U.S. patent application number 10/075522 was filed with the patent office on 2002-10-24 for fluoro oxindole derivatives as modulators of kcnq potassium channels.
Invention is credited to Dextraze, Pierre, Dworetzky, Steven I., Gribkoff, Valentin K., Hewawasam, Piyasena, Kinney, Gene G..
Application Number | 20020156120 10/075522 |
Document ID | / |
Family ID | 26756972 |
Filed Date | 2002-10-24 |
United States Patent
Application |
20020156120 |
Kind Code |
A1 |
Hewawasam, Piyasena ; et
al. |
October 24, 2002 |
Fluoro oxindole derivatives as modulators of KCNQ potassium
channels
Abstract
There is provided novel 3-fluoro-3-phenyl oxindole derivatives
of Formula I 1 wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each
are independently hydrogen, C.sub.1-4 alkyl, halogen, fluoromethyl,
trifluoromethyl, phenyl, 4-methylphenyl or 4-trifluoromethylphenyl;
R.sup.5 is C.sub.1-6 alkyl optionally substituted with one to three
same or different groups selected from fluoro and chloro, provided
R.sup.5 is not C.sub.1-6 alkyl when Y is O; Y is O or S; and
R.sup.6 and R.sup.7 each are independently hydrogen, chloro, bromo
or trifluoromethy; which are openers of the KCNQ potassium channels
and are useful in the treatment of disorders which are responsive
to the opening of the KCNQ potassium channels.
Inventors: |
Hewawasam, Piyasena;
(Middletown, CT) ; Dextraze, Pierre; (Laprairie,
CA) ; Gribkoff, Valentin K.; (Wallingford, CT)
; Kinney, Gene G.; (Collegeville, PA) ; Dworetzky,
Steven I.; (Middlefield, CT) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
26756972 |
Appl. No.: |
10/075522 |
Filed: |
February 14, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60270112 |
Feb 20, 2001 |
|
|
|
Current U.S.
Class: |
514/419 ;
548/484 |
Current CPC
Class: |
C07D 209/34
20130101 |
Class at
Publication: |
514/419 ;
548/484 |
International
Class: |
A61K 031/404; C07D
209/36 |
Claims
What is claimed is:
1. A compound of Formula I 11wherein R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 each are independently hydrogen, C.sub.1-4 alkyl, halogen
fluoromethyl, trifluoromethyl, phenyl, 4-methylphenyl or
4-trifluoromethylphenyl; R.sup.5 is C.sub.1-6 alkyl optionally
substituted with one to three same or different groups selected
from fluoro and chloro, provided R.sup.5 is not C.sub.1-6 alkyl
when Y is O; Y is O or S; and R.sup.6and R.sup.7 each are
independently hydrogen, chloro, bromo or trifluoromethyl.
2. The compound of claim 1 which is the (+) enantiomer of a
compound as defined in claim 1.
3. The compound of claim 1 wherein Y is O, and R.sup.5 is C.sub.1-6
alkyl substituted with one to three same or different groups
selected from fluoro and chloro.
4. The compound of claim 2 wherein R.sup.5 is CH.sub.2CF.sub.3 or
CH.sub.2CH.sub.2F; R.sup.6 is chloro; and R.sup.7 is hydrogen or
chloro.
5. The compound of claim 1 wherein Y is S; R.sup.1, R.sup.3,
R.sup.4 and R.sup.7 are hydrogen; R.sup.2 is trifluoromethyl; and
R.sup.6 is chloro.
6. The compound of claim 1 selected from the group consisting of:
(.+-.)-3-[5-chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-fluoro-
-6-(trifluoromethyl)-2H-indol-2-one;
(+)-3-[5-chloro-2-[(2,2,2-trifluoroet-
hoxy)phenyl]-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one;
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3,6-diflu-
oro-2H-indol-2-one;
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,-
3-dihydro-3-fluoro-6-(fluoromethyl)-2H-indol-2-one;
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-4,6-dichloro-1,3-dihy-
dro-3-fluoro-2H-indol-2-one;
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)p-
henyl]-5,6-dichloro-1,3-dihydro-3-fluoro-2H-indol-2-one;
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3,5,6-tri-
fluoro-2H-indol-2-one;
(.+-.)-6-chloro-3-[5-chloro-2-(2,2,2-trifluoroethox-
y)phenyl]-1,3-dihydro-3-fluoro-2H-indol-2-one;
(.+-.)-6-chloro-3-[5-chloro-
-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-fluoro-2H-indol-2-one;
(.+-.)-3-[5-chloro-2-(2-fluoroethoxy)phenyl]-1,3-dihydro-3-fluoro-6-(trif-
luoromethyl)-2H-indol-2-one;
(.+-.)-3-[4,5-Dichloro-2-(2-fluoroethoxy)phen-
yl]-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one;
3-[5-chloro-2-(ethylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-
-2H-indol-2-one;
3-[5-chloro-2-(2-methyl-1-propylthio)phenyl]-1,3-dihydro--
3-fluoro-6-(trifluoromethyl)-2H-indol-2-one;
3-[5-chloro-2-(1-propylthio)p-
henyl]-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one; and
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-fluoro--
6-[4-(trifluoromethyl)phenyl]-2H-indol-2-one.
7. A pharmaceutical composition for the treatment of disorders
responsive to opening of KCNQ potassium channels comprising a
therapeutically effective amount of the compound of claim 1 in
association with a pharmaceutically acceptable carrier, adjuvant or
diluent.
8. A pharmaceutical composition for the treatment of disorders
responsive to opening of KCNQ potassium channels comprising a
therapeutically effective amount of the compound of claim 2 in
association with a pharmaceutically acceptable carrier, adjuvant or
diluent.
9. A method for the treatment of disorders responsive to opening of
the KCNQ potassium channels in a mammal in need thereof, which
comprises administering to said mammal a therapeutically effective
amount of the compound of claim 1.
10. A method for the treatment of disorders responsive to opening
of the KCNQ potassium channels in a mammal in need thereof, which
comprises administering to said mammal a therapeutically effective
amount of the compound of claim 2.
11. A method of claim 9 wherein said disorder is migraine.
12. A method of claim 10 wherein said disorder is migraine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a non-provisional application which claims the
benefit of U.S. Provisional Application Number 60/270,112 filed
Feb. 20, 2001.
FIELD OF THE INVENTION
[0002] The present invention is directed to novel 3-fluoro-3-phenyl
oxindole derivatives which are modulators of KCNQ potassium
channels and are therefore useful in treating disorders responsive
to the modulation of the potassium channels. The present invention
also provides a method of treatment with the novel 3-fluoro
oxindole derivatives and to pharmaceutical compositions
thereof.
BACKGROUND OF THE INVENTION
[0003] Potassium (K.sup.+) channels are considered to be the most
diverse class of ion channels and have several critical roles in
cell function. This has been demonstrated in neurons where K.sup.+
channels are responsible, in part, for determining cell
excitability by contributing to membrane repolarization following
depolarization, resting membrane potential, and regulation of
neurotransmitter release. The M-current has long been described, by
electrophysiology recording methods and by pharmacology, as a
dominant conductance in controlling neuronal excitability.
Pharmacological activation or suppression of M-currents by small
molecules could have profound effects in controlling neuronal
excitability. Recently, Wang et al. (1998, Science, 282:1890-1893)
reported that co-assembly of the KCNQ2 and KCNQ3 potassium channels
underlies the native M-current in neurons.
[0004] Activation or opening of the KCNQ channel(s), particularly
the KCNQ2 or KCNQ2/3 channel(s), mutated or wild type, may prove to
be beneficial in increasing hyperpolarization of neurons, thereby
resulting in protection from abnormal synchronous firing during a
migraine attack. The present invention provides a solution to the
problem of abnormal synchronous firing of neurons related to
migraine headache by demonstrating that modulators, preferably
openers, of KCNQ potassium channels increases hyperpolarization of
neurons which protects against abnormal synchronous neuron firing
involved in migraine attacks.
[0005] Although the symptom pattern varies among migraine
sufferers, the severity of migraine pain justifies a need for
vigorous, yet safe and effective, treatments and therapies for the
great majority of cases. Needed in the art are agents that can be
used to combat and relieve migraine (and diseases similar to and
mechanistically related to migraine), and even prevent the
recurrence of migraine. Also needed are anti-migraine agents which
are effective in the treatment of acute migraine, as well as in the
prodrome phase of a migraine attack. Thus, a clear goal in the art
is to discover new, safe, nontoxic and effective anti-migraine
compounds for use as drugs, and in anti-migraine compositions and
treatments.
[0006] Because migraine afflicts a large percentage of the
population, there is a need to discover compounds and agents that
are useful in therapeutics and treatments, and as components of
pharmaceutical compositions, for reducing, ameliorating, or
alleviating the pain and discomfort of migraine headache and other
symptoms of migraine. The present invention satisfies such a need
by providing compounds that function as openers of the KCNQ family
of potassium channel proteins to serve as anti-migraine agents or
drugs and to comprise compositions to treat migraine, as described
herein.
[0007] A number of substituted oxindoles have been disclosed as
neuroanabolic agents by H. Kuch et al. in U.S. Pat. Nos. 4,542,148,
issued Sep. 17, 1985 and 4,614,739, issued Sep. 30,1986.
