U.S. patent application number 09/950957 was filed with the patent office on 2002-01-31 for certain 5-alkyl-2arylaminophenylacetic acids and derivatives.
Invention is credited to Fujimoto, Roger A., McQuire, Leslie W., Mugrage, Benjamin B., van Duzer, John H., Xu, Daqiang.
Application Number | 20020013369 09/950957 |
Document ID | / |
Family ID | 26736901 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013369 |
Kind Code |
A1 |
Fujimoto, Roger A. ; et
al. |
January 31, 2002 |
Certain 5-alkyl-2arylaminophenylacetic acids and derivatives
Abstract
Disclosed are the compounds of formula I 1 wherein R is methyl
or ethyl; R.sub.1 is chloro or fluoro; R.sub.2 is hydrogen or
fluoro; R.sub.3 is hydrogen, fluoro, chloro, methyl, ethyl,
methoxy, ethoxy or hydroxy; R.sub.4 is hydrogen or fluoro; and
R.sub.5 is chloro, fluoro, trifluoromethyl or methyl; and
pharmaceutically acceptable salts thereof, as selective COX-2
cyclooxygenase inhibitors; and pharmaceutically acceptable prodrug
esters thereof.
Inventors: |
Fujimoto, Roger A.;
(Morristown, NJ) ; McQuire, Leslie W.; (Warren,
NJ) ; Mugrage, Benjamin B.; (Basking Ridge, NJ)
; van Duzer, John H.; (Asbury, NJ) ; Xu,
Daqiang; (Whippany, NJ) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
26736901 |
Appl. No.: |
09/950957 |
Filed: |
September 13, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09950957 |
Sep 13, 2001 |
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09722767 |
Nov 27, 2000 |
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6310099 |
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09722767 |
Nov 27, 2000 |
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09139254 |
Aug 25, 1998 |
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6291523 |
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60069837 |
Aug 28, 1997 |
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60057803 |
Aug 28, 1997 |
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Current U.S.
Class: |
514/567 ;
562/457 |
Current CPC
Class: |
A61P 19/00 20180101;
C07C 229/42 20130101; A61P 25/00 20180101; A61P 25/04 20180101;
A61P 19/02 20180101; A61P 29/00 20180101; A61P 27/02 20180101; A61P
35/00 20180101 |
Class at
Publication: |
514/567 ;
562/457 |
International
Class: |
A61K 031/195; C07C
229/40 |
Claims
What is claimed is:
1. A compound of formula I 13wherein R is methyl or ethyl; R.sub.1
is chloro or fluoro; R.sub.2 is hydrogen or fluoro; R.sub.3 is
hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or
hydroxy; R.sub.4 is hydrogen or fluoro; and R.sub.5 is chloro,
fluoro, trifluoromethyl or methyl; or a pharmaceutically acceptable
salt thereof; or a pharmaceutically acceptable prodrug ester
thereof.
2. A compound according to claim 1 wherein R is methyl or ethyl;
R.sub.1 is chloro or fluoro; R.sub.2 is hydrogen; R.sub.3 is
hydrogen, fluoro, chloro, methyl or hydroxy; R.sub.4 is hydrogen;
and R.sub.5 is chloro, fluoro or methyl; or a pharmaceutically
acceptable salt thereof; or a pharmaceutically acceptable prodrug
ester thereof.
3. A compound according to claim 1 wherein R is methyl or ethyl;
R.sub.1 is fluoro; R.sub.2 is hydrogen; R.sub.3 is hydrogen, fluoro
or hydroxy; R.sub.4 is hydrogen; and R.sub.5 is chloro; or a
pharmaceutically acceptable salt thereof; or a pharmaceutically
acceptable prodrug ester thereof.
4. A compound according to claim 1 wherein R is methyl or ethyl;
R.sub.1 is fluoro; R.sub.2 is fluoro; R.sub.3 is hydrogen, ethoxy
or hydroxy; R.sub.4 is fluoro; and R.sub.5 is fluoro; or a
pharmaceutically acceptable salt thereof; or a pharmaceutically
acceptable prodrug ester thereof.
5. A compound according to claim 1 wherein R is methyl; R.sub.1 is
fluoro; R.sub.2 is hydrogen; R.sub.3 is hydrogen or fluoro; R.sub.4
is hydrogen; and R.sub.5 is chloro; or a pharmaceutically
acceptable salt thereof; or a pharmaceutically acceptable prodrug
ester thereof.
6. A compound according to claim 1 which is
5-methyl-2-(2'-chloro-6'-fluor- oanilino)phenylacetic acid wherein
in formula I R is methyl; R.sub.1 is fluoro; R.sub.2 is hydrogen;
R.sub.3 is hydrogen; R.sub.4 is hydrogen; and R.sub.5 is chloro; or
a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 which is
5-methyl-2-(2',4'-difluoro-6'-- chloroanilino)phenylacetic acid
wherein in formula I R is methyl; R.sub.1 is fluoro; R.sub.2 is
hydrogen; R.sub.3 is fluoro; R.sub.4 is hydrogen; and R.sub.5 is
chloro; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 which is
5-ethyl-2-(2',3',5',6'-tetrafl- uoroanilino)phenylacetic acid
wherein in formula I R is ethyl; R.sub.1 is fluoro; R.sub.2 is
fluoro; R.sub.3 is hydrogen; R.sub.4 is fluoro; and R.sub.5 is
fluoro; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1 which is
5-ethyl-2-(2',4'-dichloro-6'-m- ethylanilino)phenylacetic acid
wherein in formula I R is ethyl; R.sub.1 is chloro; R.sub.2 is
hydrogen; R.sub.3 is chloro; R.sub.4 is hydrogen; and R.sub.5 is
methyl; or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising an effective
cyclooxygenase-2 inhibiting amount of a compound of claim 1 which
is substantially free of cyclooxygenase-1 inhibiting activity in
combination with one or more pharmaceutically acceptable
carriers.
11. A pharmaceutical composition comprising an effective
cyclooxygenase-2 inhibiting amount of a compound of claim 6 which
is substantially free of cyclooxygenase-1 inhibiting activity in
combination with one or more pharmaceutically acceptable
carriers.
12. A pharmaceutical composition comprising an effective
cyclooxygenase-2 inhibiting amount of a compound of claim 7 which
is substantially free of cyclooxygenase-1 inhibiting activity in
combination with one or more pharmaceutically acceptable
carriers.
13. A pharmaceutical composition comprising an effective
cyclooxygenase-2 inhibiting amount of a compound of claim 8 which
is substantially free of cyclooxygenase-1 inhibiting activity in
combination with one or more pharmaceutically acceptable
carriers.
14. A pharmaceutical composition comprising an effective
cyclooxygenase-2 inhibiting amount of a compound of claim 9 which
is substantially free of cyclooxygenase-1 inhibiting activity in
combination with one or more pharmaceutically acceptable
carriers.
15. A method of treating cyclooxygenase-2 dependent disorders in
mammals while substantially eliminating undesirable side effects
associated with cyclooxygenase-1 inhibiting activity which
comprises administering to a mammal in need thereof an effective
cyclooxygenase-2 inhibiting amount of a compound of claim I which
is substantially free of cyclooxygenase-1 inhibiting activity.
16. A method of selectively inhibiting cyclooxygenase-2 activity in
a mammal without substantially inhibiting cycloxygenase-1 activity
which comprises administering to a mammal in need thereof an
effective cyclooxygenase-2 inhibiting amount of a compound of claim
1 which is substantially free of cyclooxygenase-1 inhibiting
activity.
17. A method of treating rheumatoid arthritis, osteoarthritis,
pain, inflammation in mammals which comprises administering to a
mammal in need thereof a correspondingly effective amount of a
compound of claim I which is substantially free of gastrointestinal
ulceration.
18. A method of treating ocular inflammatory disorders, glaucoma or
dry eye disease in mammals which comprises administering to a
mammal in need thereof a correspondingly effective amount of a
compound of claim 1.
19. A method for the preparation of a compound of formula I
according to claim 1 which comprises: (a) coupling a compound of
formula II or IIa 14wherein R has meaning as defined; R.sub.a is
lower alkyl; and R.sub.6 and R.sub.7 represent lower alkyl; or
R.sub.6 and R.sub.7 together with the nitrogen atom represent
piperidino, pyrrolidino or morpholino; with a compound of formula
III 15wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 have
meaning as defined in said claim 1, in the presence of copper and
cuprous iodide, to obtain a compound of formula IV or IVa 16and
hydrolyzing the resulting compound of formula IV or IVa to a
compound of formula I; or (b) for compounds in which R represents
ethyl, condensing a compound of formula V 17wherein R.sub.1-R.sub.7
have meaning as defined above, with a reactive functional
derivative of acetic acid, such as acetyl chloride, in a
Friedel-Crafts acylation reaction to obtain a compound of the
formula VI 18wherein R.sub.1-R.sub.7 have meaning as defined above,
and which is in turn hydrogenolyzed and then hydrolyzed to obtain a
compound of formula I wherein R represents ethyl; or (c)
hydrolyzing a lactam of formula VII 19wherein R and R.sub.1-R.sub.5
have meaning as defined, with a strong base; and in above
processes, if desired, temporarily protecting any interfering
reactive groups and then isolating the resulting compound of the
invention; and, if desired, converting any resulting compound into
another compound of the invention; and/or if desired converting a
free carboxylic acid of the invention into a pharmaceutically
acceptable ester derivative thereof; and/or if desired, converting
a resulting free acid into a salt or a resulting salt into the free
acid or into another salt.
