2-g]quinolin-2-one (Structure 48 of Scheme X, where
R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.R.sup.7.dbd.R.sup.13=Me). This compound was made
according to General Method 12 (EXAMPLE 22) from Compound 154
(EXAMPLE 51) (40 mg, 0.12 mmol), cesium fluoride (28 mg, 0.18 mmol,
1.5 equiv), and 2-iodopropane (0.02 mL, 0.18 mmol, 1.5 equiv). The
crude reaction mixture was purified by silica gel chromatography
(EtOAc/hexane, 25% to 50% gradient elution) to afford 26 mg (56%)
of
1,2,3,4-tetrahydro-7-isoprooxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazin-
o[3,2-g]quinolin-2-one as an off-white solid. Data for
1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazi-
no[3,2-g]quinolin-2-one: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.34 (s, 1H), 7.06 (s, 1H), 6.96 (s, 1H), 5.49 (sep, J=6.3, 1H),
4.17 (s, 1H), 3.47 (s, 3H), 1.45 (s, 6H), 1.39 (d, J=6.3, 6H).
[0326]
1,2,3,4-Tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl-
)pyrazino[3,2-g]quinoline. This compound was made according to
General Method 2 (EXAMPLE 1) from
1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazi-
no[3,2-g]quinolin-2-one (25 mg, 0.07 mmol) and BH.sub.3-DMS (0.14
mL, 0.27 mmol, 4.0 equiv). Purification by silica gel
chromatography (EtOAc/hexane, 10% to 25% gradient) afforded 5 mg
(25%) of
1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazi-
no[3,2-g]quinoline as a pale yellow solid. Data for
1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazi-
no[3,2-g]quinoline: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.84
(s, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 5.43 (sept, J=6.1, 1H), 3.04
(s, 2H), 3.02 (s, 3H), 1.39 (d, J=6.0, 6H), 1.29 (s, 6H).
[0327]
1,2,3,4-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-
-g]quinolin-7(6H)-one (Compound 155, Structure 49 of Scheme X,
where R.sup.1.dbd.H, R.sup.2=trifluoromethyl,
R.sup.6.dbd.R.sup.7.dbd.R.sup.13=Me). This compound was made
according to General Method 15 (EXAMPLE 22) from
1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazi-
no[3,2-g]quinoline (5 mg, 0.02 mmol) to yield 2 mg (45%) of
Compound 155, a yellow solid. Data for Compound 155: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.75 (broad s, 1H), 6.97 (s, 1H),
6.37 (s, 1H), 5.23 (bs, 1H), 2.86 (s, 2H), 2.82 (s, 3H), 1.17 (s,
6H).
EXAMPLE 53
9-(Trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-o-
ne (Compound 156, Structure 54 of Scheme XI, where
R.sup.4.dbd.H)
[0328] 6-Bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline
(Structure 51 of Scheme XI). This compound was prepared according
to General Method II (EXAMPLE 22) from 4-bromo-3-chloroaniline
(2.06 g, 10.0 mmol),, ethyl 4,4,4-trifluoroacetoacetate (2.30 g,
12.5 mmol) in 50 mL toluene followed by heating in 33 mL conc.
H.sub.2SO.sub.4 to afford 2.08 g (64%) of
6-bromo-7-chloro-4-(trifluoromethyl)-quinolin-2(1H)-one, an
off-white solid. This material was converted to the corresponding
imino ether according to General Method 12 (EXAMPLE 22) with
isopropyl iodide (4.32 g, 25.4 mmol) and CsF (3.85 g, 25.4 mmol) in
32 mL DMF to afford 1.34 g (57%) of
6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline, a white
solid, after flash chromatography (hexanes). Data for
6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (broad s, 1H), 8.00 (s, 1
H), 7.17 (s, 1H), 5.51 (hept, 1H, J=6.2), 1.40 (d, 6H, J=6.2).