[0008] 3-Substituted oxindole derivatives with utility as openers
of the large conductance calcium-activated potassium channels have
been disclosed by Hewawasam, P; Meanwell, N. A.; and Gribkoff, V.
K. in U.S. Pat. Nos. 5,565,483, issued Oct.15, 1996 and 5,602,169,
issued Feb. 11, 1997, both of which are disclosed to be useful in
the treatment of disorders that are responsive to the opening of
the large conductance calcium-activated potassium channels, also
called maxi-K channels. Because of their voltage and calcium
dependence, maxi-K channels are distinct from KCNQ potassium
channels, which are only voltage dependent. In addition, the
pharmacology and kinetics of maxi-K channels versus KCNQ channels
are frequently quite different, and the large conductance or maxi-K
channels are responsive to the opener compounds specifically
disclosed in U.S. Pat. No. 5,565,483. Thus, the compounds and their
uses described in these patents are distinct from those of the
present invention.
SUMMARY OF THE INVENTION
[0009] The present invention provides novel 3-fluoro oxindole
derivatives having the general Formula I 2
[0010] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R and Y are as defined below, or a nontoxic
pharmaceutically acceptable salt, solvate or hydrate thereof which
are openers or activators of KCNQ potassium channels. The present
invention also provides pharmaceutical compositions comprising said
3-fluoro oxindole derivatives and to the method of treatment of
disorders sensitive to KCNQ potassium channel opening activity such
as migraine.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention provides novel 3-fluoro oxindole
derivatives which are modulators of the KCNQ potassium channels and
which have the general Formula I 3
[0012] wherein
[0013] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each are independently
hydrogen, C.sub.1-4 alkyl, halogen, fluoromethyl, trifluoromethyl,
phenyl, 4-methylphenyl or 4-trifluoromethylphenyl;
[0014] R.sup.5 is C.sub.1-6 alkyl optionally substituted with one
to three same or different groups selected from fluoro and chloro,
provided R.sup.5 is not C.sub.1-6 alkyl when Y is O;
[0015] Y is O or S; and
[0016] R.sup.6 and R.sup.7 each are independently hydrogen, chloro,
bromo or trifluoromethyl.
[0017] The present invention also provides a method for the
treatment or alleviation of disorders associated with KCNQ
potassium channel polypeptides and, in particular, human KCNQ
potassium channel polypeptides which are especially involved in
reducing or alleviating migraine or a migraine attack, which
comprises administering together with a conventional adjuvant,
carrier or diluent a therapeutically effective amount of a compound
of Formula I.
[0018] The term "C.sub.1-6 alkyl" as used herein and in the claims
means straight or branched chain alkyl groups such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,
4-methylbutyl, hexyl and the like. The term "C.sub.1-4 alkyl" as
used herein and in the claims means straight or branched chain
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, and tert-butyl. The term "halogen" as used herein and in
the claims is intended to include bromine, chlorine, iodine and
fluorine.
[0019] As the compounds of the present invention possess an
asymmetric carbon atom at the 3-position of the oxindole ring, the
present invention includes the racemate as well as the individual
enantiomeric forms of the compounds of Formula I as described
herein and in the claims. Preferred embodiments of compounds of
Formula I are the racemate and the single enantiomer which includes
mostly the one stereoisomer having a (+) optical rotation is most
preferred. Mixtures of isomers of the compounds of the examples or
chiral presursors thereof can be separated into individual isomers
according to methods which are known per se, e.g. fractional
crystallization, adsorption chromatography or other suitable
separation processes. Resulting racemates can be separated into
antipodes in the usual manner after introduction of suitable
salt-forming groupings, e.g. by forming a mixture of
diastereosiomeric salts with optically active salt-forming agents,
separating the mixture into diastereomeric salts and converting the
separated salts into the free compounds. The enantiomeric forms may
also be separated by fractionation through chiral high pressure
liquid chromatography columns, according to procedures described
herein.
[0020] Certain of the compounds of the present invention can exist
in unsolvated forms as well as solvated forms including hydrated
forms such as monohydrate, dihydrate, trihydrate, hemihydrate,
tetrahydrate and the like. The products may be true solvates, while
in other cases, the products may merely retain adventitious solvent
or be a mixture of solvate plus some adventitious solvent. It
should be appreciated by those skilled in the art that solvated
forms are equivalent to unsolvated forms and are intended to be
encompassed within the scope of the present invention.
[0021] In the method of the present invention, the term
"therapeutically effective amount" means the total amount of each
active component of the method that is sufficient to show a
meaningful patient benefit, i.e., amelioration or healing of
conditions which respond to modulation of the KCNQ potassium
channels. When applied to an individual active ingredient,
administered alone, the term refers to that ingredient alone. When
applied to a combination, the term refers to combined amounts of
the active ingredients that result in the therapeutic effect,
whether administered in combination, serially or simultaneously.
The term "KCNQ" as used herein and in the claims means the family
of KCNQ2, KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides as
well as heteromultimers of different individual family members
which include but are not limited to KCNQ2/3, KCNQ2/5 and KCNQ3/5.
The terms "treat, treating, treatment" as used herein and in the
claims means preventing, alleviating or ameliorating diseases
and/or symptoms associated with dysfunction of cellular membrane
polarization and conductance of human KCNQ2, KCNQ3, KCNQ4, and
KCNQ5 potassium channel polypeptides and, in particular, migraine
and/or symptoms that precede a full-blown migraine attack.
[0022] Preferred compounds for use in the method of the present
invention include the compounds of Formula I listed below:
[0023]
(.+-.)-3-[5-chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3--
fluoro-6-(trifluoromethyl)-2H-indol-2-one;
[0024] Isolation of
(+)-3-[5-chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1,3--
dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one;
[0025]
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3,6-
-difluoro-2H-indol-2-one;
[0026]
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-f-
luoro-6-(fluoromethyl)-2H-indol-2-one;
[0027]
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-4,6-dichloro-1,-
3-dihydro-3-fluoro-2H-indol-2-one;
[0028]
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-5,6-dichloro-1,-
3-dihydro-3-fluoro-2H-indol-2-one;
[0029]
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3,5-
,6-trifluoro-2H-indol-2-one;
[0030]
(.+-.)-6-chloro-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-di-
hydro-3-fluoro-2H-indol-2-one;
[0031]
(+)-6-chloro-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihyd-
ro-3-fluoro-2H-indol-2-one;
[0032]
(.+-.)-3-[5-chloro-2-(2-fluoroethoxy)phenyl]-1,3-dihydro-3-fluoro-6-
-(trifluoromethyl)-2H-indol-2-one;
[0033]
(.+-.)-3-[4,5-dichloro-2-(2-fluoroethoxy)phenyl]-1,3-dihydro-3-fluo-
ro-6-(trifluoromethyl)-2H-indol-2-one;
[0034]
3-[5-chloro-2-(2-fluoroethylthio)phenyl]-1,3-dihydro-3-fluoro-6-(tr-
ifluoromethyl)-2H-indol-2-one;
[0035]
3-[5-chloro-2-(ethylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluorom-
ethyl)-2H-indol-2-one;
[0036]
3-[5-chloro-2-[(2-methylphenylmethyl)thio]phenyl]-1,3-dihydro-3-flu-
oro-6-(trifluoromethyl)-2H-indol-2-one;
[0037]
3-[5-chloro-2-(2-methyl-1-propylthio)phenyl]-1,3-dihydro-3-fluoro-6-
-(trifluoromethyl)-2H-indol-2-one;
[0038]
3-[5-chloro-2-(1-propylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluo-
romethyl)-2H-indol-2-one;
[0039]
3-[5-chloro-2-(2,5-difluorophenylmethylthio)phenyl]-1,3-dihydro-3-f-
luoro-6-(trifluoromethyl)-2H-indol-2-one;
[0040]
3-[5-chloro-2-(3-chloro-1-propylthio)phenyl]-1,3-dihydro-3-fluoro-6-
-(trifluoromethyl)-2H-indol-2-one; and
[0041]
(.+-.)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-f-
luoro-6-[4-(trifluoromethyl)phenyl]-2H-indol-2-one.
[0042] The general procedures used to synthesize the compounds of
Formula I are described in Reaction Schemes 1-4 and are illustrated
in the examples. Reasonable variations of the described procedures,
which would be evident to one skilled in the art, are intended to
be within the scope of the present invention. 4
[0043] The starting material isatins of Formula Ill, used in
Reaction Scheme 1, were obtained from either commercial sources or
prepared by well-known literature procedures such as those
described by Hewawasam, P. et al. in U.S. Pat. Nos. 5,565,483 and
5,602,169; Hewawasam, P., et al., Tetrahedron Lett., 1994, 35,
7303; Gassman, P. et al., J. Org. Chem., 1977, 42, 1344; Stolle,
R., J. Prakt. Chem., 1922, 105, 137; and Sandmeyer, T., Helv. Chim.
Acta, 1919, 2, 234. Reaction Scheme 1, Step A, (i) shows the
desired substituted isatin of Formula III is first treated with a
suitable base in an aprotic solvent at approximately 0.degree. C.
in order to generate the corresponding isatin salt. Preferred bases
include metal hydride bases, particularly sodium hydride, and a
preferred aprotic solvent is THF. The isatin salt is then reacted
with an appropriate 2-magnesium bromide aryloxy ether of Formula IV
in an appropriate solvent, such as THF within the temperature range
of -20.degree. C. to room temperature (rt) to provide the
3-hydroxyoxindoles of Formula V. The 2-magnesium bromide aryloxy
ethers (Grignard reagents) of Formula IV used in Reaction Scheme 1,
Step A, (ii) were prepared from the corresponding 2-bromo aryloxy
ethers (such as Preparations 1-3) according to the procedure as
described for Step A of Preparation 4. Reaction Scheme 1, Step B
depicts the fluorination of the 3-hydroxyoxindole of Formula V to
provide the corresponding 3-fluorooxindole compound of Formula Ia.