20. A compound according to claim 1 of formula 20wherein R is
methyl or ethyl; R.sub.1 is chloro or fluoro; R.sub.2 is hydrogen
or fluoro; R.sub.3 is hydrogen, fluoro, chloro, methyl, ethyl,
methoxy, ethoxy or hydroxy; R.sub.4 is hydrogen or fluoro; and
R.sub.5 is chloro, fluoro, trifluoromethyl or methyl; or a
pharmaceutically acceptable salt thereof.
21. A compound according to claim 20 wherein R is methyl or ethyl;
R.sub.1 is chloro or fluoro; R.sub.2 is hydrogen; R.sub.3 is
hydrogen, fluoro, chloro, methyl or hydroxy; R.sub.4 is hydrogen;
and R.sub.5 is chloro, fluoro or methyl; or a pharmaceutically
acceptable salt thereof.
22. A compound according to claim 20 wherein R is methyl or ethyl;
R.sub.1 is fluoro; R.sub.2 is hydrogen; R.sub.3 is hydrogen, fluoro
or hydroxy; R.sub.4 is hydrogen; and R.sub.5 is chloro; or a
pharmaceutically acceptable salt thereof.
23. A compound according to claim 20 wherein R is methyl or ethyl;
R.sub.1 is fluoro; R.sub.2 is fluoro; R.sub.3 is hydrogen, ethoxy
or hydroxy; R.sub.4 is fluoro; and R.sub.5 is fluoro; or a
pharmaceutically acceptable salt thereof.
24. A compound according to claim 20 wherein R is methyl or ethyl;
R.sub.1 is fluoro; R.sub.2 is hydrogen; R.sub.3 is hydrogen or
fluoro; R.sub.4 is hydrogen; and R.sub.5 is chloro; or a
pharmaceutically acceptable salt thereof.
25. A compound according to claim 20 which is carboxymethyl
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetate wherein in
formula I R is methyl; R.sub.1 is fluoro; R.sub.2 is hydrogen;
R.sub.3 is hydrogen; R.sub.4 is hydrogen; and R.sub.5 is chloro; or
a pharmaceutically acceptable salt thereof.
26. A compound according to claim 20 which is carboxymethyl
5-methyl-2-(2',4'-difluoro-6'-chloroanilino)phenylacetate wherein
in formula I R is methyl; R.sub.1 is fluoro; R.sub.2 is hydrogen;
R.sub.3 is fluoro; R.sub.4 is hydrogen; and R.sub.5 is chloro; or a
pharmaceutically acceptable salt thereof.
27. A compound according to claim 20 which is carboxymethyl
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetate wherein in
formula I R is ethyl; R.sub.1 is fluoro; R.sub.2 is fluoro; R.sub.3
is hydrogen; R.sub.4 is fluoro; and R.sub.5 is fluoro; or a
pharmaceutically acceptable salt thereof.
28. A compound according to claim 20 which is carboxymethyl
5-ethyl-2-(2'4'-dichloro-6'-methylanilino)phenylacetate wherein in
formula I R is ethyl; R.sub.1 is chloro; R.sub.2 is hydrogen;
R.sub.3 is chloro; R.sub.4 is hydrogen; and R.sub.5 is methyl; or a
pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising an effective
antiinflammatory amount of a compound of claim 20 which is
substantially free of gastrointestinal ulceration in combination
with one or more pharmaceutically acceptable carriers.
30. A pharmaceutical composition comprising an effective
antiinflammatory amount of a compound of claim 25 which is
substantially free of gastrointestinal ulceration in combination
with one or more pharmaceutically acceptable carriers.
31. A pharmaceutical composition comprising an effective
antiinflammatory amount of a compound of claim 26 which is
essentially free of gastrointestinal ulceration in combination with
one or more pharmaceutically acceptable carriers.
32. A pharmaceutical composition comprising an effective
antiinflammatory amount of a compound of claim 27 which is
substantially free of gastrointestinal ulceration in combination
with one or more pharmaceutically acceptable carriers.
33. A pharmaceutical composition comprising an effective
antiinflammatory amount of a compound of claim 28 which is
substantially free of gastrointestinal ulceration in combination
with one or more pharmaceutically acceptable carriers.
34. A method of treating cyclooxygenase dependent disorders in
mammals without causing undesirable gastrointestinal side effects
which comprises administering to a mammal in need thereof an
effective amount of a compound according to claim 20 which is
substantially free of gastrointestinal ulceration.
35. A method of treating rheumatoid arthritis, osteoarthritis, pain
or inflammation in mammals without causing undesirable
gastrointestinal side effects which comprises administering to a
mammal in need thereof a correspondingly effective amount of a
compound of claim 20 which is substantially free of
gastrointestinal ulceration.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application No. 60/069,837 filed Aug. 28, 1997 and of U.S.
provisional application No. 60/057,803 filed Aug. 28, 1997.
BACKGROUND AND SUMMARY OF THE INVENTION
[0002] The invention relates to 5-alkyl-2-arylaminophenylacetic
acids and derivatives thereof as defined herein which are
particularly potent and selective cyclooxygenase-2(COX-2)
inhibitors, methods for preparation thereof, pharmaceutical
compositions comprising said compounds, methods of selectively
inhibiting COX-2 activity and of treating conditions in mammals
which are responsive to COX-2 inhibition using said compounds or
pharmaceutical compositions comprising said compounds of the
invention.
[0003] Various substituted 2-arylaminophenylacetic acids and
derivatives thereof have been disclosed e.g. in J. Med. Chem. 33,
2358 (1990), U.S. Pat. Nos. 3,558,690, 3,652,762, 4,173,577 and
4,548,952, and in PCT applications WO94/04484, WO 97/09977, WO
96/00716 and DE 3,445,011 as analgesic agents, non-steroidal
antiinflammatory agents and cyclooxygenase inhibitors. As to
5-alkyl-2-arylaminophenylacetic acids, the only example known to be
described in the literature is
5-methyl-2-(2,6-dimethylanilino)-phenylacetic acid and its sodium
salt (U.S. Pat. No. 3,558,690) for which no biological data has
been reported.
[0004] 2-(2,6-Dichlorophenylamino) phenylacetoxyacetic acid
(aceclofenac) and salts thereof have been disclosed e.g. in U.S.
Pat. No. 4,548,952, and in PCT application WO 96/00716 as
non-steroidal antiinflammatory and analgesic agents. The
pharmacological properties of aceclofenac are apparently the result
of in vivo conversion to diclofenac and/or derivatives thereof.
[0005] Non-steroidal antiinflammatory agents block prostaglandin
synthesis by inhibition of the enzyme cyclooxygenase.
Cyclooxygenase is now known to comprise a constitutive isoform
(cyclooxygenase-1, COX-1) and an inducible isoform
(cyclooxygenase-2, COX-2). COX-1 appears responsible for protective
beneficial features of prostaglandins, e.g. for the
gastrointestinal tract, kidney, etc., while the inducible isoform
COX-2 appears responsible for pathological conditions associated
with prostaglandins, such as inflammatory conditions. A limitation
to the use of conventional nonsteroidal antiinflammatory drugs
(NSAIDS), including aceclofenac and diclofenac sodium which is the
sodium salt of 2,6-dichloroanilinophenylacetic acid, is
gastrointestinal toxicity now attributed to the inhibition of the
COX-1 isoform of cyclooxygenase. Selective inhibition of inducible
COX-2 in vivo has been reported to be antiinflammatory and
non-ulcerogenic (Proc. Natl. Acad. Sci. (USA) 1994;
91:3228-3232).
[0006] The present invention provides novel 5-alkyl substituted
2-arylaminophenylacetic acids and derivatives which surprisingly
inhibit COX-2 without significantly inhibiting COX-1. The invention
thus provides novel nonsteroidal antiinflammatory agents which are
surprisingly free of undesirable side effects usually associated
with the classical nonsteroidal antiinflammatory agents, such as
gastrointestinal and renal side effects.
[0007] The compounds of the present invention are thus particularly
useful or may be metabolically converted to compounds which are
particularly useful as COX-2 selective cyclooxygenase inhibitors.
They are thus particularly useful for the treatment of
cyclooxygenase-2 dependent disorders in mammals, including
inflammation, pyresis, pain, osteoarthritis, rheumatoid arthritis,
migraine headache, cancer such as digestive tract (e.g. colon)
cancer and melanoma, neurodegenerative diseases (such as multiple
sclerosis), Alzheimer's disease, osteoporosis, asthma, lupus and
psoriasis while substantially eliminating undesirable
gastrointestinal ulceration associated with conventional
cyclooxygenase inhibitors. The compounds of the invention are also
UV absorbers, in particular UV-B absorbers, and are useful for
blocking or absorbing UV radiation, for instance for the treatment
and prevention of sunburn, e.g. in suntan products.