[0329]
2-{[6-Bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl-
}-1-ethanamine (Structure 52 of XI, where R.sup.4.dbd.H). A
solution of
6-bromo-7-chloro-2-isopropoxy-4-trifluoromethyl)quinoline (0.500 g,
1.36 mmol), 2-aminoethanethiol hydrochloride (0.185 g, 1.63 mmol),
NaH (60% in mineral oil, 0.136 g, 3.40 mmol) in 6.8 mL DMF was
stirred at 0.degree. C., then allowed to warm to rt After 4 h, the
mixture was poured into a cold saturated NH.sub.4Cl:water (60 mL,
1:1). The solution was extracted with EtOAc (2.times.60 mL), and
the combined organic layers washed sequentially with water (30 mL),
brine (30 mL), dried over MgSO.sub.4, filtered, and concentrated.
Flash chromatography (9:1 CH.sub.2Cl.sub.2:MeOH) afforded 0.404 g
(73%) of
2-{[6-bromo-2-isopropoxy-4-trifluoromethyl)-7-quinolinyl]sulfanyl}-1-etha-
namine, a yellow-brown solid. Data for
2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-eth-
anamine: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (broad s,
1H), 7.63 (s, 1H), 7.10 (s, 1H), 5.54 (hept, 1H, J=6.2), 3.17-3.25
(m, 2H), 3.08-3.15 (m, 2H), 1.41 d, 6H, J=6.2).
[0330]
2,3-Dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2--
g]quinoline (Structure 53 of Scheme XI, where R.sup.4.dbd.H). A 10
mL Schlenk flask was charged with palladium acetate (10.7 mg,
0.0476 mmol), R-BINAP (32.6 mg, 0.0524 mmol) and sodium t-butoxide
(0.137 g, 1.43 mmol). The flask was placed under vacuum, then bled
with nitrogen. This process was repeated twice. The solids were
dissolved in 3 mL toluene, and a solution of
2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-eth-
anamine (0.390 g, 0.953 mmol) in 3.3 mL toluene was added. The
flask was heated to 100.degree. C. for 4 h, whereupon the reaction
was quenched with sat'd NH.sub.4Cl (30 mL) and water (30 mL). The
mixture was extracted with EtOAc (2.times.60 mL), and the combined
organic layers washed with brine (30 mL), dried over MgSO.sub.4,
filtered, and concentrated. Flash chromatography (4:1
hexanes:EtOAc) afforded 0.242 g (77%) of
2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,-
2-g]quinoline, a yellow solid. Data for
2,3-dihydro-7-isopropoxy-9-trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinol-
ine: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.56 (s, 1H),
6.99.(s, 1H), 6.90 (broad s, 1H), 5.44 (hept, 1H, J=6.2), 4.35
(broad s, 1H), 3.64-3.70 (m, 2H), 3.11-3.16 (m, 2H), 1.37 (d, 6H,
J=6.2).
[0331]
9-(Trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quin-
olin-7-one (Compound 156, Structure 54 of Scheme XI, where
R.sup.4.dbd.H). This compound was prepared according to General
Method 15 (EXAMPLE 22) from
2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[;3,2-g-
]quinoline (15 mg, 0.046 mmol) and 0.15 mL conc. HCl and 0.5 mL
HOAc to afford 12 mg (91%) of Compound 156, a yellow solid. Data
for Compound 156: .sup.1H NMR (400 MHz, ace-d.sub.6) .delta. 10.8
(v broad s, 1H), 7.12 (s, 1H), 6.92 (broad s, 1H), 6.75 (s, 1H),
5.74 (broad s, 1H), 3.58-3.64 (m, 2H), 3.12-3.20 (m, 2H).
EXAMPLE 54
1-Methyl-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]qui-
nolin-7-one (Compound 157, Structure 56 of Scheme XI, where
R.sup.4.dbd.H, R.sup.x=Me)
[0332]
2,3-Dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thia-
zino[3,2-g]quinoline (Structure 55 of Scheme XI, where
R.sup.4.dbd.H, R.sup.x=Me). To a solution of
2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quino-
line (11 mg, 0.033 mmol) and paraformaldehyde (9.9 mg, 0.33 mmol)
in 0.5 mL acetic acid was added NaBH.sub.3CN (12 mg, 0.19 mmol).