A preferred method for the fluorination is to treat the
3-hydroxyoxindole of Formula V with diethylaminosulfur trifluoride
(DAST) in an aprotic solvent, such as dichloromethane (as described
in Example 1) to afford the 3-fluorooxindole of Formula Ia. The
substantially pure enantiomeric forms of the 3-fluorooxindoles of
Formula Ia may readily be obtained by the separation of the racemic
mixture using chiral high pressure liquid chromatography methods as
described in Examples 2 and 3. 5
[0044] Reaction Scheme 2 depicts the reaction of a magnesium
phenolate (prepared by mixing an appropriate phenol and ethyl
magnesium bromide) with the desired isatins of Formula III in
CH.sub.2Cl.sub.2 to afford the desired 3-hydroxyoxindoles of
Formula VI (as described in Preparation 5). Selective alkylation of
the phenolic hydroxyl moiety of the 3-hydroxyoxindole derivatives
of Formula VI is accomplished by treating the compound of Formula
VI with R.sup.5X (wherein X is a leaving group such as bromo or
iodo) in the presence of a base, such as potassium carbonate, in
2-butanone at approximately 80.degree. C. to afford the
3-hydroxyoxindole ethers of Formula V. The addition of a catalytic
amount of an alkali metal halide such as potassium iodide may be
desirable in this step (see Preparation 6). Finally, fluorination
of the 3-hydroxyoxindole ethers of Formula V with
diethylaminosulfur trifluoride (as described in Example 4) provided
the desired 3-fluorooxindole derivatives of Formula Ia. The
substantially pure enantiomeric forms of the 3-fluorooxindoles of
Formula Ia may readily be obtained by the separation of the racemic
mixture using chiral high pressure liquid chromatography methods as
described in Examples 2 and 3. 6
[0045] Diazotization of the 2-bromoanilines of Formula VII as shown
in Reaction Scheme 3, Step (a), is carried out by treatment with
sodium nitrite and hydrogen tetrafluoroborate in ethanol to provide
the diazonium tetrafluoroborate of Formula VIII (as described for
the preparation of 2-bromo-4-chlorobenzenediazonium
tetrafluoroborate in Preparation 7). Thioalkylation of the
2-bromobenzene diazonium salts of Formula VIII is carried out in
Step (b) by treating an acetonitrile solution of the diazonium salt
with a sodium thioalkoxide at 0.degree. C. (as described for the
preparation of 2-bromo-4-chloro-1-methylthiobenzene in Preparation
8). 2-Bromobenzene disulfides of Formula IX are prepared by
treating a hot aqueous solution of potassium ethyl xanthate with
the diazonium salt of Formula VIII followed by treatment with
potassium hydroxide and ethanol (as described for the preparation
of 2-bromo-4-chlorobenzene disulfide in Preparation 9).
2-Bromobenzenethiols of Formula XI are prepared by reduction of the
disulfide of Formula IX with sodium borohydride in THF (as
described for the preparation of 2-bromo-4-chlorobenzenethiol
in
[0046] Preparation 10). 2-Bromo-1-(tetrahydropyran-2-ylthio)benzene
derivatives of Formula XII are prepared from the thiols of Formula
XI by treatment with para-toluenesulfonic acid (p-TSA) and
3,4-dihydro-2-H-pyran in CH.sub.2Cl.sub.2 as described for the
preparation of 2-bromo-4-chloro-1-(tetrahydropyran-2-ylthio)benzene
in Preparation 11. 7
[0047] Reaction Scheme 4 depicts the preparation of compounds of
Formula Ib. Lithiation of
2-bromo-1-(tetrahydropyran-2-ylthio)benzene derivatives is effected
by treatment with a strong base, such as tert-butyllithium in
anhydrous THF at approximately -78.degree. C. The resultant aryl
lithium intermediate of Formula XIIa is added to the sodium salt of
the desired isatin of Formula III (prepared by treatment of isatin
with NaH in THF) in THF to provide intermediates of Formula XIV (as
described for the preparation of
3-(5-chloro-2-(tetrahydropyran-2-ylthio)phenyl)-3-hydroxy--
1H-6-trifluoromethyl-1,3-dihydroindol-2-one in Preparation 12). The
intermediate of Formula XIV is then treated with silver nitrate in
a polar solvent, such as DMF, to provide the silver salt of Formula
XV. The silver salt of the compound of Formula XV is then alkylated
by treatment with an appropriate electrophile, R.sup.5X (e.g. ethyl
iodide as used for the synthesis of
3-(5-chloro-2-ethylthiophenyl)-3-hydroxy-1H-6-trifluorom-
ethyl-1,3-dihydroindol-2-one in Preparation 14). Alternatively,
hydroxyindolones of Formula XVI can be prepared by addition of a
Grignard reagent of Formula Xa to the desired isatins of Formula
III as described in Preparation 13. Finally, fluorination of
3-hydroxyindole derivatives of Formula XVI is carried out using
diethylaminosulfur trifluoride in an aprotic solvent such as
CH.sub.2Cl.sub.2 at approximately -78.degree. C. to provide the
fluoro derivatives of Formula Ib (as described in Example 5).
BIOLOGICAL ACTIVITY
[0048] KCNQ Oocyte Methods and Results
[0049] Potassium (K.sup.+) channels are structurally and
functionally diverse families of K.sup.+-selective channel proteins
which are ubiquitous in cells, indicating their central importance
in regulating a number of key cell functions [Rudy, B.,
Neuroscience, 25: 729-749 (1988)]. While widely distributed as a
class, K.sup.+ channels are differentially distributed as
individual members of this class or as families. [Gehlert, D. R.,
et al., Neuroscience, 52: 191-205 (1993)]. In general, activation
of K.sup.+ channels in cells, and particularly in excitable cells
such as neurons and muscle cells, leads to hyperpolarization of the
cell membrane, or in the case of depolarized cells, to
repolarization. In addition to acting as an endogenous membrane
voltage clamp, K.sup.+ channels can respond to important cellular
events such as changes in the intracellular concentration of ATP or
the intracellular concentration of calcium (Ca.sup.2+). The central
role of K.sup.+ channels in regulating numerous cell functions
makes them particularly important targets for therapeutic
development. [Cook, N. S., Potassium channels: Structure,
classification, function and therapeutic potential. Ellis Horwood,
Chinchester (1990)]. One class of K.sup.+ channels, the KCNQ family
exemplified by KCNQ2, KCNQ2/3 heteromultimeres, and KCNQ5, is
regulated by transmembrane voltage and plays a potentially
important role in the regulation of neuronal excitability
[Biervert, C., et al., Science, 279: 403-406 (1998); Lerche, C. et
al., J. Biol. Chem. 275:22395-22400 (2000); Wang, H. et al.
Science, 282:1890-1893 (1998)].
[0050] An opener of KCNQ channels, such as the KCNQ2 and KCNQ2/3
channel opener retigabine, exerts its cellular effects by
increasing the open probability of these channels [Main J., Mol
Pharmacol 58(2):253-62 (2000); Wickenden, A. et al. Mol. Pharm.
58:591-600 (2000)]. This increase in the opening of individual KCNQ
channels collectively results in the hyperpolarization of cell
membranes, particularly in depolarized cells, produced by
significant increases in whole-cell KCNQ-mediated conductance.
[0051] The ability of compounds described in the present invention
to open KCNQ channels and increase whole-cell outward (K.sup.+)
KCNQ-mediated currents was assessed under voltage-clamp conditions
by determining their ability to increase cloned mouse KCNQ2
(mKCNQ2)-mediated, heteromultimeric KCNQ2/3
(m.mu.KCNQ2/3)-mediated, and human KCNQ5 (hKCNQ5)-mediated outward
currents heterologously expressed in Xenopus oocytes. Oocytes were
prepared and injected using standard techniques; each oocyte was
injected with approximately 50 nl of mKCNQ2, or hKCNQ5 cRNA. In the
case of mKCNQ2/3 heteromultimeric channel expression, equal amounts
(25-50 nL) of ech cRNA were co-injected. Injection of equivalent
amounts of water (50 nl) did not result in expression of outward
currents at the voltage steps used to detect KCNQ expression.
Following injection, oocytes were maintained at 17.degree. in ND96
medium consisting of (in mM): NaCl, 90; KCl, 1.0; CaCl.sub.2, 1.0;
MgCl.sub.2, 1.0; HEPES, 5.0; pH 7.5. Horse serum (5%) and
penicillin/streptomycin (5%) were added to the incubation medium.
Recording commenced 2-6 days following mRNA injection. Prior to the
start of an experiment oocytes were placed in a recording chamber
and incubated in Modified Barth's Solution (MBS) consisting of (in
mM): NaCl, 88; NaHCO.sub.3, 2.4; KCl, 1.0; HEPES, 10; MgSO.sub.4,
0.82; Ca(NO.sub.3).sub.2, 0.33; CaCl.sub.2, 0.41; pH 7.5.