[0008] Ocular applications of the compounds of the invention
include the treatment of ocular inflammation, of ocular pain
including pain associated with ocular surgery such as PRK or
cataract surgery, of ocular allergy, of photophobia of various
etiology, of elevated intraocular pressure (in glaucoma) by
inhibiting the production of trabecular meshwork inducible
glucocorticoid response (TIGR) protein and of dry eye disease.
[0009] The compounds of the present invention are useful for the
treatment of neoplasia particularly neoplasia that produce
prostaglandins or express cyclooxygenase, including both benign and
cancerous tumors, growths and polyps, in particular epithelium
cell-derived neoplasia. Compounds of the present invention are in
particular useful for the treatment of liver, bladder, pancreatic,
ovarian, prostate, cervical, lung and breast cancer and, especially
gastrointestinal cancer, for example cancer of the colon, and skin
cancer, for example squamous cell or basal cell cancers and
melanoma, as indicated above.
[0010] The term "treatment" as used herein is to be understood as
including both therapeutic and prophylactic modes of therapy, e.g.
in relation to the treatment of neoplasia, therapy to prevent the
onset of clinically or preclinically evident neoplasia, or for the
prevention of initiation of malignant cells or to arrest or reverse
the progression of premalignant to malignant cells, as well as the
prevention or inhibition of neoplasia growth or metastasis. In this
context, the present invention is, in particular, to be understood
as embracing the use of compounds of the present invention to
inhibit or prevent development of skin cancer, e.g. squamous or
basal cell carcinoma consequential to UV light exposure, e.g.
resulting from chronic exposure to the sun.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The invention relates to compounds of formula I 2
[0012] wherein
[0013] R is methyl or ethyl;
[0014] R.sub.1 is chloro or fluoro;
[0015] R.sub.2 is hydrogen or fluoro;
[0016] R.sub.3 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy,
ethoxy or hydroxy;
[0017] R.sub.4 is hydrogen or fluoro; and
[0018] R.sub.5 is chloro, fluoro, trifluoromethyl or methyl;
[0019] pharmaceutically acceptable salts thereof; and
[0020] pharmaceutically acceptable prodrug esters thereof.
[0021] A particular embodiment of the invention relates to the
compounds of formula I wherein R is methyl or ethyl; R.sub.1 is
chloro or fluoro; R.sub.2 is hydrogen; R.sub.3 is hydrogen, fluoro,
chloro, methyl or hydroxy; R.sub.4 is hydrogen; and R.sub.5 is
chloro, fluoro or methyl; pharmaceutically acceptable salts
thereof; and pharmaceutically acceptable prodrug esters
thereof.
[0022] A preferred embodiment relates to the compounds of formula I
wherein R is methyl or ethyl; R.sub.1 is fluoro; R.sub.2 is
hydrogen; R.sub.3 is hydrogen, fluoro or hydroxy; R.sub.4 is
hydrogen; and R.sub.5 is chloro; pharmaceutically acceptable salts
thereof; and pharmaceutically acceptable prodrug esters
thereof.
[0023] Another preferred embodiment of the invention relates to
compound of formula I wherein R is ethyl or methyl; R.sub.1 is
fluoro; R.sub.2 is hydrogen or fluoro; R.sub.3 is hydrogen, fluoro,
ethoxy or hydroxy; R.sub.4 is hydrogen or fluoro; and R.sub.5 is
chloro, fluoro or methyl; pharmaceutically acceptable salts
thereof; and pharmaceutically acceptable prodrug esters
thereof.
[0024] Further preferred are said compounds wherein R is methyl or
ethyl; R.sub.1 is fluoro; R.sub.2-R.sub.4 are hydrogen or fluoro;
and R.sub.5 is chloro or fluoro; pharmaceutically acceptable salts
thereof; and pharmaceutically acceptable prodrug esters
thereof.
[0025] A further embodiment of the invention relates to the
compounds of formula I wherein R is methyl or ethyl; R.sub.1 is
fluoro; R.sub.2 is fluoro; R.sub.3 is hydrogen, ethoxy or hydroxy;
R.sub.4 is fluoro; and R.sub.5 is fluoro; pharmaceutically
acceptable salts thereof; and pharmaceutically acceptable prodrug
esters thereof.
[0026] Another preferred embodiment of the invention relates to the
compounds of formula I wherein R is methyl; R.sub.1 is fluoro;
R.sub.2 is hydrogen; R.sub.3 is hydrogen or fluoro; R.sub.4 is
hydrogen; and R.sub.5 is chloro; pharmaceutically acceptable salts
thereof; and pharmaceutically acceptable prodrug esters
thereof.
[0027] Particular embodiments of the invention relate to compounds
of formula I
[0028] (a) wherein R is methyl; R.sub.1 is fluoro; R.sub.2 is
hydrogen; R.sub.3 is hydrogen; R.sub.4 is hydrogen; and R.sub.5 is
chloro; pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable prodrug esters thereof;
[0029] (b) wherein R is methyl; R.sub.1 is fluoro; R.sub.2 is
hydrogen; R.sub.3 is fluoro; R.sub.4 is hydrogen; and R.sub.5 is
chloro; pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable prodrug esters thereof;
[0030] (c) wherein R is ethyl; R.sub.1 is fluoro; R.sub.2 is
fluoro; R.sub.3 is hydrogen; R.sub.4 is fluoro; and R.sub.5 is
fluoro; pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable prodrug esters thereof; and
[0031] (d) wherein R is ethyl; R.sub.1 is chloro; R.sub.2 is
hydrogen; R.sub.3 is chloro; R.sub.4 is hydrogen; and R.sub.5 is
methyl; pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable prodrug esters thereof.
[0032] The general definitions used herein have the following
meaning within the scope of the present invention.
[0033] Pharmaceutically acceptable prodrug esters are ester
derivatives which are convertible by solvolysis or under
physiological conditions to the free carboxylic acids of formula I.
Such esters are e.g. lower alkyl esters (such as the methyl or
ethyl ester), carboxy-lower alkyl esters such as the carboxymethyl
ester, nitrooxy-lower alkyl esters (such as the 4-nitrooxybutyl
ester), and the like. Preferred are the 5-alkyl substituted
2-arylaminophenylacetoxyacetic acids of formula Ia 3
[0034] wherein R and R.sub.1-R.sub.5 have meaning as defined
hereinabove for compounds of formula I; and pharmaceutically
acceptable salts thereof.
[0035] Pharmaceutically acceptable salts represent metal salts,
such as alkaline metal salts, e.g. sodium, potassium, magnesium or
calcium salts, as well as ammonium salts, which are formed e.g.
with ammonia and mono- or di-alkylamines, such as diethylammonium
salts, and with amino acids, such as arginine and histidine
salts.
[0036] A lower alkyl group contains up to 7 carbon atoms,
preferably 1 to 4 carbon atoms and represents for example methyl,
ethyl, propyl or butyl, and may be straight chain or branched.
[0037] The compounds of the invention are useful as selective
cyclooxygenase-2 inhibitors or as prodrugs thereof. The selective
cyclooxygenase-2 (COX-2) inhibitors and prodrugs thereof of the
invention are particularly useful for the treatment of e.g.
inflammation, pyresis, pain, osteoarthritis, rheumatoid arthritis
and other conditions responsive to the inhibition of
cyclooxygenase-2 and are typically substantially free of
undesirable gastrointestinal side effects associated with
conventional non-steroidal antiinflammatory agents.
[0038] The above-cited properties are demonstrable in vitro and in
vivo tests using advantageously mammals, e.g. rats, mice, dogs,
monkeys and isolated cells or enzyme preparations thereof. Said
compounds can be applied in vitro in the form of solutions, e.g.
aqueous solutions, and in vivo advantageously orally, topically or
parenterally, e.g. intravenously. The dosage in vitro may range
from about 10.sup.-5 to 10.sup.-9 molar concentrations. The dosage
in vivo may range, depending on the route of administration,
between about 1 and 100 mg/kg.
[0039] Cyclooxygenase inhibition is determined in vitro using
cellular assays for inhibition of both cyclooxygenase-1 and
cyclooxygenase-2.
[0040] The cellular assays for testing cyclooxygenase inhibitors
are based on the fact that the cyclooxygenase enzyme (prostaglandin
H synthase) catalyzes the rate limiting step in prostaglandin
synthesis from arachidonic acid. Two enzymes mediate the reaction:
COX-1 is a constitutive form of the enzyme whereas COX-2 is induced
in response to various growth factors and cytokines. Cell lines
have been established which express one form of the enzyme: a human
skin fibroblast line which can be induced with IL-1 to synthesize
COX-2, and the kidney epithelial cell line 293 which has been
stably transfected to constitutively express COX-1. Both isoforms
metabolize arachidonic acid into the stable metabolite
prostaglandin E.sub.2. Arachidonic acid can be added exogenously to
increase output to easily measurable levels. The levels of
prostaglandin E.sub.2 in the extracellular medium are assayed by
radioimmunoassay as a measure of enzyme activity. The relative
activities of each isoform are compared to assess compound
selectivity.
[0041] In vitro cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2) inhibition is determined in the cell-based assays in order
to assess the in vitro activity and selectivity for COX-2
inhibition, using a prostaglandin E.sub.2 radioimmunoassay. The
cells utilized are primary human fibroblasts induced with
interleukin-1 to produce COX-2, and the human kidney epithelial
cell line 293 stably transfected to produce COX-1 constitutively.