After 16 h, the solution was quenched with sat'd NaHCO.sub.3 (20
mL), and was extracted with EtOAc (20 mL). The organic layer was
washed sequentially with sat'd NaHCO.sub.3 (10 mL) and brine (10
mL), dried over MgSO.sub.4, filtered and concentrated to afford 11
mg (97%) of
2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,-
2-g]quinoline, a yellow solid. Data for
2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-(1,4]thiazino[3,-
2-g]quinoline: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (s,
1H), 7.01 (s, 1H), 6.98 (broad s, 1H), 5.45 (hept, 1H, J=6.2),
3.58-3.64 (m, 2H), 3.14-3.20 (m, 2H), 3.05 (s, 3H), 1.37 (d, 6H,
J=6.2).
[0333]
1-Methyl-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3-
,2-g]quinolin-7-one (Compound 157, Structure 56 of Scheme XI, where
R.sup.4.dbd.H, R.sup.x.dbd.H). This compound was prepared according
to General Method 15 (EXAMPLE 22) from
2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,-
2-g]quinoline (11 mg, 0.032 mmol) and 0.2 mL HCl and 0.6 mL HOAc
heated at 80.degree. C. for 3 h to afford 7 mg (73%) of Compound
157, a yeUow solid, after flash chromatography (23:2
CH.sub.2Cl.sub.2:MeOH). Data for Compound 157: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 11.5 (broad s, 1H), 7.11 (s, 1H), 6.95 (s,
1H), 6.90 (broad s, 1H), 3.52-3.60 (m, 2H), 3.15-3.20 (m, 2H), 3.01
(s, 3H).
EXAMPLE 55
1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]th-
iazino[3,2-g]quinolin-7-one (Compound 158, Structure 56 of Scheme
XI, where R.sup.4.dbd.H, R.sup.x.dbd.CF.sub.3)
[0334]
2,3-Dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluorometh-
yl)-1H-[1,4]thiazino[3,2-g]quinoline (Structure 55 of Scheme XI,
where R.sup.4.dbd.H, R.sup.x.dbd.CF.sub.3). This compound was
prepared according to General Method 7 (EXAMPLE 5) from
2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quino-
line (11 mg, 0.034 mmol), trifluoroacetaldehyde ethyl hemiacetal
(49 mg, 0.34 mmol) and NaBH.sub.3CN (14 mg, 0.22 mmol) in 0.7 mL
TFA to afford 7.8 mg (56%) of
2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H--
[1,4)thiazino(3,2-g]quinoline, a yellow oil, after flash
chromatography (9:1 hexanes:EtOAc). Data for
2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H--
[1,4]thiazino[3,2-g]quinoline: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.62 (s, 1H), 7.21 (broad s, 1H), 7.0; (s, 1H), 5.46 (hept,
1H, J=6.1), 3.97 (q, 2H, J=8.8), 3.77-3.83 (m, 2H), 3.08-3.14 (m,
2H), 1.38 (d, 6H, J=6.1).
[0335]
1-2,2,2-Trifluoroethyl)-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H--
[1,4]thiazino[3,2-g]quinolin-7-one (Comnound 158, Structure 56 of
Scheme XI, where R.sup.4.dbd.H, R.sup.x.dbd.CF.sub.3). This
compound was prepared according to General Method 15 (EXAMPLE 22)
from
2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H--
[1,4]thiazino[3,2-g]quinoline (7.8 mg, 0.019 mmol) in 0.2 mL HCl
and 0.6 mL HOAc to afford 3.6 mg (51%) of Compound 158, a yellow
solid, afat flash chromatography (23:2 CH.sub.2Cl.sub.2:MeOH). Data
for Compound 158: .sup.1H NMR (400 MHz, ace-d.sub.6) .delta. 10.8
(broad s, 1H), 7.21 (s, 1H), 7.15 (broad s, 1H), 6.80 (s, 1H), 4.18
(q, 2H, J=9.3), 3.77-3.83 (m, 2H), 3.18-3.24 (m, 2H).