[0052] Oocytes were impaled with electrodes (1-2 M.OMEGA.) and
standard 2-electrode voltage clamp techniques were employed to
record whole-cell membrane currents. Recordings were accomplished
using standard two-electrode voltage clamp techniques [Stuhmer, W.,
et al., Methods in Enzymology, Vol. 207: 319-339 (1992)].
Voltage-clamp protocols typically consisted of a series of voltage
steps 1-5 sec duration, in +10 mV steps from a holding potential of
-90 mV to a maximal potential of +40 mV; records were digitized at
5 kHz and stored on a computer using pClamp data acquisition and
analysis software (Axon Instruments). Compounds were evaluated at a
single concentration (10 or 20 .mu.M); the effect of the selected
compounds of Formula I on KCNQ2 current was expressed as the
percent of control current and is listed in Table I.
1 TABLE 1 Example No. KCNQ2 Current* 1 ++** 2 ++** 9 + 10 + 11 ++
12 ++ 14 + *Unless otherwise noted, at 20 .mu.M expressed as
percent increase over KCNQ current in controls; **at 10 .mu.M + =
120-150% ++ = >150%
[0053] In Vivo Electrophysiology
[0054] Male Long-Evans rats (Harlan, 250-400 g) were used in the
experiments described in this example. Prior to testing, rats were
allowed access to food and water ad libitum and were maintained on
a 12:12-h light/dark cycle. Rats were group housed in an
Association for Assessment and Accreditation of Laboratory Animal
Care (AAALAC) accredited facility and cared for in strict
compliance with all applicable regulations.
[0055] Superior sagital sinus (SSS) stimulation and recording were
performed in a manner consistent with previously published methods
using cat (Hoskin et al., 1996) and rat (Cumberbatch et al., 1998;
1999) animal models. Rats were anesthetized with 1.2 g/kg i.p.
urethane (#U-2500, Sigma Chemical Company, St. Louis, Mo.) and
given supplemental urethane as needed. In the case of intravenous
(i.v.) drug administration, the jugular veins of the rats were
cannulated using sylastic tubing pre-filled with vehicle.
[0056] Rats were placed in a stereotaxic device (#1730, David Kopf
Instruments, Tujunga, Calif.) and an incision was made to expose
the entire skull that continued caudally to the level of the C1/C2
vertebral juncture. Using a microdrill (#770, Dremel, Racine, Wis.)
and #4 carbide burr (Henry Schein, Melville, N.Y.), a square
section of skull was removed extending from the bregma position,
rostrally, to the lambda position, caudally. The underlying dura
mater was incised bilateral to the SSS and a small section of
Parafilm.RTM. (American National Can, Neenah, Wis.) was placed
under the SSS to isolate the stimulation electrode. The SSS was
stimulated using insulated silver electrodes bent at their ends to
form a hook. The dorsal region of the vertebra corresponding to C2
was removed for access to the trigeminal nucleus caudalis.
[0057] Stimulated field responses were recorded in the trigeminal
nucleus caudalis using Teflon coated stainless-steel
microelectrodes (5 megaohms impedance, Frederick Haer, Brunswick,
Me.) and amplified and filtered (0.1 Hz-10 kHz) using a
differential amplifier (#IsoDAM8, World Precision Instruments,
Sarasota, Fla.). Stimulation voltage (250 .mu.gsec, 40-130 V) was
delivered using a Grass S88 (Grass Medical Instruments, Quincy,
Mass.) stimulator and stimulus isolation unit (Grass #SIU5) at a
rate of 0.3 Hz. Amplified potentials were captured with an
analog-to-digital converter (#1401 plus, Cambridge Electronic
Design, Cambridge, UK) and commercially available software
(#Signal, Cambridge Electronic Design). Low temperature wax was
applied to both the recording and stimulation sites to prevent
dehydration.
[0058] Three baseline measures (i.e., 100% of control), each
consisting of 100 evoked trigeminal field potentials, were sampled
prior to drug injection. The primary measure for efficacy were
changes in trigeminal field potential amplitude following injection
of test compound. A decrease in trigeminal field response amplitude
was considered to evidence anti-migraine activity. Following
injection of test substances, data were sampled for 1 hour,
averaged into 5 minute bins (90 evoked potentials) and expressed as
a percent change from average baseline values for the purposes of
statistical analysis. Data were analyzed using repeated measures
analyses of variance comparing vehicle and drug effects. A
difference was considered significant when p<0.05.
[0059] In one embodiment of the present invention, openers or
activators of the KCNQ2 potassium channel protein have been found
to be effective in the above-described model of migraine involving
vasculo-trigeminal systems which are integrally involved in the
transmission of migraine pain. A non-limiting representative
compound used in the SSS-stimulated trigeminal model for migraine
as described in Example 2 produced a dose-dependent reduction in
the SSS-stimulated trigeminal field response (overall ANOVA,
p<0.001). The compound of Example 2 was prepared as a solution
in 100% polyethylene glycol (MW=400) using sonication to aid in
dissolution and administered via the i.v. catheter described above
at a maximum volume of 0.3 cc. Significant reductions compared with
vehicle were observed following the use of doses 0.1, 1.0, 10.0,
30.0 and 50.0 mg/kg i.v. , (p<0.01 in all cases), with the
highest dose (50 mg/kg i.v.) producing a nearly complete blockade
of this response (i.e., 86.7.+-.1.67% decrease from control
amplitude).
[0060] The results of the KCNQ potassium channel openers described
above demonstrate that the compounds of the present invention
results in the hyperpolarization of cell membranes and for the in
vivo SSS-field potential experiments demonstrate that the KCNQ2
openers are useful for modulating neuronal activity and may result
in protection from abnormal synchronous firing during a migraine
attack. Accordingly, the KCNQ opener or activator compounds
described according to the present invention are capable of
limiting neuronal activity within the trigeminovascular system and
are thus particularly useful for the treatment of migraine headache
and migraine attack in individuals suffering from the pain and
discomfort of migraine. The compounds of the present invention are
therefore useful in the treatment of acutemigraine, as well as the
potential for prophylactic treatment of migraine as demonstrated by
efficacy in a model of cortical spreading depression. Furthermore,
the compounds of the present invention could reduce, ameliorate,
eliminate or prevent one, or a number of, the characteristic
cluster of symptoms, namely, nausea, photophobia, phonophobia and
basic functional disabilities, that are further associated with
migraine and migraine pain that occur after the prodrome phase of a
migraine headache.
[0061] In another embodiment, this invention includes
pharmaceutical compositions comprising at least one compound of
Formula I in combination with a pharmaceutical adjuvant, carrier or
diluent.
[0062] In still another embodiment, this invention relates to a
method of treatment or prevention of disorders responsive to
opening of KCNQ potassium channels in a mammal in need thereof,
which comprises administering to said mammal a therapeutically
effective amount of a compound of Formula I.
[0063] For therapeutic use, the pharmacologically active compounds
of Formula I will normally be administered as a pharmaceutical
composition comprising as the (or an) essential active ingredient
at least one such compound in association with a solid or liquid
pharmaceutically acceptable carrier and, optionally, with
pharmaceutically acceptable adjutants and excipients employing
standard and conventional techniques.
[0064] The pharmaceutical compositions include suitable dosage
forms for oral, parenteral (including subcutaneous, intramuscular,
intradermal and intravenous) bronchial or nasal administration.
Thus, if a solid carrier is used, the preparation may be tableted,
placed in a hard gelatin capsule in powder or pellet form, or in
the form of a troche or lozenge. The solid carrier may contain
conventional excipients such as binding agents, fillers, tableting
lubricants, disintegrants, wetting agents and the like. The tablet
may, if desired, be film coated by conventional techniques. If a
liquid carrier is employed, the preparation may be in the form of a
syrup, emulsion, soft gelatin capsule, sterile vehicle for
injection, an aqueous or non-aqueous liquid suspension, or may be a
dry product for reconstitution with water or other suitable vehicle
before use. Liquid preparations may contain conventional additives
such as suspending agents, emulsifying agents, wetting agents,
non-aqueous vehicle (including edible oils), preservatives, as well
as flavoring and/or coloring agents. For parenteral administration,
a vehicle normally will comprise sterile water, at least in large
part, although saline solutions, glucose solutions and like may be
utilized. Injectable suspensions also may be used, in which case
conventional suspending agents may be employed. Conventional
preservatives, buffering agents and the like also may be added to
the parenteral dosage forms. Particularly useful is the
administration of a compound of Formula I directly in parenteral
formulations. The pharmaceutical compositions are prepared by
conventional techniques appropriate to the desired preparation
containing appropriate amounts of the active ingredient, that is,
the compound of Formula I according to the invention. See, for
example, Remington's Pharmaceutical Sciences, Mack Publishing
Company, Easton, Pa., 17th edition, 1985.
[0065] The dosage of the compounds of Formula I to achieve a
therapeutic effect will depend not only on such factors as the age,
weight and sex of the patient and mode of administration, but also
on the degree of potassium channel activating activity desired and
the potency of the particular compound being utilized for the
particular disorder of disease concerned. It is also contemplated
that the treatment and dosage of the particular compound may be
administered in unit dosage form and that the unit dosage form
would be adjusted accordingly by one skilled in the art to reflect
the relative level of activity. The decision as to the particular
dosage to be employed (and the number of times to be administered
per day) is within the discretion of the physician, and may be
varied by titration of the dosage to the particular circumstances
of this invention to produce the desired therapeutic effect.