Cells are plated out into well plates in which the assay is
performed. Fibroblasts are stimulated to synthesize COX-2 by
treatment overnight with IL-1; the 293 cells require no induction.
Both cell lines are pre-treated with compound dilutions for 15
minutes at 37.degree. C., then 40 .mu.M arachidonic acid is added
as exogenous substrate for the production of PGE.sub.2, which is
measured in supernatant by radioimmunoassay. For IC.sub.50
determinations, compounds are tested at 5 concentrations in
quadruplicate (highest concentration 30 .mu.M); the mean inhibition
of PGE.sub.2 (compared to cells not treated with compound) for each
concentration is calculated, a plot made of mean % inhibition vs.
log compound concentration for all experiments, and the overall
IC.sub.50 value calculated using a 4-parameter logistic fit.
[0042] IC.sub.50 values for compounds of formula I in the COX-2
inhibition assay are as low as about 0.005 .mu.M whereas IC.sub.50
values in the COX-1 inhibition assay are greater than 30 .mu.M.
[0043] Illustrative of the invention, the compounds of examples 1
(d), 1(g) and 3(a) have an IC.sub.50 of about 0.13, 0.25, 0.007
.mu.M, respectively, for COX-2 inhibition with no significant COX-1
inhibition at 30 .mu.M.
[0044] The inhibition of prostaglandin-E.sub.2 production produced
by COX-2 can be determined in vivo in the lipopolysaccharide
(LPS)-challenged subcutaneous air pouch model in the rat (see
"Advances in Inflammation Research", Raven Press, 1986 and J. Med.
Chem. 39, 1846 (1996)).
[0045] Female Lewis rats are anesthetized and then dorsal air
pouches are prepared by subcutaneous injection of 10 ml of air
through a sterile 0.45 micron syringe-adapted filter. Twenty-four
hours after preparation, the air pouches are injected with LPS (8
.mu.g/pouch) suspended in sterile phosphate buffered saline.
Compounds for evaluation are suspended in fortified cornstarch and
administered by gavage one hour prior to LPS challenge. The pouch
contents are harvested three hours after LPS challenge and
PGE.sub.2 levels present in the pouch fluids are measured by enzyme
immunoassay. ED.sub.50 values for inhibition of PGE.sub.2 formation
are calculated by least squares linear regression. Illustrative of
the invention, the compounds of examples 1(d), 1(g), 3(a) and 6(a)
have an ED.sub.50 in the range of about 0.2 mg/kg p.o. to about 0.6
mg/kg p.o..
[0046] The in vivo inhibition of thromboxane B.sub.2 (TXB.sub.2)
produced by COX-1 can be measured ex vivo in the serum of rats
after oral administration of compound.
[0047] Briefly, rats are fasted overnight, administered compound in
fortified cornstarch vehicle by gavage, and sacrificed by carbon
dioxide inhalation 30 minutes to eight hours later. Blood is
collected by cardiac puncture into tubes without anti-coagulant,
allowed to clot and serum is separated by centrifugation. Serum is
stored frozen for later analysis of thromboxane B.sub.2 by
radioimmunoassay. Each experiment contains the following groups
(5-6 rats per group): vehicle control and test compounds, either at
different doses or different time points. Thromboxane B.sub.2 data
is expressed as a percentage of the levels measured in the vehicle
control group.
[0048] Illustrative of the invention, the compounds of examples
1(d), 1(g), 3(a), and 6(a) cause less than a 50% inhibition of
serum thromboxane B.sub.2 production at an oral dose which is
50-150 times the ED.sub.50 value for in vivo COX-2 inhibition.
[0049] Antiinflammatory activity is determined using the
carrageenan induced rat paw edema assay. Sprague Dawley rats
(200-225 g) are fasted overnight, then orally dosed with the
compound suspended in a fortified cornstarch solution. After one
hour, a 0.1 ml volume of 1% carrageenan in saline is injected into
the subplantar region of the left hind paw which causes an
inflammatory response. At 3 hours post carrageenan, the rats are
euthanatized and both hind paws are cut off at the paw hair line
and weighed on an electronic balance. The amount of edema in the
inflamed paw is determined by subtracting the weight of the
non-inflamed paw (right) from the weight of the inflamed paw
(left). The percent inhibition by the compound is determined for
each animal as the percent paw weight gained as compared to the
control average. ED.sub.30 values are determined for each
dose-response using the curve fitting formula,
100/1+(Drug Concentration/ED.sub.30).sup.slope
[0050] Mean ED.sub.30 values are calculated as the average of
ED.sub.30 values determined from independent dose response
assays.
[0051] Illustrative of the invention, the compounds of examples
1(d), 1(g), 3(a) and 6(a) inhibit carrageenan-induced edema with an
ED.sub.30 in the range of about 0.14 mg/kg p.o. to about 1.65 mg/kg
p.o.
[0052] The gastric tolerability assay is used to assess gross
ulceration in the rat, measured four hours after oral
administration of the test compound. The test is carried out as
follows:
[0053] Rats are fasted overnight, administered compound in
fortified cornstarch vehicle by gavage, and sacrificed by carbon
dioxide inhalation four hours later. The stomachs are removed and
gross gastric lesions counted and measured to give the total lesion
length per rat. Each experiment contains the following groups (5-6
rats per group): vehicle control, test compounds, and diclofenac as
a reference compound.
[0054] Data are calculated as the mean number of ulcers in a group,
the mean length of ulcers (mm) in the group and as the ulcer index
(UI).
UI=mean length of ulcers in a group.times.ulcer incidence
[0055] where ulcer incidence is the fraction of animals in the
group with lesions (100% incidence is 1).
[0056] Illustrative of the invention, the compounds of examples
1(d), 1(g), 3(a) and 6(a) are essentially free of any gastric
ulcerogenic effect at 100 mg/kg p.o.
[0057] Intestinal tolerability can be determined by measuring the
effect on intestinal permeability. Lack of increase in permeability
is indicative of intestinal tolerability.
[0058] The method used is a modification of a procedure by Davies,
et al., Pharm. Res. 1994; 11:1652-1656 and is based on the fact
that excretion of orally administered .sup.51Cr-EDTA, a marker of
small intestinal permeability, is increased by NSAIDs. Groups of
rats (.gtoreq.12/group) are administered a single, oral dose of
test compound or vehicle by gastric intubation. Immediately
following compound dose, each rat is administered .sup.51Cr-EDTA (5
.mu.Ci/rat) by gastric intubation. The rats are placed in
individual metabolic cages and given food and water ad libitum.
Urine is collected over a 24 hour period. Twenty-four hours after
administration of .sup.51Cr-EDTA the rats are sacrificed. To
quantify compound effect on intestinal permeability, the excreted
.sup.51Cr-EDTA measured in the urine of compound treated rats is
compared to the excreted .sup.51Cr-EDTA measured in the urine of
vehicle treated rats. Relative permeability is determined by
calculating the activity present in each urine sample as a percent
of the administered dose after correcting for background
radiation.
[0059] Illustrative of the invention, the compounds of examples
1(d), 1(g), 3(a) and 6(a) demonstrate no
[0060] The analgesic activity of the compounds of the invention is
determined using the well-known Randall-Selitto assay.
[0061] The Randall-Selitto paw pressure assay measures
antinociception (analgesic activity) in inflamed tissue by
comparing the pressure threshold in the inflamed paw of the rat
after oral administration of test drug with that in the inflamed
paw of rats administered corn starch vehicle orally.
[0062] Groups of 10 male Wistar rats weighing 40-50 gms are fasted
overnight prior to testing. Hyperalgesia is induced by the
injection of 0.1 ml of a 20% suspension of Brewer's yeast with a 26
gauge needle into the subplantar region of the right hindpaw. The
left paw is not injected and is used as the control paw for
determination of hyperalgesia. Vehicle (Fortified corn starch
suspension 3%) at 10 ml/kg, reference compound (diclofenac is run
in every experiment at the same dose as test compounds) and test
compounds at different doses suspended in vehicle at 10 ml/kg are
administered orally 2 hours after the yeast injection. The
threshold for paw withdrawal is quantified with a Basile
Analgesy-meter 1 hour after oral administration of test compounds.
The nociceptive threshold is defined as the force in grams at which
the rat withdraws its foot or vocalizes. Either vocalization or
foot withdrawal is recorded as a response.
[0063] The data are analyzed by comparing the mean pain threshold
of the corn starch vehicle-related group for the inflamed and
non-inflamed paws to that of individual drug-treated rats.
Individual rats in the drug-treated groups and positive control
(diclofenac) group are called reactors if the individual pain
threshold in each paw exceeds the control group mean threshold by
two standard deviations of that mean. The mean pain thresholds of
the inflamed paw in the control group are compared to the
individual pain thresholds of the inflamed paw in the test drug
group. The non-inflamed control mean pressure threshold is compared
to the non-inflamed individual pressure thresholds in the test
groups. Results are expressed as number of reactors in each test
group (n=10) for inflamed and non-inflamed paws. Percentages are
calculated by dividing number of reactors by total number of rats
used for a compound.