EXAMPLE 56
Steroid Receptor Activity
[0336] Utilizing the "cis-trans" or "co-transfection" assay
described by Evans et al., Science, 240:889-95 (May 13, 1988), the
disclosure of which is herein incorporated by reference, the
compounds of the present invention were tested and found to have
strong, specific activity as both agonists, partial agonists and
antagonists of AR. This assay is described in further detail in
U.S. Pat. Nos. 4,981,784 and 5,071,773, the disclosures of which
are incorporated herein by reference.
[0337] The co-transfection assay provides a method for identifying
functional agonists and partial agonists that mimic, or antagonists
that inhibit, the effect of native hormones, and quantifying their
activity for responsive IR proteins. In this regard, the
co-transfection assay mimics an in vivo system in the laboratory.
Importantly, activity in the co-transfection assay correlates very
well with known in vivo activity, such that the co-transfection
assay functions as a qualitative and quantitative predictor of a
tested compounds in vivo pharmacology. See, e.g. T. Berger et al.
41 J. Steroid Biochem. Molec. Biol. 773 (1992), the disclosure of
which is herein incorporated by reference.
[0338] In the co-transfection assay, a cloned cDNA for an IR (e.g.,
human PR, AR or GR) under the control of a constitutive promoter
(e.g., the SV 40 promoter) is introduced by transfection (a
procedure to induce cells to take up foreign genes) into a
background cell substantially devoid of endogenous IRs. This
introduced gene directs the recipient cells to make the IR protein
of interest. A second gene is also introduced (co-transfected) into
the same cells in conjunction with the IR gene. This second gene,
comprising the cDNA for a reporter protein, such as firefly
luciferase (LUC), controlled by an appropriate hormone responsive
promoter containing a hormone response element (HRE). This reporter
plasmid functions as a reporter for the transcription-modulating
activity of the target IR Thus, the reporter acts as a surrogate
for the products (mRNA then protein) normally expressed by a gene
under control of the target receptor and its native hormone.
[0339] The co-transfection assay can detect small molecule agonists
or antagonists of target IRs. Exposing the transfected cells to an
agonist ligand compound increases reporter activity in the
transfected cells. This activity can be conveniently measured,
e.g., by increasing luciferase production, which reflects
compound-dependent, IR-mediated increases in reporter
transcription. To detect antagonists, the co-transfection assay is
carried out in the presence of a constant concentration of an
agonist to the target IR (e.g., progesterone for PR) known to
induce a defined reporter signal. Increasing concentrations of a
suspected antagonist will decrease the reporter signal (e.g.,
luciferase production). The co-transfection assay is therefore
useful to detect both agonists and antagonists of specific IRs.
Furthermore, it determines not only whether a compound interacts
with a particular IR, but whether this interaction mimics
(agonizes) or blocks (antagonizes) the effects of the native
regulatory molecules on target gene expression, as well as the
specificity and strength of this interaction.
[0340] The activity of selected steroid receptor modulator
compounds of the present invention were evaluated utilizing the
co-transfection assay, and in standard IR binding assays, according
to the following illustrative Examples.
Co-Transfection Assay
[0341] CV-1 cells (African green monkey kidney fibroblasts) were
cultured in the presence of Dulbecco's Modified Eagle Medium (DMEM)
supplemented with 10% charcoal resin-stripped fetal bovine serum
(CH-FBS) then transferred to 96-well microtiter plates one day
prior to transfection.