[0066] A suitable dose of a compound of Formula I or pharmaceutical
composition thereof for a mammal, including man, suffering from, or
likely to suffer from any condition as described herein is an
amount of active ingredient from about 0.01 .mu.g/kg to 10 mg/kg
body weight. For parenteral administration, the dose may be in the
range of 0.1 .mu.g/kg to 1 mg/kg body weight for intravenous
administration. For oral administration, the dose may be in the
range of 0.1 .mu.g/kg to 5 mg/kg body weight. The active ingredient
will preferably be administered in equal doses from one to four
times a day. However, usually a small dosage is administered, and
the dosage is gradually increased until the optimal dosage for the
host under treatment is determined.
[0067] However, it will be understood that the amount of the
compound actually administered will be determined by a physician,
in the light of the relevant circumstances including the condition
to be treated, the choice of compound of be administered, the
chosen route of administration, the age, weight, and response of
the individual patient, and the severity of the patient's
symptoms.
[0068] The following examples are given by way of illustration and
are not to be construed as limiting the invention in any way
inasmuch as many variations of the invention are possible within
the spirit of the invention.
DESCRIPTION OF SPECIFIC EMBODIMENTS
Preparation of Intermediates
[0069] Preparation 1
[0070] Preparation of
2-Bromo-4-chloro(2,2,2-trifluoroethoxy)benzene:
[0071] Step A: Neat methanesuffonyl chloride (28 mL, 0.36 mol) was
added dropwise to a stirred cold (0.degree. C.) solution of
2,2,2-trifluoroethanol (30 g, 0.3 mol) and triethylamine (50 mL,
0.36 mol) in CH.sub.2Cl.sub.2 (60 mL). The reaction mixture was
allowed to warm to ambient temperature and maintained at room
temperature for 1-2 hours. The reaction mixture was quenched with
1N HCl (50 mL) and the organic layer was separated and then washed
consecutively with water and brine. The organic layer was dried
over MgSO.sub.4, filtered and the filtrate was concentrated in
vacuo to afford a colorless oil which was distilled under reduced
pressure to afford 2,2,2-trifluoroethylmethane sulfonate (51.8 g;
98%): bp 100-105.degree. C. @ 25-30 torr.
[0072] Step B: To a stirred cold (0.degree. C.) suspension of oil
free NaH (0.12 mol, 4.8 g of 60% NaH in mineral oil) in anhydrous
DMF (50 mL), a solution of 2-bromo-4-chlorophenol in DMF (50 mL)
was added over 30 minutes under nitrogen. The resultant gray
suspension of the sodium salt of 2-bromo-4-chlorophenol was treated
with neat 2,2,2-trifluoroethylmetha- ne sulfonate (21.4 g, 0.12
mol). The stirred mixture was heated at reflux temperature for 2-3
days. The mixture was cooled in an ice water bath and extracted
with diethyl ether (2.times.100 mL). The combined ether extract was
washed with 1 N NaOH (3.times.100 mL), 1N HCl, brine, dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated in
vacuo to provide a golden-yellow oil (18.4 g) which was then
distilled in vacuo to afford the title compound as a colorless oil
(14.7 g): bp 100-103.degree. C. @ 0.5 torr.
[0073] Preparation 2
[0074] Preparation of
2-Bromo-4-chloro(2,2-difluoroethoxy)benzene:
[0075] A stirred suspension of 2-bromo-4-chlorophenol (2.07 g, 10
mmol), 2-bromo-1,1-difluoroethane (1.74 g, 12 mmol) and potassium
carbonate (1.65 g, 12 mmol) in 2-butanone (10 mL) was heated at
reflux temperature for 16 hours. The suspension was allowed to cool
and then filtered. The filtrate was concentrated and distilled in
vacuo to afford the title compound as a colorless oil (2.28 g,
84%): bp 78-80.degree. C. @ 0.1 torr
[0076] Preparation 3
[0077] Preparation of 2-Bromo-4-chloro(2-fluoroethoxy)benzene:
[0078] A stirred suspension of 2-bromo-4-chlorophenol (2.07 g, 10
mmol), 1-bromo-2-fluoroethane (1.52 g, 12 mmol) and potassium
carbonate (1.65 g, 12 mmol) in 2-butanone (10 mL) was heated at
reflux temperature for 16 hours. The suspension was allowed to cool
and then filtered. The filtrate was concentrated in vacuo and then
distilled in vacuo to afford the titled compound as a colorless oil
(2.25 g, 89%): bp 80-82.degree. C. @ 0.1 torr
[0079] Preparation 4
[0080] Preparation of
(.+-.)-3-[5-Chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-
-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one:
[0081] Step A: To a stirred suspension of magnesium turnings in dry
THF (30 mL), was added dibromoethane (0.77 mL) under nitrogen and
allowed to react for 10-15 minutes. Neat
2-bromo-4-chloro(2,2,2-trifluoroethoxy)benz- ene (13.0 g, 45 mmol)
was then added. Once the ensuing exothermic reaction had subsided
the reaction mixture was heated to reflux for 2-3 hours then was
allowed to cool to room temperature.
[0082] Step B: In a separate flask, neat 6-(trifluoromethyl)isatin
(6.45 g, 30 mmol) was added to a cold (0.degree. C.) suspension of
oil free NaH (60% in oil, 1.44 g, 36 mmol) in dry THF (30 mL) under
nitrogen. The mixture was stirred until gas evolution ceased. The
sodium salt of the 6-(trifluoromethyl)isatin was cooled to
-20.degree. C. and then the Grignard reagent 2-(magnesium
bromide)-4-chloro(2,2,2-trifluoroethoxy)ben- zene (from Step A,
above) was added via syringe. The reaction mixture was allowed to
warm to room temperature and maintained at room temperature for 30
minutes. The reaction mixture was diluted with diethyl ether and
then quenched with 1N HCl. The organic layer was separated and
washed consecutively with 0.5N NaOH (2.times.50 mL), 1N HCl, water,
brine and then dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated in vacuo to provide a light brown solid
(16.3 g) which was triturated with CH.sub.2Cl.sub.2 to afford the
titled compound (8.92 g, 70%) as a white solid: mp 226-228.degree.
C.
[0083] Preparation 5
[0084] Preparation of
(.+-.)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hy-
droxy-6-(trifluoromethyl)-2H-indole-2-one:
[0085] To a solution of 4-chlorophenol (2.87 g, 22.3 mmol) in THF
(30 mL) at 0.degree. C., 1.0 M solution of ethyl magnesium bromide
(22.3 mL, 22.3 mmol) in THF was added dropwise. The resulting white
suspension was then concentrated to dryness and dissolved in
CH.sub.2Cl.sub.2 (30 mL). Neat 6-(trifluoromethyl)isatin (4.0 g,
18.6 mmol) was then added at once. After stirring at room
temperature for 4 hours, the reaction was quenched with 1N HCl
solution. The organic layer was separated, washed with water and
brine, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated in vacuo to provide a dark red oil which was purified
by flash column chromatography (silica gel, 1:1 hexanes/EtOAc) to
afford the title compound as an orange solid (5.48 g, 86% yield).
.sup.1H NMR (DMSO-d.sub.6): .delta. 10.61 (s, 1H), 9.73 (s, 1H),
7.73(d, J=2.7 Hz, 1H), 7.15-7.21 (m, 2H), 7.03-7.07 (m, 2H), 6.81
(s, 1H), 6.61 (d, J=8.6 Hz, 1H).
[0086] Preparation 6
[0087] Preparation of
(.+-.)-3-[5-chloro-2-[4-(trifluoromethyl)phenylmetho-
xy]phenyl]-1,3-dihydro-3-hydroxy-6-(trifluoromethyl
)-2H-indole-2-one
[0088] To a solution of
(.+-.)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3--
hydroxy-6-(trifluoromethyl)-2H-indole-2-one (Preparation 5, 80 mg,
0.233 mmol) in 2-butanone (3 mL), was added 4-(trifluoromethyl)
benzyl bromide (61 mg, 0.256 mmol), K.sub.2CO.sub.3 (32 mg, 0.233
mmol) and a catalytic amount of Kl. The reaction mixture was heated
at 75-80.degree. C. for 2 days. The reaction mixture was then
filtered and the filtrate was concentrated in vacuo. The resulting
crude product was purified by preparative HPLC to afford the title
compound (70 mg, 60% yield); MS m/e 500 (M--H).sup.-.
[0089] Preparation 7
[0090] Preparation of 2-bromo-4-chlorobenzenediazonium
tetrafluoroborate:
[0091] A solution of 2-bromo-4-chloroaniline (10.0 g, 48.4 mmol)
and HBF.sub.4 in EtOH (60 mL) kept at 0.degree. C. was treated with
an aqueous solution (20 mL) of NaNO.sub.2 (3.34 g, 48.4 mmol).
After completion of the addition, diethyl ether (200 mL) was added
to the mixture. The solid was collected by filtration, washed with
water and dried under high vacuum affording the title compound
(14.2 g, 96%) as white crystals.