[0064] Illustrative of the invention, the compounds of examples
1(d), 1(g), 3(a) and 6(a) all increase the pain threshold in the
inflamed paw at 10 mg/kg administered orally. These compounds
selectively elevate the pain threshold in the inflamed paw with no
threshold elevation in the non-inflamed paw indicating a peripheral
mechanism.
[0065] The antiarthritic effect of the compounds of the invention
can be determined in the well-known chronic adjuvant arthritis test
in the rat.
[0066] Ocular effects can be demonstrated in well-known ophthalmic
assay methods. Similarly antitumor activity can be demonstrated in
well-known antitumor animal tests.
[0067] The compounds of formula I can be prepared e.g.
[0068] (a) by coupling a compound of formula II or IIa 4
[0069] wherein R has meaning as defined above; R.sub.a is lower
alkyl, preferably isopropyl; and R.sub.6 and R.sub.7 represent
lower alkyl; or R.sub.6 and R.sub.7 together with the nitrogen atom
represent piperidino, pyrrolidino or morpholino;
[0070] with a compound of formula III 5
[0071] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 have
meaning as defined above in the presence of copper and cuprous
iodide to obtain a compound of formula IV or IVa 6
[0072] and hydrolyzing the resulting compound of formula IV or IVa
to a compound of formula I; or
[0073] (b) for compounds in which R represents ethyl, by condensing
a compound of formula V 7
[0074] wherein R.sub.1-R.sub.7 have meaning as defined herein, with
a reactive functional derivative of acetic acid, such as acetyl
chloride, in a Friedel-Crafts acylation to reaction to obtain a
compound of the formula VI 8
[0075] wherein R.sub.1-R.sub.7 have meaning as defined herein which
is in turn hydrogenolyzed and then hydrolyzed to obtain a compound
of formula I wherein R represents ethyl; or
[0076] (c) by hydrolyzing a lactam of formula VII 9
[0077] wherein R and R.sub.1-R.sub.5 have meaning as defined
herein, with a strong base; and in above processes, if desired,
temporarily protecting any interfering reactive groups and then
isolating the resulting compound of the invention; and, if desired,
converting any resulting compound into another compound of the
invention; and/or if desired converting a free carboxylic acid of
the invention into a pharmaceutically acceptable ester derivative
thereof; and/or if desired, converting a resulting free acid into a
salt or a resulting salt into the free acid or into another
salt.
[0078] In starting compounds and intermediates, which are converted
to the compounds of the invention in a manner described herein,
functional groups present such as amino, hydroxy and carboxyl
groups, are optionally protected by conventional protecting groups
that are common in preparative organic chemistry. Protected
hydroxy, amino and carboxyl groups are those that can be converted
under mild conditions into free amino, hydroxy and carboxyl groups
without other undesirable side reactions taking place. For example,
hydroxy protecting groups are preferably benzyl or substituted
benzyl groups, or acyl groups such as pivaloyl.
[0079] The preparation of compounds of formula IV according to
process (a) is carried out under conditions of a modified Ullmann
condensation for the preparation of diarylamines, e.g. in the
presence of copper powder and copper (I) iodide and potassium
carbonate, in an inert high boiling solvent such as nitrobenzene,
toluene, xylene or N-methylpyrrolidone, at elevated temperature,
e.g. in the range of 100.degree.-200.degree. C., preferably at
reflux temperature, according to general methodology described by
F. Nohara, Chem. Abstr. 94, 15402x (1951) and Moser et al., J. Med.
Chem. 33, 2358 (1990).
[0080] Intermediates of Formula IV wherein R.sub.1 or R.sub.5 is
methyl or ethyl can be prepared from intermediates of formula IV,
wherein R.sub.1 or R.sub.5 is bromo by reaction with tetramethyltin
or tetraethyltin under conditions of a Heck reaction, that is in
the presence of a palladium salt (such as Pd(OAc).sub.2 or
PdCl.sub.2), a triarylphosphine (such as tri (o-tolyl)phosphine)
and a base (such as triethylamine, sodium acetate) in a polar
solvent such as dimethylformamide.
[0081] Hydrolysis of the resulting ortho-anilinophenylacetamides of
formula IV is carried out in aqueous alkali hydroxide, e.g. in 6N
NaOH in the presence of an alcohol (e.g. ethanol, propanol,
butanol) at elevated temperature, such as reflux temperature of the
reaction mixture.
[0082] The hydrolysis of esters of formula IVa is carried out
according to methods known in the art, e.g. under basic conditions
as described above for the compounds of formula IV or alternatively
under acidic conditions, e.g. using methanesulfonic acid.
[0083] The starting materials of formula II or IIa are generally
known or can be prepared using methodology known in the art, e.g.
as described by F. Nohara in Japanese patent application No.
78/96,434 (1978).
[0084] For example, 5-methyl or 5-ethylanthranilic acid is
converted to the ortho-diazonium derivatives followed by treatment
with an alkali metal iodide in acid (e.g. sulfonic acid) to obtain
5-alkyl-2-iodobenzoic acid. Reduction to the corresponding benzyl
alcohol (e.g. with diborane), conversion of the alcohol first to
the bromide and then to the nitrile, hydrolysis of the nitrile to
the acetic acid and conversion to the N,N dialkylamide according to
methodology known in the art yields a starting material of formula
II.
[0085] Alternatively, the starting materials of formula II wherein
R is ethyl can be prepared by Friedel-Crafts acetylation of
oxindole with e.g. acetyl chloride in the presence of aluminum
chloride, reduction of the resulting ketone by e.g. catalytic
hydrogenolysis, followed by hydrolytic cleavage of the resulting
5-ethyloxindole to 5-ethyl-2-aminophenylacetic acid. Diazotization
in the presence of e.g. potassium iodide yields
5-ethyl-2-iodo-phenylacetic acid which is converted to an amide of
formula II. Esters of formula IIa are prepared from the
corresponding acids according to esterification methods known in
the art.
[0086] The anilines of formula III are either known in the art or
are prepared according to methods well-known in the art or as
illustrated herein.
[0087] The preparation of 5-ethyl substituted compounds according
to process (b) is carried out under conditions of Friedel-Crafts
acylation e.g. in the presence of aluminum chloride in an inert
solvent such as 1,2-dichloroethane, followed by hydrogenolysis,
e.g. using palladium on charcoal catalyst, preferably in acetic
acid as solvent, at room temperature and about 3 atmospheres
pressure.
[0088] The starting materials of formula V are prepared generally
as described under process (a) but starting with an amide of
formula II in which R represents hydrogen, e.g. as described in J.
Med. Chem. 33, 2358 (1990).
[0089] The preparation of the compounds of the invention according
to process (c) can be carried out under conditions known in the art
for the hydrolytic cleavage of lactams, preferably with a strong
aqueous base, such as aqueous sodium hydroxide, optionally in the
presence of an organic water miscible solvent such as methanol at
elevated temperature in the range of about 50-100.degree. C., as
generally described in U.S. Pat. No. 3,558,690.
[0090] The oxindole starting materials are prepared by N-acylation
of a diarylamine of the formula VIII 10
[0091] wherein R and R.sub.1-R.sub.5 have meaning as defined above
with a haloacetyl chloride, preferably chloroacetyl chloride,
advantageously at elevated temperature, e.g. near 100.degree. C.,
to obtain a compound of the formula IX 11
[0092] wherein R and R.sub.1-R.sub.5 have meaning as defined
hereinabove. Cyclization of a compound of formula IX is carried out
under conditions of Friedel-Crafts alkylation in an inert solvent,
such as dichlorobenzene, in the presence of Friedel-Crafts
catalysts, e.g. aluminum chloride and ethylaluminum dichloride, at
elevated temperature, e.g. at 120-175.degree. C.
[0093] The diarylamines of formula VIII can be prepared by an
Ullmann condensation and other methods known in the art, e.g. a
Buchwald coupling reaction.
[0094] For example, the diarylamines of formula VIII wherein
R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are fluoro and R.sub.3 is
hydrogen can be prepared by reacting the corresponding aniline
(4-ethyl- or 4-methyl-aniline) with pentafluorobenzene in the
presence of a strong base such as lithium amide or n-butyllithium,
as generally described in J. of Fluorine Chemistry 5, 323
(1975).
[0095] Esters of the carboxylic acids of formula I are prepared by
condensation of the carboxylic acid, in the form of a salt or in
the presence of a base, with a halide (bromide or chloride)
corresponding to the esterifying alcohol (such as benzyl
chloroacetate) according to methodology well known in the art, e.g.
in a polar solvent such as dimethyl formamide, and if required
further modifying the resulting product.
[0096] For example, if the esterification product is itself an
ester, such can be converted to the carboxylic acid, e.g. by
hydrogenolysis of a resulting benzyl ester. Also if the
esterification product is itself a halide, such can for instance be
converted to the nitrooxy derivative by reaction with e.g. silver
nitrate.
[0097] For example, the compounds of formula la are preferably
prepared by condensing a salt of a carboxylic acid of formula I
above with a compound of formula
X--CH.sub.2 COOR.sub.a
[0098] wherein X is a leaving group and R.sub.a is a carboxy
protecting group to obtain a compound of formula Ia in carboxy
protected form, and subsequently removing the protecting group
R.sub.a.