[0342] To determine AR agonist and antagonist activity of the
compounds of the present invention, the CV-1 cells were transiently
transfected by calcium phosphate coprecipitation according to the
procedure of Berger et al., 41 J. Steroid Biochem Mol. Biol., 733
(1992) with the following plasmids: pRShAR (5 ng/well), MTV-LUC
reporter (100 ng/well), pRS-.beta.-Gal (50 ng/well) and filler DNA
(PGEM; 45 ng/well). The receptor plasmid, pRShAR, contains the
human AR under constitutive control of the SV-40 promoter, as more
fully described in J. A. Simental et al., "Transcriptional
activation and nuclear targeting signals of the human androgen
receptor", 266 J. Biol. Chem, 510 (1991).
[0343] The reporter plasmid, MTV-LUC, contains the cDNA for firefly
luciferase (LUC) under control of the mouse mammary tumor virus
(MTV) long terminal repeat, a conditional promoter containing an
androgen response element. See e.g., Berger et al. suora. In
addition, pRS-.beta.-Gal, coding for constitutive expression of E.
coli .beta.-galactosidase (.beta.-Gal), was included as an internal
control for evaluation of transfection efficiency and compound
toxicity.
[0344] Six hours after transfection, media was removed and the
cells were washed with phosphate-buffered saline (PBS). Media
containing reference compounds (i.e. progesterone as a PR agonist,
mifepristone ((11 beta,
17beta)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9--
dien-3-one: RU486; Roussel Uclaf) as a PR antagonist;
dihydrotestosterone (DHT; Sigma Chemical) as an AR agonist and
2-OH-flutamide (the active metabolite of
2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]pronanamide;
Schering-Plough) as an AR antagonist; estradiol (Sigma) as an ER
agonist and ICI 164,384 (N-butyl-3,17-dihydroxy-N-methyl-(7-alpha,
17-beta)-estra-1,3,5(10)-triene-7-undecanamide; ICI Americas) as an
ER antagonist; dexamethasone (Sigma) as a GR agonist and RU486 as a
GR antagonist; and aldosterone (Sigma) as a MR agonist and
spironolactone
((7-alpha-[acetylthio]-17-alpha-hydroxy-3-oxopregn-4-ene-21-carboxylic
acid gamma-lactone; Sigma) as an MR antagonist) and/or the
modulator compounds of the present invention in concentrations
ranging from 10-12 to 10-5M were added to the cells. Three to four
replicates were used for each sample. Transfections and subsequent
procedures were performed on a Biomek 1000 automated laboratory
work station
[0345] After 40 hours, the cells were washed with PBS, lysed with a
Triton X-100-based buffer and assayed for LUC and &Gal
activities using a luminometer or spectrophotometer, respectively.
For each replicate, the normalized response (NR) was calculated
as:
LUC response/.beta.-Gal rate
where .beta.-Gal rate=.beta.Gal/.beta.-Gal incubation time.
[0346] The mean and standard error of the mean (SEM) of the NR were
calculated. Data was plotted as the response of the compound
compared to the reference compounds over the range of the
dose-response curve. For agonist experiments, the effective
concentration that produced 50% of the maximurn response
(EC.sub.50) was quantified. Agonist efficacy was a function (%) of
LUC expression relative to the maximum LUC production by the
reference agonist for PR, AR, ER, GR or NM Antagonist activity was
determined by testing the amount of LUC expression in the presence
of a fixed amount of DHT as an AR agonist and progesterone as a PR
agonist at the EC.sub.50 concentration. The concentration of test
compound that inhibited 50% of LUC expression induced by the
reference agonist was quantified (IC.sub.50). In addition, the
efficacy of antagonists was determined as a function (%) of maximal
inhibition. TABLE-US-00001 TABLE 1 Agonist, partial agonist,
antagonist and binding activity of androgen receptor modulator
compounds of present invention and the reference agonist compound,
dihydrotestosterone (DHT), and reference antagonists compound,
2-hydroxyflutamide (Flut) and Casodex (Cas), on hAR in CV-1 cells.