[0092] Preparation 8
[0093] Preparation of 2-bromo-4-chloro-1-methylthiobenzene:
[0094] A cold (0.degree. C.) solution of
2-bromo-4-chlorobenzenediazonium tetrafluoroborate (5.0 g, 16.3
mmol) in CH.sub.3CN (50 mL) was treated portion wise with sodium
thiomethoxide (1.15 g, 16.4 mmol) and a strong evolution of gas
(N.sub.2) was observed. The mixture was warmed up to 23.degree. C.,
stirred for 0.25 hours and filtered. The filtrate was concentrated
in vacuo; the residue was taken up in CH.sub.2Cl.sub.2, stirred and
the solution was then filtered. The CH.sub.2Cl.sub.2 filtrate was
concentrated in vacuo affording a brown syrup that was distilled
under vacuum to provide the purified title compound; bp 125.degree.
C./0.4 mm, 1.4 g, 37%. .sup.1H NMR (CDC1.sub.3) .delta. 7.56 (d, J
=2.5 Hz, H-3, 1H), 7.30 (dd, J=2.5 Hz, J=8.6 Hz, H-5, 1H), 7.07 (d,
J=8.6 Hz, H-6, 1H),2.49 (s, CH.sub.3, 3H). IR 1569, 1544, 1450,
1434, 1371,1248, 1105, 1024, 868, 803, 784 cm.sup.-1. Anal. Calcd.
for C.sub.7H.sub.6BrCIS: C, 35.39; H, 2.55. Found: C, 34.89; H,
2.51.
[0095] Preparation 9
[0096] Preparation of 2-bromo-4-chlorobenzene disulfide:
[0097] To a hot aqueous solution (70.degree. C., 100 mL) of
potassium ethyl xanthate (13.5 g, 84.2 mmol) was carefully added an
aqueous suspension (50 mL) of 2-bromo-4-chlorobenzenediazonium
tetrafluoroborate (13 g, 42.4 mmol). After the addition was
completed, the mixture was stirred at 70.degree. C. for 1 hour and,
treated successively with KOH (12.5N, 20 mL) and EtOH (40 mL). The
mixture was stirred at 80.degree. C. for 16 hours and after cooling
to 23.degree. C. was acidified with concentrated HCl and extracted
with diethyl ether. The organic layer was dried over MgSO.sub.4,
filtered and the filtrate was concentrated in vacuo. The crude
material was purified by chromatography on a silica gel column with
a mixture of 20% EtOAc/hexane as eluting solvent to afford 8.6 g of
the title compound. Trituration in MeOH provided an analytical
sample; mp 75-78.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.
7.65-7.55 (m, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.35-7.2 (m, 2H); IR
1558, 1540, 1446, 1437, 1097, 1018, 806, 777 cm.sup.-1.
[0098] Preparation 10
[0099] Preparation of 2-bromo-4-chlorobenzenethiol:
[0100] A solution of 2-bromo-4-chlorobenzene disulfide (3.8 g, 8.5
mmol) in THF (30 mL) was treated with NaBH.sub.4 (0.83 g, 22.0
mmol). The mixture was refluxed for a while and treated with MeOH
(2 mL); heating was resumed for 0.5 hours. Mixture was cooled to
23.degree. C., acidified with HCl (3N) and extracted with
Et.sub.2O. The Et.sub.2O extracts were dried over MgSO.sub.4,
filtered, and the filtrate was concentrated in vacuo to afford the
title compound which was used without further purification.
[0101] Preparation 11
[0102] Preparation of
2-bromo-4-chloro-1-(tetrahydropyran-2-ylthio)benzene- :
[0103] A mixture of 2-bromo-4-chlorothiophenol (3.74 g, 16.8 mmol),
p-toluene sulfonic acid (0.427 g, 1.7 mmol) and
3,4-dihydro-2-H-pyran (0.985 ml, 16.8 mmol) in CH.sub.2Cl.sub.2 (30
mL) was stirred at 23.degree. C. for 18 hours. After the addition
of NaOH, the organic phase was separated, dried over MgSO.sub.4,
filtered and the filtrate was concentrated in vacuo to afford the
title compound as a yellow oil, (4.91 g, 95%). .sup.1H NMR
(CDCl.sub.3) 67 7.6-7.5 (m, 2H), 7.35-7.2 (m, 1H), 5.37 (t, J=4.5
Hz, SCHO, 1H), 4.25-4.1 (m, CH.sub.2O, 1H), 3.7-3.55 (m, CH.sub.2O,
1H), 2.2-2.05 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.6 (m, 3H): IR 1566,
1542, 1450, 1367, 1257, 1188, 1101, 1037, 1024, 1008, 867, 809, 783
cm.sup.-1; Anal. Calcd. for C.sub.11H.sub.12BrCIOS: C, 42.95; H,
3.93. Found: C, 43.15; H, 3.91.
[0104] Preparation 12
[0105] Preparation of
3-(5-chloro-2-(tetrahydropyran-2-vithio)phenyl)-3-hy-
droxy-1H-6-trifluoromethyl-1,3-dihydroindol-2-one:
[0106] A cold (-78.degree. C.) solution of
2-bromo-4-chloro-1-(tetrahydrop- yran-2-ylthio)benzene (1.5 g, 4.87
mmol) in dry THF (10 mL) under an argon atmosphere was treated with
tert-BuLi (1.7 M, 6.3 mL, 10.7 mmol) and stirred for 0.5 hours. The
resulting solution was added to a solution (23.degree. C.) of
6-trifluoromethyl-1-H-indole-2,3-dione sodium salt (generated by
addition of NaH to a cold (-15.degree. C.) solution of
6-trifluoromethyl-1-H-indole-2,3-dione in dry THF (15 mL) that was
stirred for 0.25 hours). The mixture was quenched by addition of an
aqueous saturated solution of NH.sub.4Cl and diluted with
Et.sub.2O. The organic layer was separated, dried over MgSO.sub.4,
filtered and the filtrate was concentrated in vacuo to afford a
residue (2.16 g, 100%). The residue was triturated with a
CH.sub.2Cl.sub.2/hexane mixture to afford the purified title
compound; .sup.1H NMR (DMSO-d6) .delta. 10.84 and 10.82-(2s, 1H),
8.03 and 8.00 (2s, 1H), 7.5-7.4 (m, 2H), 7.3-7.2 (m, 1H), 7.15-6.95
(m, 2H), 5.0-4.9 (m, SCHO, 1H), 3.95-3.8 (m, OCH.sub.2, 1H),
3.7-3.5 (m, 1H), 3.45-3.3 (m, OCH.sub.2, 1H), 1,9-0.9 (m, 6H); IR
1718, 1637, 1458, 1319, 1167, 1134, 1116, 1057, 1036, 1009
cm.sup.-1; Anal. Calcd. for C.sub.20H17CIF.sub.3NO.sub.3S: C,
54.12; H, 3.86; N, 3.16. Found: C, 54.05; H, 3.62; N, 3.16; High
Resolution Mass Spectrum (HRMS)/ESI
C.sub.20H.sub.16O.sub.3F.sub.3N.sup.35CIS (M--H); 442.049153 found:
442.04978.
[0107] Preparation 13
[0108] Preparation of
3-(5-chloro-2-(2-methylprop-2-ylthio)phenyl)-3-hydro-
xy-1H-6-trifluoromethyl-1,3-dihydroindol-2-one:
[0109] A mixture of
2-bromo-4-chloro-1-(2-methylprop-2-ylthio)benzene (0.90 g, 3.3
mmol) and magnesium turnings (0.10 g, 4.0 mmol) in dry THF (5 mL)
was heated gently to initiate the reaction and then stirred at
23.degree. C. for 0.75 hours. The resultant brown slurry was added
to a solution (23.degree. C.) of the
6-trifluoromethyl-1-H-indole-2,3-dione sodium salt in dry THF (10
mL) (generated from isatin (0.43 g, 2.0 mmol) and NaH (0.063 g, 2,6
mmol) at 0.degree. C.). The mixture was warmed up to 23.degree. C.
and stirred for 1 hour. After quenching the reaction with saturated
aqueous NH.sub.4Cl solution, the mixture was extracted with
Et.sub.2O. The Et.sub.2O extracts were concentrated in vacuo and
the residue was purified by silica gel column chromatography to
afford the title compound: .sup.1H NMR (DMSO-d6) .delta. 10.79 (s,
NH, 1H), 8.04 (s, 1H), 7.5-7.4 (m, 2H), 7.21 (d, J=8.1 Hz, 1H),
7.08 (s, 1H), 7.02 (d, J=6.6 Hz, 1H), 7.01 (s, 1H), 0.97 (s, S-tBu,
9H); IR 1720, 1637, 1460, 1319, 1169, 1134, 1122, 1057 cm.sup.-1;
HRMS/ESI C.sub.19H.sub.17O.sub.2N- F.sub.3 .sup.35CIS (M--H).sup.-;
414.054161 found: 414.054161
[0110] Preparation 14
[0111] Preparation of
3-(5-chloro-2-ethylthiophenyl)-3-hydroxy-1H-6-triflu-
oromethyl-1,3-dihydroindol-2-one:
[0112] A solution of
3-(5-chloro-2-(tetrahydropyran-2-ylthio)phenyl)-3-hyd-
roxy-1H-6-trifluoromethyl-1,3-dihydroindol-2-one (0.153 g, 0.344
mmol) in DMF (2 mL) was first treated with an aqueous solution of
AgNO.sub.3 (0.5M, 0.69 ml), stirred at 23.degree. C. for 0.25 hours
and then treated with ethyl iodide (55 .mu.l, 0.688 mmol). The
mixture was stirred at 80.degree. C. for 2 hours, and was then
treated with HCl (3N) after cooling to 23.degree. C. The reaction
mixture was then filtered on a Celite pad. The filter cake was
washed with CH.sub.3OH. The filtrate and washings were combined and
concentrated in vacuo. The residue was dissolved in EtOAc and the
solution washed with H.sub.2O and brine. The organic layer was
dried over MgSO.sub.4, filtered and the filtrate concentrated in
vacuo. The crude material was purified by silica gel column
chromatography to afford the title compound (0.53 g, 40%) as white
crystals; mp 167-169.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.