[0099] The esterification can be carried under esterification
conditions known in the art, e.g. in a polar solvent such as
dimethylformamide, at a temperature range of room temperature to
about 100.degree. C., preferably at a range of 40-60.degree. C.
[0100] The salt of the acid of formula I is preferably an alkali
metal salt, e.g. the sodium salt which may be prepared in situ.
[0101] Leaving group X is preferably halo, e.g. chloro or bromo, or
lower alkylsulfonyloxy, e.g. methanesulfonyloxy.
[0102] Carboxy protecting group R.sub.a is preferably benzyl.
[0103] The resulting benzyl esters can be converted to the free
acids of formula Ia preferably by hydrogenolysis with hydrogen in
the presence of e.g. Pd/C catalyst in acetic acid at atmospheric
pressure or under Parr hydrogenation at a temperature ranging from
room temperature to about 50.degree. C.
[0104] The invention includes any novel starting materials and
processes for their manufacture.
[0105] Finally, compounds of the invention are either obtained in
the free form, or as a salt thereof if salt forming groups are
present.
[0106] The acidic compounds of the invention may be converted into
metal salts with pharmaceutically acceptable bases, e.g. an aqueous
alkali metal hydroxide, advantageously in the presence of an
ethereal or alcoholic solvent, such as a lower alkanol. Resulting
salts may be converted into the free compounds by treatment with
acids. These or other salts can also be used for purification of
the compounds obtained. Ammonium salts are obtained by reaction
with the appropriate amine, e.g. diethylamine, and the like.
[0107] Compounds of the invention having basic groups can be
converted into acid addition salts, especially pharmaceutically
acceptable salts. These are formed, for example, with inorganic
acids, such as mineral acids, for example sulfuric acid, a
phosphoric or hydrohalic acid, or with organic carboxylic acids,
such as (C.sub.1-C.sub.4)alkanecarboxylic acids which, for example,
are unsubstituted or substituted by halogen, for example acetic
acid, such as saturated or unsaturated dicarboxylic acids, for
example oxalic, succinic, maleic or fumaric acid, such as
hydroxycarboxylic acids, for example glycolic, lactic, malic,
tartaric or citric acid, such as amino acids, for example aspartic
or glutamic acid, or with organic sulfonic acids, such as
(C.sub.1-C.sub.4)-alkylsulfonic acids (for example methanesulfonic
acid) or arylsulfonic acids which are unsubstituted or substituted
(for example by halogen). Preferred are salts formed with
hydrochloric acid, methanesulfonic acid and maleic acid.
[0108] In view of the close relationship between the free compounds
and the compounds in the form of their salts, whenever a compound
is referred to in this context, a corresponding salt is also
intended, provided such is possible or appropriate under the
circumstances.
[0109] The compounds, including their salts, can also be obtained
in the form of their hydrates, or include other solvents used for
their crystallization.
[0110] The pharmaceutical compositions according to the invention
are those suitable for enteral, such as oral or rectal,
transdermal, topical, and parenteral administration to mammals,
including man, to inhibit COX-2-activity, and for the treatment of
COX-2 dependent disorders, and comprise an effective amount of a
pharmacologically active compound of the invention, alone or in
combination, with one or more pharmaceutically acceptable
carriers.
[0111] More particularly, the pharmaceutical compositions comprise
an effective cyclooxygenase-2 inhibiting amount of a selective
cyclooxygenase-2 inhibiting compound of the invention which is
substantially free of cyclooxygenase-1 inhibiting activity and of
side effects attributed thereto.
[0112] The pharmacologically active compounds of the invention are
useful in the manufacture of pharmaceutical compositions comprising
an effective amount thereof in conjunction or admixture with
excipients or carriers suitable for either enteral or parenteral
application. Preferred are tablets and gelatin capsules comprising
the active ingredient together with a) diluents, e.g. lactose,
dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)
lubricants, e.g. silica, talcum, stearic acid, its magnesium or
calcium salt and/or polyethyleneglycol; for tablets also c) binders
e.g. magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose and or
polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches,
agar, alginic acid or its sodium salt, or effervescent mixtures;
and/or e) absorbents, colorants, flavors and sweeteners. Injectable
compositions are preferably aqueous isotonic solutions or
suspensions, and suppositories are advantageously prepared from
fatty emulsions or suspensions. Said compositions may be sterilized
and/or contain adjuvants, such as preserving, stabilizing, wetting
or emulsifying agents, solution promoters, salts for regulating the
osmotic pressure and/or buffers. In addition, they may also contain
other therapeutically valuable substances. Said compositions are
prepared according to conventional mixing, granulating or coating
methods, respectively, and contain about 0.1 to 75%, preferably
about 1 to 50%, of the active ingredient.
[0113] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0114] Suitable formulations for transdermal application include an
effective amount of a compound of the invention with carrier.
Advantageous carriers include absorbable pharmacologically
acceptable solvents to assist passage through the skin of the host.
For example, transdermal devices are in the form of a bandage
comprising a backing member, a reservoir containing the compound
optionally with carriers, optionally a rate controlling barrier to
deliver the compound of the skin of the host at a controlled and
predetermined rate over a prolonged period of time, and means to
secure the device to the skin.
[0115] Suitable formulations for topical application, e.g. to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, for example, for delivery
by aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application, e.g. for the
treatment of skin cancer, for example, for prophylactic use in sun
creams, lotions, sprays and the like. In this regard it is noted
that compounds of the present invention are capable of absorbing UV
rays in the range of 290-320 nm while allowing passage of tanning
rays at higher wavelengths. They are thus particularly suited for
use in topical, including cosmetic, formulations well-known in the
art. Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives. Formulations suitable for
topical application can be prepared e.g. as described in U.S. Pat.
No. 4,784,808. Formulations for ocular administration can be
prepared e.g. as described in U.S. Pat. Nos. 4,829,088 and
4,960,799.
[0116] The pharmaceutical formulations contain an effective COX-2
inhibiting amount of a compound of the invention as defined above,
either alone or in combination with another therapeutic agent.
[0117] For example, suitable additional active agents for use in
relation to the treatment of neoplasia include e.g. any of the
anti-neoplastic agents or radioprotective agents recited in
International Patent Application WO 98/16227.
[0118] In conjunction with another active ingredient, a compound of
the invention may be administered either simultaneously, before or
after the other active ingredient, either separately by the same or
different route of administration or together in the same
pharmaceutical formulation.
[0119] The dosage of active compound administered is dependent on
the species of warm-blooded animal (mammal), the body weight, age
and individual condition, and on the form of administration. A unit
dosage for oral administration to a mammal of about 50 to 70 kg may
contain between about 5 and 500 mg, of the active ingredient.
[0120] The present invention also relates to methods of using the
compounds of the invention and their pharmaceutically acceptable
salts, or pharmaceutical compositions thereof, in mammals for
inhibiting COX-2 and for the treatment of COX-2 dependent
conditions as described herein, e.g. inflammation, pain, rheumatoid
arthritis, osteoarthritis, ocular inflammatory disorders, glaucoma
and dry eye disease.
[0121] Particularly the present invention relates to a method of
selectively inhibiting cyclooxygenase-2 activity in a mammal
without substantially inhibiting cycloxygenase-1 activity which
comprises administering to a mammal in need thereof an effective
cyclooxygenase-2 inhibiting amount of a compound of the
invention.
[0122] Thus the present invention also relates to a method of
treating cyclooxygenase-2 dependent disorders in mammals, which
comprises administering to a mammal in need thereof an effective
cyclooxygenase-2 inhibiting amount of a compound of the
invention.
[0123] More particularly the present invention relates to a method
of treating cyclooxygenase-2 dependent disorders in mammals while
substantially eliminating undesirable side effects associated with
cyclooxygenase-1 inhibiting activity which comprises administering
to a mammal in need thereof an effective cyclooxygenase-2
inhibiting amount of a selective cyclooxygenase-2 inhibiting
compound of the invention which is substantially free of
cyclooxygenase-1 inhibiting activity.
[0124] More specifically such relates to a method of e.g. treating
rheumatoid arthritis, osteoarthritis, pain or inflammation in
mammals without causing undesirable gastrointestinal ulceration,
which method comprises administering to a mammal in need thereof a
correspondingly effective amount of a compound of the
invention.
[0125] The following examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
Temperatures are given in degrees Centrigrade. If not mentioned
otherwise, all evaporations are performed under reduced pressure,
preferably between about 15 and 100 mm Hg (=20-133 mbar). The
structure of final products, intermediates and starting materials
is confirmed by standard analytical methods, e.g. microanalysis and
spectroscopic characteristics (e.g. MS, IR, NMR). Abbreviations
used are those conventional in the art.