AR Agonist AR Antagonist CV-1 Cells CV-1 Cells Cmpd Efficacy
Potency Efficacy Potency No. (%) (nM) (%) (nM) 101 56 18 na na 102
.sup. na.sup.1 na 58 22 103 92 6.4 24 8000 104 na na 68 26 105 88
3.5 na na 106 80 4 na na 107 92 26 na na 108 80 14 na na 109 na na
57 24 110 90 44 na na 111 88 2.4 na na 112 80 2.6 na na 113 na na
78 61 114 94 62 na na 115 82 7.8 na na 116 24 39 35 14 117 36 40 na
na 118 76 11 na na 119 20 39 na na 120 na na 69 112 121 69 1.4 na
na 122 na na 75 632 123 91 3.4 na na 124 54 3.6 na na 125 74 0.70
na na 128 na na 42 1345 129 42 1340 76 13 130 48 8.9 na na 131 46
31 na na 132 72 1.7 na na 137 na na 84 18 145 69 6 30 5024 DHT 100
6 na na Fluox 120 2.8 na na Flut na na 83 25 Cas na na 81 201
.sup.1na = not active (i.e. efficacy of <20 and potency of
>10,000 nM for the cotransfection assay, and Ki > 1000 nM for
the binding assay). nt = not tested.
[0347] TABLE-US-00002 TABLE 2 Overall agonist and antagonist
potency of selected androgen receptor modulator compounds of
present invention and the reference agonist and antagonist
compounds shown in Table 1 on PR, AR, ER, GR and MR. GR MR PR
Potency AR Potency ER Potency Potency Potency Cmpd Agon Antag Agon
Antag Agon Antag Antag Antag No. (nM) (nM) (nM) (nM) (nM) (nM) (nM)
(nM) 101 na na 18 na na na 6500 na 102 na 4100 na 22 na 5900 3200
na 103 na 4500 6.4 8000 na na na na 104 na 2000 na 26 na na 830
1800 105 na 3000 3.5 na na na 6700 na 114 na na 6.2 na na na na na
121 na 415 1.4 na na na 1050 2570 123 na 2470 3.4 na na na 3160 na
137 na na na 18 na na na na Fluox 1210 224 2.8 na na na 263 193
Prog 4 na 1300 na na na na nt RU486 na 0.1 na 12 na 1500 0.7 1100
DHT na 1800 6 na 1700 na na nt Flut na 1900 na 26 na na na na Estr
nt nt na na 7 na na nt ICI 164 na na na na na 160 na na Spir nt 268
nt nt na na 2000 25 na = not active (i.e., efficacy of >20 and
potency of >10,000); nt = not tested.
EXAMPLE 57
[0348] The activity of selected compounds of the present invention
as AR agonists was investigated in an immature castrated male rat
model, a recognized test of the androgen activity of a given
compound, as described in L. G. Hershberger et al., "Myotrophic
Activity of 19-Nortestosterone and Other Steroids Determined by
Modified Levator Ani Muscle Method" 83 Proc. Soc. Exptl. Biol.
Med., 175 (1953), and P. C. Walsh and R. F. Gittes, "Inhibition of
extratesticular stimuli to prostatic growth in the castrated rat by
antiandrogens", 86 Endocrinology, 624 (1970); the disclosures of
which are herein incorporated by reference.
[0349] The basis of this assay is the fact that the male sexual
accessory organs, such as the prostate and seminal vesicles, play
an important role in reproductive function These glands are
stimulated to grow and are maintained in size and secretory
function by the continued presence of serum testosterone (T), which
is the major serum androgen (>95%) produced by the Leydig cells
in the testis under the control of the pituitary luteinizing
hormone (LH) and follicle stimulating hormone (FSH). Testosterone
is converted to the more active form, dihydrotestosterone (DHT),
within the prostate by 5-alpha-reductase. Adrenal androgens also
contribute about 20% of total DHT in the rat prostate, and about
40% of that in 65-year-old men. F. Labrie et al. 16 Clin. Invest.