10.81 (s, NH, 1H), 8.0 (d, J=2.0 Hz, 1H), 7.5-7.2 (m, 2H), 7.23 (d,
J=8.6 Hz, 1H), 7.08 (d, J =6.0 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H),
2.7-2.6 (m, SCH.sub.2, 1H,), 2.6-2.45 (m, SCH.sub.2 partially
masked by DMSO, 1H), 0.83 (t, J=7 Hz, CH.sub.3, 3H); IR 1716, 1635,
1458, 1317, 1173, 1130, 1057 cm.sup.-1; Anal. Calcd. for
C.sub.17H.sub.13CIF.sub.3NO.sub.2S: C, 52.65; H, 3.38; N, 3.61.
Found: C, 52.29; H, 3.10; N, 3,60; HRMS/ESI
C.sub.17H.sub.12O.sub.2F.sub.3N.sup.35CIS (M--H).sup.-; 387.02295
found: 386.02097.
[0113] The following examples illustrate the preparation of the
compounds of Formula I by following the general procedures
described herein.
EXAMPLE 1
(.+-.)-3-[5-Chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-fluoro--
6-(trifluoromethyl)-2H-indol-2-one
[0114] Neat diethylaminosulfur trifluoride (3.66 mL, 0.03 mol) was
added dropwise to a cold (-78.degree. C.) stirred partial solution
of
(.+-.)-3-[5-chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-hydrox-
y-6-(trifluoromethyl)-2H-indol-2-one (Preparation 4, 6.4 g, 0.015
mol) in anhydrous CH.sub.2Cl.sub.2 (45 mL) under a nitrogen
atmosphere. The resultant mixture was allowed to warm in an
ice-bath and maintained at 0.degree. C. After 1 hour, TLC showed
absence of starting material. The reaction mixture was quenched
with slow addition of cold water (20-25 mL) at 0.degree. C. The
organic layer was separated, washed with water (30 mL), brine (30
mL) and then dried over MgSO.sub.4 and filtered. The filtrate was
concentrated in vacuo to give the crude product (6.9 g). The crude
product was purified by recrystallization from
CH.sub.2Cl.sub.2/ether/hexanes to provide the titled compound as an
off-white crystalline solid (5.94 g, 93%): mp 208-210.degree. C.;
.sup.1H NMR (DMSO-d.sub.6): .delta. 4.50-4.65 (m, 2H), 7.12 (m,
2H), 7.30-7.35 (m, 2H), 7.56 (dd, 1H, J=5.3 and 1.6 Hz), 7.72 (d,
1H, J=1.4 Hz), 11.20 (s, 1H).
[0115] Anal. Calcd. for C1.sub.7H.sub.9CIF.sub.7NO.sub.2: C, 47.74;
H, 2.12, N, 3.27. Found: C, 47.63; H, 2.18, N, 3.21.
EXAMPLE 2
Isolation of
(+)-3-[5-Chloro-2-f(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-
-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one
[0116] The racemic compound
(.+-.)-3-[5-chloro-2-[(2,2,2-trifluoroethoxy)p-
henyl]-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one
obtained in Example 1 was separated into its enantiomers using a
Chiracel-OD analytical HPLC column (250.times.4 mm) using 9:1
hexanes/isopropyl alcohol as the eluting solvent at a flow rate of
0.7 mL/min. The detection method employed a HP 1090 UV detector
with diode array at a wavelength of 220 nm. The first enantiomer
which eluted from the column had a retention time of about 8.64
minutes and was determined to be the (+)-enantiomer of the title
compound. On a preparative scale, up to two grams of the racemate
may be resolved with a single injection on a 5.times.50 cm
Chiracel-OD preparative HPLC column using 9:1 hexanes/isopropyl
alcohol at a flow rate of 60 mL/min with baseline separation. The
(+)-enantiomer was identical to the racemate with respect to NMR,
mass spectra, TLC and IR. The title compound was found to have a
mp=68-69.degree. C. and [.alpha.].sub.D.sup.25+120.5.degree.
(CHCl.sub.3).
EXAMPLE 3
Isolation of
(-)-3-[5-Chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-
-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one
[0117] Using the same isolation process as described above for
Example 2, the second enantiomer eluted from the same column at a
retention time of about 15.19 minutes was determined to be the
(-)-enantiomer of the title compound. The (-)-enantiomer was
identical to the racemate with respect to NMR, mass spectra, TLC
and IR. The title compound was found to have a mp=69-70.degree. C.
and [.alpha.].sub.D.sup.25-128.1.degree. (CHCl.sub.3).
EXAMPLE 4
Preparation of
(.+-.)-3-[5-chloro-2-[4-(trifluoromethyl)phenylmethoxy]-phe-
nyl]-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one
[0118] To a suspension of
(.+-.)-3-[5-chloro-2-[4-(trifluoromethyl)phenyl--
methoxy]phenyl]-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indole-2-one
(Preparation 6, 45 mg, 0.09 mmol) in CH.sub.2Cl.sub.2 (3 mL), was
added dropwise neat diethylaminosulfur trifluoride (0.018 mL, 0.135
mmol) at -78.degree. C. The reaction mixture was warmed to room
temperature for 15 minutes and then quenched with water. The
organic layer was separated, washed with water, dried over
MgSO.sub.4 and filtered. The filtrate was concentrated in vacuo to
provide the title compound (35 mg, 77% yield). MS m/e 502
(MH.sup.-). .sup.1H NMR (CDCl.sub.3): .delta. 7.84 (d, J=1.95 Hz,
1H), 7.68 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.36 (dd, J=8.7 Hz, 2.5
Hz, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 7.05 (d, J=8.1 Hz, 2H),
6.81(dd, J=8.8 Hz, 1.1 Hz, 1H), 6.73 (s, 1H), 4,88 (d, 11.0 Hz,
1H), 4.73 (d, J=11.0 Hz, 1H).
EXAMPLE 5
Preparation of
3-(5-chloro-2-methylthiophenyl)-3-fluoro-1H-6-trifluorometh- yl-1
3-dihydroindol-2-one
[0119] A solution of
3-(5-chloro-2-methylthiophenyl)-3-hydroxy-1H-6-triflu-
oromethyl-1,3-dihydroindol-2-one (0.28 g, 0.75 mmol) in
CH.sub.2Cl.sub.2 (12 mL) was cooled at -78.degree. C. and treated
with diethylaminosulfur trifluoride (0.130 mL, 0.97 mmol). After
removing the cooling bath, the mixture was stirred at 23.degree. C.
for 0.25 hours and quenched by the addition of water. The two
phases were separated and the aqueous phase was extracted with
EtOAc. The combined organic layers were dried over MgSO.sub.4,
filtered and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography on silica gel. Trituration of
the pure product with a CH.sub.2Cl.sub.2/hexane mixture afforded
the title compound (0.243 g, 86%), as a crystalline solid.
mp157-158.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 11.37 (s,
NH, 1H), 7.75 (s, 1H), 7.57 (dd, J=2.5 Hz, J=8.6 Hz,1H), 7.53 (d,
J=8.6 Hz,1H), 7.4-7.3 (m, 2H), 7.2 (s, 1H), 2.22 (s, SCH.sub.3,
3H); IR 1728, 1637, 1458, 1318, 1235, 1174, 1130, 1058
cm.sup.-1;
[0120] Anal. Calcd. for C.sub.16H.sub.10CIF.sub.4NOS: C, 51.14; H,
2.68; N, 3.73. Found: C, 51.08; H, 2.38; N, 3,53; HRMS/MAB
C.sub.16H.sub.9O.sub.3F.sub.4N.sup.35CIS (M+); 375.01077 found:
375.0097.
PROCEDURE FOR EXAMPLES 6-13
[0121] 8
[0122] Examples 6-11 were prepared by reacting the Grignard reagent
derived from 2-bromo-4-chloro(2,2,2-trifluoroethoxy)benzene
(Preparation 1) and an appropriately substituted 2,3-indolinedione
according to the methods described previously for Preparation 4.
The resulting intermediate
(.+-.)-3-[5-chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1,3-dih-
ydro-3-hydroxy-2H-indol-2-one derivative was then fluorinated using
diethylaminosulfur trifluoride according to the method as described
for Example 1 to provide the compounds of Examples 6-11. Examples
12 and 13 were obtained from Example 11 by separation of the
enantiomers according to the methods as previously described for
Examples 2 and 3.