EXAMPLE 1
[0126] (a)
N,N-dimethyl-5-methyl-2-(2',4'-dichloro-6'-methylanilino)phenyl-
acetamide (1.5 g, 4.3 mmol) is hydrolyzed with 6N NaOH (70 ml) as a
two phase solution with n-BuOH (40 ml) at reflux temperature for 14
hours. After cooling to room temperature, the mixture is poured
over ice (100 ml). Toluene (100 ml) is added and the mixture
transferred to a separatory funnel. The aqueous phase is brought to
a pH of 1 with 3 N HCl. The organic phase is separated and the
aqueous phase re-extracted with toluene (100 ml). The combined
organic solution is dried (MgSO.sub.4) and concentrated under high
vacuum (35-50 mbar), on a rotovap, taking care not to warm above
50.degree.. Upon crystallization from Et.sub.2O/hexane,
5-methyl-2-(2',4'-dichloro-6'-methylanilino)phenyl- acetic acid is
obtained as a tan solid, m.p. 137-141.degree..
[0127] The starting material,
N,N-dimethyl-5-methyl-2-(2',4'-dichloro-6'-m-
ethylanilino)phenylacetamide is prepared in the following
manner:
[0128] 5-Methyl-2-iodobenzoic acid (100 g, 0.38 mol) is dissolved
in THF (350 ml) and cooled in an ice bath. Borane-THF complex (380
ml of 1 M in THF, 0.38 mol) is added dropwise. After addition is
complete, the reaction is warmed to room temperature and stirred
for 14 hours. The mixture is transferred to a large erlenmeyer
flask, cooled in an ice bath, and carefully quenched with water
(250 ml). Evaporation of the THF on a rotovap gives a white
suspension which is treated with additional water (1 L) and then
filtered and dried in a vacuum dessicator over P.sub.2O.sub.5 to
give 2-iodo-5-methylbenzyl alcohol as a white solid, m.p.
82-85.degree..
[0129] The benzylic alcohol (99.8 g, 0.38 mol) is dissolved in 48%
HBr (500 ml) and heated to reflux temperature for 4 hours. The
resulting benzylic bromide is isolated as a yellow solid by pouring
the cooled mixture into a large volume (1.5 L) of water followed by
filtration. The benzylic bromide (caution: lachrymator) is
dissolved in EtOH (400 ml) and stirred at room temperature. Sodium
cyanide (56 g, 1.14 mol) is dissolved in a minimum amount
(.about.100 ml) of water and then added to the ethanolic solution
of the benzylic bromide. The reaction is heated to reflux
temperature for 3 hours and then cooled to room temperature.
Ethanol is removed on a rotovap and the residue washed with a large
volume (1 L) of water. The resulting
2'-iodo-5'-methylphenylacetonitrile is isolated as a white solid,
m.p. 77-79.degree., by filtration.
[0130] The nitrile (94.5 g, 0.37 mol) is dissolved in EtOH (350 ml)
and treated with NaOH (29.4 g, 0.74 mol) which has been dissolved
in water (200 ml). The reaction is heated to reflux temperature for
14 hours. After cooling to room temperature, ethanol is removed on
a rotovap and 6N HCl added until the pH=1. The solid
5-methyl-2-iodophenylacetic acid is filtered off and washed with
water (2.times.500 ml). After drying over P.sub.2O.sub.5 in a
vacuum dessicator, the solid 5-methyl-2-iodophenyl acetic acid (mp
112-114.degree., 83 g, 0.30 mol) is dissolved in CH.sub.2Cl.sub.2
(450 ml) that contains several drops of DMF. To the solution
thionyl chloride (32 ml, 0.450 mol) is added and the reaction
heated to reflux temperature overnight. After cooling to room
temperature, the reaction mixture is diluted with additional
CH.sub.2Cl.sub.2 (500 ml) and washed with water (2.times.250 ml),
saturated NaHCO.sub.3 (250 ml) and brine (250 ml). The solution is
dried (MgSO.sub.4) and concentrated on a rotovap to give
5-methyl-2-iodophenylacetyl chloride as a yellowish oil.
[0131] Dimethylamine (200 ml of 2 M solution in THF) is added
dropwise to a solution of 5-methyl-2-iodophenylacetyl chloride in
Et.sub.2O (500 ml) which is cooled in an ice bath. After the
addition is complete, EtOAc (350 ml) is added and the solution is
washed with water (350 ml), brine (250 ml) and dried (MgSO.sub.4).
Evaporation on a rotovap and trituration with 1:1 Et.sub.2O/hexanes
gives N,N-dimethyl-5-methyl-2-iodophenylacetam- ide as a light tan
solid, m.p. 47-49.degree..
[0132] N,N-Dimethyl-5-methyl-2-iodophenylacetamide (3.5 g, 11.5
mmol) and 2,4-dichloro-6-methylaniline (4.1 g, 23 mmol) are stirred
in xylenes (100 ml) with copper powder (0.18 g, 2.9 mmol),
copper(I) iodide (0.55 g, 2.9 mmol) and anhydrous potassium
carbonate (1.6 g, 11.5 mmol). The reaction is heated to reflux
temperature for 48 hours. While still slightly warm (40.degree.)
the brown suspension is filtered through a pad of Celite, which in
turn is rinsed with toluene (75 ml). The filtrate is evaporated on
a rotovap and flash chromatographed on silica gel (R.sub.f 0.30 in
40% EtOAc/hexane) to give
N,N-dimethyl-5-methyl-2-(2',4'-dichloro-6'-methylan-
ilino)phenylacetamide as an off-white crystalline solid, m.p.
119-124.degree..
[0133] Similarly prepared are:
[0134] (b) 5-methyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetic
acid, m.p. 153-156.degree.;
[0135] (c) 5-methyl-2-(2',6'-dichloroanilino)phenylacetic acid,
m.p. 168-170.degree.;
[0136] potassium salt, m.p. 318-320.degree.; sodium salt, m.p.
>300.degree.;
[0137] (d) 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic
acid, m.p. 158-159.degree.;
[0138] (e) 5-methyl-2-(2',6'-dichloro-4'-methylanilino)phenylacetic
acid, m.p. 179-182.degree.;
[0139] (f) 5-methyl-2-(2'-chloro-6'-methylanilino)phenylacetic
acid, m.p. 138-140.degree.;
[0140] (g) 5-methyl-2-(2',4'-difluoro-6'-chloroanilino)phenylacetic
acid, m.p. 157-159.degree.;
[0141] (h) 5-methyl-2-(2'-fluoro-4',6'-dichloroanilino)phenylacetic
acid, m.p. 178-180.degree.;
[0142] (i)
5-methyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid,
m.p. 154-156.degree..
[0143] (j)
5-methyl-2-(2'-chloro-4'-hydroxy-6'-fluoroanilino)phenylacetic
acid, m.p. 180-182.degree..
[0144] The starting material for compound of Example 1(j),
2-chloro-4-pivaloyloxy-6-fluoroaniline, is prepared in the
following manner:
[0145] To a mixture of 7.0 g (0.045 mol) of 3-fluoro-4-nitrophenol
and 6.7 g (0.067 mol) of triethylamine in 20 ml of methylene
chloride cooled to 0.degree. is added 6.5 g (0.054 mol) of pivaloyl
chloride in a dropwise manner. The reaction is allowed to warm to
room temperature and stirred overnight. The reaction is quenched
with water and extracted with ethyl acetate. The organic layer is
washed successively with 1 N hydrochloric acid, saturated aqueous
sodium bicarbonate, and saturated brine, and then dried over
magnesium sulfate. Filtration and removal of the solvents gives
crude 2-fluoro-4-pivaloyloxy-nitrobenzene which is dissolved in 200
ml of absolute ethanol. To the solution is added 0.9 g of 5%
palladium on carbon, and the mixture is then hydrogenated under 30
psi hydrogen for two hours. The catalyst is filtered and the
solvent removed to give 2-fluoro-4-pivaloyloxyaniline.
[0146] A mixture of 7.3 g (0.035 mol) of
2-fluoro-4-pivaloyloxyaniline and 5.1 g (0.038 mol) of
N-chlorosuccinimide in 50 ml of fluorobenzene is heated to reflux
under a nitrogen atmosphere for two hours. After cooling to room
temperature, the solvent is removed, water is added, and the
mixture is extracted with ethyl acetate. The organic layer is
washed with 1 N sodium hydroxide, and saturated brine, and dried
over magnesium sulfate. Filtration and removal of the solvents
gives a residue which is purified by silica gel chromatography (20%
ethyl acetate/hexane) to give
2-chloro-4-pivaloyloxy-6-fluoroaniline.
[0147] Conversion of 2-chloro-4-pivaloyloxy-6-fluoroaniline to
5-methyl-2-(2'-chloro-4'-hydroxy-6'-fluoroanilino)phenylacetic acid
is carried out in a manner similar to that described in Example 1,
the pivaloyl group being hydrolyzed in the last step along with the
dimethylamide to give the final product.
EXAMPLE 2
[0148] Similarly prepared according to procedures described in
Example I are:
[0149] (a) 5-ethyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid,
m.p. 147-148.degree.;
[0150] The starting material,
5-ethyl-2-iodo-N,N-dimethylphenylacetamide is prepared as
follows:
[0151] AlCl.sub.3 (303g, 2.27 mol) is placed in a 3-necked flask
fitted with a thermometer and a dropping funnel. While stirring DMF
(50 ml) is added dropwise and the temperature rises to about
60.degree.. The mixture is cooled down to 45.degree., and oxindole
(33 g, 0.25 mol) is added in 3 portions. After an additional 10
minutes, acetyl chloride (36 ml, 0.5 mol) is added. The mixture is
stirred for an additional 30 minutes at room temperature. The
mixture is poured onto ice (3000 g). This results in the formation
of a solid which is filtered off, washed first with water and then
with cold methanol (1000 ml), and then dried to give
5-acetyloxindole.