Med., 475-492 (1993). However, this is not a major pathway, since
in both animals and humans, castration leads to almost complete
involution of the prostate and seminal vesicles without concomitant
adrenalectomy. Therefore, under normal conditions, the adrenals do
not support significant growth of prostatic tissue. M. C. Luke and
D. S. Coffey, "The Physiology of Reproduction" ed. by E. Knobil and
J. D. Neill, 1, 1435-1487 (1994). Since the male sex organs are the
tissues most responsive to modulation of androgen activity, this
model is used to determine the androgen-dependent growth of the sex
accessory organs in immature castrated rats. In addition to the
prostate and seminal vesicles, the levator ani demonstrates
androgen dependent growth (Herschberger, supra). Androgens which
show the greatest levator ani growth also show the greatest
anabolic activity by nitrogen retention methods. Hence, the levator
ani is a useful endpoint to measure myotrophic effects on muscle.
Compounds which show anabolic activities could be useful in the
treatment of muscle-wasting disorders. Further, compounds which
possess such anabolic activity without concomitant androgenic
activity (tissue selectivity) would be of practical therapeutic
value. Male immature rats (50-60 g, 21-day-old, Sprague -Dawley,
Harlan) were castrated under metofane anesthesia. Immediately after
surgery, animals groups were dosed for 3 days as follows: [0350]
(1) control vehicle; [0351] (2) Fluoxymestcrone (Fluox) (1.0, 3.0,
and 100 mg/kg, oral administration daily); and [0352] (3) a
compound of the present invention (different doses, oral
administration daily) to demonstrate agonist activity
[0353] At the end of the 3-day treatment, the animals were
sacrificed, and -the ventral prostates (VP), seminal vesicles (SV),
and levator ani (LA) were collected and weighed. The sexual organ
weights were first standardized as mg per 100 g of body weight, and
the increase in organ weight induced by the compounds of the
present invention was compared to the castrate control animals. The
organ weight of the intact control animals is considered fully
efficacious (100%). Super-anova (one factor) was used for
statistical analysis.
[0354] The gain and loss of sexual organ weights reflect the
changes of cell number (DNA content) and cell mass (protein
content), depending upon the serum androgen concentration. See Y.
Okuda et al., 145 J Urol., 188-191 (1991), the disclosure of which
is herein incorporated by reference. Therefore, measurement of
organ wet weights is sufficient to indicate the bioactivity of
androgens and androgen antagonists. In immature castrated rats,
replacement of exogenous androgens increased the weights of the
ventral prostate (VP), the seminal vesicles (SV), and the levator
ani (LA) in a dose-dependent manner as shown in Table 4.
TABLE-US-00003 TABLE 4 Androgen Induced Ventral Prostate, Seminal
Vesicle, and Levator Ani Growth in castrated immature rats at oral
dosing, once daily, for 3 days, with fluoxymesterone (fluox) and
Compound 105. Treatment VP VP eff SV SV eff LA LA eff (mg/kg) (wet
wt).sup.1 (% of intact).sup.2 (wet wt).sup.1 (% intact).sup.2 (wet
wt).sup.1 (% intact).sup.2 Cx 24.2 .+-. 1.8 0.0 .+-. 8.1 7.7 .+-.
1.0 0.0 .+-. 20 27.7 .+-. 3.2 0.0 .+-. 163 intact 46.6 .+-. 3.4 100
.+-. 15 12.8 .+-. 1.3 100 .+-. 25 29.5 .+-. 1.0 100 .+-. 60 105 (3)
26.9 .+-. 1.1 12 .+-. 5 8.5 .+-. 0.7 15 .+-. 13 33.0 .+-. 2.4 306
.+-. 140 105 (10) 35.9 .+-. 2.7 52 .+-. 12 9.9 .+-. 0.4 42 .+-. 8.2
36.3 .+-. 1.3 498 .+-. 73 105 (30) 30.1 .+-. 2.1 26 .+-. 9 11.7
.+-. 1.4 78 .+-. 26 35.8 .+-. 1.2 469 .+-. 71 105 (100) 42.1 .+-.