EXAMPLE 6
(.+-.)-3-[5-Chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3,6-difluo-
ro-2H-indol-2-one; (R.sup.1, R.sup.3, R.sup.4 are H; R.sup.2 is
F)
[0123] mp 200-202.degree. C.; MS m/e 376 (M--H).sup.-
EXAMPLE 7
(.+-.)-3-[5-Chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-fluoro-6-
-(fluoromethyl)-2H-indol-2-one; (R.sup.1, R.sup.3, R.sup.4 are H;
R.sup.2 is CH.sub.2F)
[0124] mp 150-151.degree. C.; MS m/e 390 (M--H).sup.-.
EXAMPLE 8
(.+-.)-3-[5-Chloro-2-(2,2,2-trifluoroethoxy)phenyl]-46-dichloro-1,3-dihydr-
o-3-fluoro-2H-indol-2-one; (R.sup.1 and R.sup.4 are H; R.sup.2 and
R.sup.3 are Cl)
[0125] mp 230-232.degree. C.; MS m/e 427 (M--H).sup.-.
EXAMPLE 9
(.+-.)-3-[5-Chloro-2-(2,2,2-trifluoroethoxy)phenyl]-5,6-dichloro-1,3-dihyd-
ro-3-fluoro-2H-indol-2-one; (R.sup.1 and R.sup.3 are H; R.sup.2 and
R.sup.4 are Cl)
[0126] mp 200-202.degree. C.; MS m/e 427 (M--H).sup.-.
EXAMPLE 10
(.+-.)-3-[5-Chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3,5,6-trif-
luoro-2H-indol-2-one; (R.sup.1 and R.sup.3 are H; R.sup.2 and
R.sup.4 are F)
[0127] mp 200-203.degree. C.; MS m/e 394 (M--H).sup.-.
EXAMPLE 11
(.+-.)-6-Chloro-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-
-fluoro-2H-indol-2-one; (R.sup.1, R.sup.3, R.sup.4 are H; R.sup.2
is Cl)
[0128] mp 167-169 .degree. C.; MS m/e 393 (M--H).sup.-.
EXAMPLE 12
(+)-6-Chloro-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl-1,3-dihydro-3-flu-
oro-2H-indol-2-one; (R.sup.1, R.sup.3, R.sup.4 are H; R.sup.2 is
Cl)
[0129] [.alpha.].sub.D.sup.25+149.3.degree. (CHCl.sub.3); MS m/e
393 (M--H).sup.-.
EXAMPLE 13
(-)-6-Chloro-3-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-fl-
uoro-2H-indol-2-one; (R.sup.1, R.sup.3, R.sup.4 are H; R.sup.2 is
Cl)
[0130] [.alpha.].sub.D.sup.25-146.3.degree. (CHCl.sub.3); MS m/e
393 (M--H).sup.-.
PROCEDURE FOR EXAMPLES 14-15
[0131] 9
[0132] Examples 14 and 15 were prepared by reacting the Grignard
reagent derived from either 2-bromo-4-chloro(2-fluoroethoxy)benzene
(Preparation 3, for Example 14) or
2-bromo-4,5-dichloro(2-fluoroethoxy)benzene (for Example 15),
respectively, and the sodium salt of 6-trifluoromethyl
2,3-indolinedione according to the methods described previously for
Preparation 4. The resulting intermediate
(.+-.)-3-[5-chloro-2-[(2-fluoro-
ethoxy)phenyl]-1,3-dihydro-3-hydroxy-2H-indol-2-one (for Example
14) or
(.+-.)-3-[4,5-dichloro-2-[(2-fluoroethoxy)phenyl]-1,3-dihydro-3-hydroxy-2-
H-indol-2-one (for Example 15) was then fluorinated using
diethylaminosulfur trifluoride according to the method as described
for Example I to provide the title compounds of Examples 14 and 15,
respectively.
EXAMPLE 14
(.+-.)-3-[5-Chloro-2-(2-fluoroethoxy)phenyl-1,3-dihydro-3-fluoro-6-(triflu-
oromethyl)-2H-indol-2-one; (R.sup.7 is H)
[0133] MS m/e 390 (M--H.sup.-); .sup.1H-NMR (CDCl.sub.3,
.delta.=ppm) 7.83 (d, J=1.9 Hz, 1H), 7.66 (brd s, 1H), 7.50 (dd,
J=8.7,2.4 Hz, 1H), 7.33-7.19 (m, 2H), 7.16 (s, 1H), 6.73 (d, J=7.5
Hz, 1H), 4.68-3.85 (m, 4H).
EXAMPLE 15
(.+-.)-3-[4,5-Dichloro-2-(2-fluoroethoxy)phenyl]-1,3-dihydro-3-fluoro-6-(t-
rifluoromethyl)-2H-indol-2-one; (R.sup.7 is Cl)
[0134] MS m/e 448 (M+Na).sup.+.
PROCEDURE FOR EXAMPLES 16-22
[0135] 10
[0136] Examples 16-22 were prepared by fluorination of the
3-hydroxy moiety of the corresponding
3-[5-chloro-2-(alkylthio)phenyl]-1,3-dihydro--
3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one with
diethylaminosulfur trifluoride according to the procedure as
previously described in Example 5. The
3-[5-chloro-2-(alkylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluoro-
methyl)-2H-indol-2-one was then isolated as in Example 5 to provide
the title compounds of Examples 16-22. The
3-[5-chloro-2-(alkylthio)phenyl]-1-
,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one
intermediates were prepared by alkylation of the silver salt of the
thiol (described in Preparation 14) with an appropriate
electrophile according to the procedure previously described for
Preparation 14. For example,
3-[5-chloro-2-(2-fluoroethylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluor-
omethyl)-2H-indol-2-one (compound of Example 16) was prepared by
alkylation of the thiol silver salt (of Preparation 14) with
1-bromo-2-fluoroethane followed by fluorination with
diethylaminosulfur trifluoride.
EXAMPLE 16
3-[5-Chloro-2-(2-fluoroethylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluoro-
methyl)-2H-indol-2-one; (R.sup.5 is CH.sub.2CH.sub.2F)
[0137] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.35 (s, NH, 1H), 7.79
(s, 1H), 7.68 (d, J=9.6 Hz, 1H), 7.6 (dd, J=2.5 Hz, J=8.6 Hz, 1H),
7.3-7.3 (m, 2H), 7.21 (s, 1H), 4.35-4.1 (2m, CH.sub.2F, 2H),
3.15-2.8 (m, SCH.sub.2, 2H); IR 1734, 1635, 1458, 1319, 1236, 1170,
1130, 1057 cm.sup.-1; HRMS/ESI C.sub.17H.sub.10OF.sub.5N.sup.35ClS
(M--H).sup.-; 406.009176 found: 406.0098.
EXAMPLE 17
3-[5-Chloro-2-(ethylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluoromethyl)--
2H-indol-2-one; (R.sup.5 is CH.sub.2CH.sub.3)
[0138] mp 105-7.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.
11.36 (s, NH, 1H), 7.78 (s, 1H), 7.65-7.5 (m, 2H), 7.4-7.25 (m,
2H), 7.2 (s, 1H), 2.8-2.55 (2m, SCH.sub.2, 2H), (t, J=7 Hz,
CH.sub.3, 3H); IR 1741, 1637, 1462, 1319, 1234, 1178, 1132, 1057
cm.sup.-1;
[0139] Anal. Calcd. for C.sub.17H.sub.12CIF.sub.4NOS: C, 52.38; H,
3.10; N, 3.73. Found: C, 52.16; H, 3.19; N, 3.65;
[0140] HRMS/ESI C.sub.17H.sub.11OF.sub.4N.sup.35CIS (M--H).sup.-;
388.020238 found: 388.0202 (.delta.=4.2 ppm).
EXAMPLE 18
3-[5-Chloro-2-[(2-methylphenylmethyl)thiolphenyl]-1,3-dihydro-3-fluoro-6-(-
trifluoromethyl)-2H-indol-2-one; (R.sup.5 is
2-methylphenylmethyl)
[0141] MS m/e 464 (M--H).sup.-.
EXAMPLE 19
3-[5-Chloro-2-(2-methyl-1-propylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifl-
uoromethyl)-2H-indol-2-one; (R.sup.5 is
CH.sub.3CH(CH.sub.3)CH.sub.2)
[0142] MS m/e 416 (M--H).sup.-.
EXAMPLE 20
3-[5-Chloro-2-(1-propylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifluoromethy-
l)-2H-indol-2-one; (R.sup.5 is CH.sub.3CH.sub.2CH.sub.2)
[0143] MS m/e 402 (M--H).sup.-.
EXAMPLE 21
3-[5-Chloro-2-(2,5-difluorophenylmethylthio)phenyl]-1,3-dihydro-3-fluoro-6-
-(trifluoromethyl)-2H-indol-2-one; (R.sup.5 is
2,5-difluorophenylmethyl)
[0144] MS m/e 489 (M--H).sup.-.
EXAMPLE 22
3-[5-Chloro-2-(3-chloro-1-propylthio)phenyl]-1,3-dihydro-3-fluoro-6-(trifl-
uoromethyl)-2H-indol-2-one; (R.sup.5 is
ClCH.sub.2CH.sub.2CH.sub.2)
[0145] MS m/e 437 (M--H).sup.-.
EXAMPLE 23
(.+-.)-3-[5-Chloro-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dihydro-3-fluoro-6-
-[4-(trifluoromethyl)phenyl]-2H-indol-2-one
[0146] mp 103-105.degree. C.; MS m/e 502 (M--H).sup.-
* * * * *