1.6 80 .+-. 7 14.4 .+-. 1.0 131 .+-. 19 39.7 .+-. 0.6 696 .+-. 36
Fluox (1) 49.3 .+-. 4.1 112 .+-. 18 24.3 .+-. 3.7 325 .+-. 73 44.6
.+-. 4.0 977 .+-. 230 Fluox (3) 57.5 .+-. 2.4 148 .+-. 10 31.8 .+-.
4.2 472 .+-. 82 45.3 .+-. 3.1 1020 .+-. 180 Fluox (100) 82.3 .+-.
7.2 259 .+-. 32 46.7 .+-. 1.7 762 .+-. 34 49.8 .+-. 5.4 1280 .+-.
310 .sup.1Weight of organ in mg/100 g body weight. .sup.2% Efficacy
compared to intact control (100% is full maintenance).
[0355] TABLE-US-00004 TABLE 5 Androgen Induced Ventral Prostate,
Seminal Vesicle, and Levator Ani Growth in castrated immature rats
at oral dosing, once daily, for 3 days, with fluoxymesterone
(fluox) and Compound 123. Treatment VP VP eff SV SV eff (% LA LA
eff (% (mg/kg) (wet wt).sup.1 (% of intact).sup.2 (wet wt).sup.1 of
intact).sup.1 (wet wt).sup.1 of intact).sup.2 Cx 26.6 .+-. 2.1 0.0
.+-. 12 9.4 .+-. 0.8 0.0 .+-. 11 30.0 .+-. 3.6 0.0 .+-. 163 intact
44.0 .+-. 5.1 100 .+-. 29 17 .+-. 1.5 100 .+-. 19 32.1 .+-. 3.0 100
.+-. 137 123 (3) 28.8 .+-. 2.8 13 .+-. 16 10.6 .+-. 0.9 15 .+-. 12
32.4 .+-. 3.6 109 .+-. 165 123 (10) 38.6 .+-. 0.6 69 .+-. 3.6 9.3
.+-. 0.3 -1 .+-. 4.2 34.4 .+-. 1.6 203 .+-. 75 123 (30) 37.9 .+-.
3.1 65 .+-. 18 13.9 .+-. 0.8 57 .+-. 9.9 42.1 .+-. 2.7 554 .+-. 124
123 (100) 44.6 .+-. 5.3 101 .+-. 30 19.6 .+-. 1.5 129 .+-. 19 48.5
.+-. 2.0 844 .+-. 91 Fluox (1) 31.8 .+-. 3.8 30 .+-. 22 22.4 .+-.
3.2 165 .+-. 41 42.6 .+-. 2.6 574 .+-. 116 Fluox (3) 47.1 .+-. 3.4
118 .+-. 19 29.0 .+-. 2.0 250 .+-. 26 51.8 .+-. 1.4 995 .+-. 65
Fluox (100) 73.5 .+-. 3.5 269 .+-. 20 37.4 .+-. 1.1 356 .+-. 14
60.4 .+-. 1.1 1384 .+-. 51 .sup.1Weight of organ in mg/100 g body
weight .sup.2% Efficacy compared to intact control (100% is full
maintenance).
[0356] In this immature castrated rat model, a known AR agonist
(fluoxymesterone) was administered orally with 1.0, 3.0, and 100
mg/kg, increasing the androgen-mediated increases in the weights of
VP, SV and LA in a dose-dependent manner as shown in Table 4.
Compounds 105 and 123 also exhibited AR agonist activity by
promoting the androgen-mediated maintenance/increase in the weights
of the VP, SV and LA as summarized in Tables 4 and 5.
[0357] While in accordance with the patent statutes, description of
the preferred embodiments and processing conditions have been
provided, the scope of the invention is not to be limited thereto
or thereby. Various modifications and alterations of the present
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the present invention,
reference is made to the following non-limiting enumerated
embodiments.
* * * * *