[0152] The 5-acetyloxindole (54 g, 308 mmol), acetic acid (400 ml)
and palladium on carbon (10%, 5 g) are combined and treated with
hydrogen for 14 hours at 55 psi. The catalyst is removed by
filtering through a bed of Celite, the filtrate is concentrated
under reduced pressure and the residue is treated with ether to
give 5-ethyloxindole
[0153] 5-Ethyloxindole (.about.54 g, .about.335 mmol), ethanol (750
ml), water (150 ml) and potassium hydroxide (65 g, 1.62 mol) are
combined and heated at reflux for 3 days. The mixture is allowed to
cool and then filtered through a bed of Celite. The filtrate is
concentrated under reduced pressure, water is added and the pH
adjusted to 6.5. The precipitate is filtered off, washed with water
and dried in an oven overnight to yield 5-ethyl-2-aminophenylacetic
acid. A mixture of water (405 ml) and concentrated HCl (48 ml) is
stirred and cooled to 0.degree.. 5-Ethyl-2-aminophenylacetic acid
(53.7 g, 300 mmol) is slowly added while maintaining the
temperature at 0-2.degree.. After this addition a solution of
sodium nitrite (22.2 g, 322 mmol) in 60 ml water is added dropwise
over 30 minutes keeping the temperature at 0-2.degree.. After a
further 20 minutes a solution of potassium iodide (48 g, 290 mmol)
in 18 ml conc HCl and 130 ml water is added dropwise while keeping
the temperature below 10.degree. C. The reaction mixture is allowed
to warm to room temperature and then heated to reflux for 2 hours.
The mixture is extracted with ethyl acetate and ether (1:1 mixture,
4.times.300 ml), the organic layer is then washed first with a 30%
aqueous solution of sodium thiosulfite and then with a sodium
hydroxide solution (0.1 M) before being acidified to pH 6 and
extracted with ethyl acetate. This solution is washed with
saturated brine, dried (magnesium sulfate), filtered, and the
solvent removed under reduced pressure. The residue is treated with
hexane to yield 5-ethyl-2-iodophenylacetic acid.
[0154] 5-Ethyl-2-iodophenylacetic acid is dissolved in methylene
chloride (400 ml) and DMF (1 ml) is added. Thionyl chloride (21 ml,
300 mmol) is then added dropwise over 20 minutes. The mixture is
heated to reflux and heating continued for 3.5 hours when the
mixture is cooled and ice-water (400 ml) and methylene chloride
(300 ml) are added. The layers are separated, the organic layer is
washed with a sodium bicarbonate solution, saturated brine, dried
(magnesium sulfate), and evaporated under reduced pressure to yield
5-ethyl-2-iodophenylacetyl chloride.
[0155] The acid chloride (46 g, 150 mmol) is dissolved in ether
(500 ml) and stirred at -35.degree.. Dimethylamine (250 ml of 2M
solution in THF, 500 mmol) is added dropwise at -35.degree. and the
mixture allowed to warm to room temperature and then stirred for 60
hours. Ethyl acetate and water are added and the layers separated.
The organic layer is washed with saturated brine and the combined
aqueous layers washed with ether. The combined organic layers are
now dried (magnesium sulfate), and the solvent is removed under
reduced pressure. Hexane is added to yield N,N-dimethyl
5-ethyl-2-iodophenylacetamide as a solid.
[0156] (b) 5-ethyl-2-(2'-chloro-6'-methylanilino)phenylacetic acid,
m.p. 125-126.degree.;
[0157] (c) 5-ethyl-2-(2',3',6'-trifluoroanilino)phenylacetic acid,
m.p. 138-140.degree.;
[0158] (d)
5-ethyl-2-(2',3',5',6'-tetrafluoro-4'-ethoxyanilino)phenylaceti- c
acid, m.p. 131-132.degree.;
[0159] (e) 5-ethyl-2-(2'-chloro-4',6'-difluoroanilino)phenylacetic
acid, m.p. 160-162.degree.;
[0160] (f) 5-ethyl-2-(2',4'-dichloro-6'-fluoroanilino)phenylacetic
acid, m.p. 169-171.degree..
EXAMPLE 3
[0161] (a)
N,N-Dimethyl-5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylac-
etamide (26 g, 0.073 mol) and 6N NaOH (150 ml) are stirred as a two
phase solution with n-BuOH (150 ml) at reflux temperature for 14
hours. After cooling to room temperature, the reaction is poured
over ice (500 ml). Toluene (500 ml) is added and the mixture
transferred to a separatory funnel. The aqueous phase is brought to
a pH of 1 with 3 N HCl. The organic layer is separated and the
aqueous phase re-extracted with toluene (250 ml). The combined
organic layers are dried (MgSO.sub.4) and concentrated under high
vacuum (35-50 mbar) on a rotovap taking care not to warm above
50.degree.. Small white needles are obtained by crystallization of
the residue from hexane, m.p. 164-166.degree.. Recrystallization
from cyclohexane gives 5-ethyl-2-(2',3',5',6'-tetrafluo-
roanilino)phenylacetic acid a white solid, m.p.
165-169.degree..
[0162] The starting material
N,N-dimethyl-5-ethyl-2-(2',3',5',6'-tetrafluo-
roanilino)phenylacetamide is prepared in the following manner:
[0163] N,N-Dimethyl-2-iodophenylacetamide (60 g, 0.208 mol),
2',3',5',6'-tetrafluoroaniline (100 g, 0.606 mol), copper powder
(6.6 g, 0.104 mol), copper(I) iodide (19.8 g, 0.104 mol) and
anhydrous potassium carbonate (28.7 g, 0.208 mol) are stirred
together in 1000 ml of xylenes. The reaction is heated to reflux
temperature for 48 hours. While still slightly warm (40.degree.)
the brown suspension is filtered through a pad of Celite which in
turn is rinsed with toluene (250 ml). The filtrate is evaporated on
a rotovap and then flash chromatographed on silica-gel (Rf 0.25 in
30% EtOAc/hexane). Crystallization from pentane/Et.sub.2O gives
N,N-dimethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetamide,
m.p. 109-110.degree..
[0164] Under an inert atmosphere, acetyl chloride (29.1 ml, 0.385
mol) is slowly added to a suspension of aluminum chloride (51.2 g,
0.385 mol) stirred in 1,2-dichloroethane (750 ml). After stirring
at room temperature for 1 hour a yellow solution is obtained. The
solution is cooled in an ice bath and
N,N-dimethyl-2-(2',3',5',6'-tetrafluoroanilino)- phenylacetamide
(40 g, 0.123 mol) is added.
[0165] The reaction is allowed to warm to room temperature and then
warmed to 80.degree. for 0.5 hours. The reaction is poured over ice
and extracted with EtOAc (2.times.750 ml). The organic extract is
washed with water (750 ml), saturated NaHCO.sub.3 solution (500 ml)
and brine (500 ml). Evaporation on a rotovap and trituration with
Et.sub.2O gives
N,N-dimethyl-5-acetyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetamide
as a white solid, m.p. 112-114.degree..
[0166]
N,N-dimethyl-5-acetyl-2-(2',3',5',6'-tetrafluoroanilino)phenylaceta-
mide (30 g, 0.802 mol) is dissolved in HOAc (150 ml) and
hydrogenated (55 psi) with a 10% Pd/C (1.5 g) catalyst for 8 hours.
The catalyst is removed by filtration through Celite and the
filtrate poured into water (500 ml) and EtOAc (500 ml). The organic
layer is washed with water (750 ml), neutralized with saturated
Na.sub.2CO.sub.3 solution (500 ml) and washed with brine (500 ml).
Evaporation on a rotovap followed by trituration with hexanes gives
N,N-dimethyl-5-ethyl-2-(2',3',5',6'-tetraf-
luoroanilino)phenylacetamide, m.p. 105-106.degree..
[0167] Similarly prepared are:
[0168] (b) 5-ethyl-2-(2',4'-dichloro-6'-methylanilino)phenylacetic
acid, m.p. 180-183.degree.;
[0169] (c) 5-ethyl-2-(2',6'-dichloroanilino)phenylacetic acid, m.p.
133-136.degree..
EXAMPLE 4
[0170] (a) N-(2,3,5,6-tetrafluorophenyl)-5-ethyloxindole (72.67 g;
0.235 mol, is slurried in water containing a little methanol (10%
v/v; 253 ml), and sodium hydroxide solution (50 wt %; 16.1 ml) is
added. The mixture is stirred at 80-85.degree. for 2-4 hours, then
cooled to ambient temperature. The reaction solution is partially
concentrated under reduced pressure (25-30 mm). After removal of 50
ml of the solvent, the mixture is diluted with water (150 ml) and
t-butyl methyl ether (250 ml). The cooled mixture is acidified to
pH 6.5-7.0 with aqueous HCl (12.1 N; 19.5 ml), keeping the
temperature at 0-5.degree.. The aqueous layer is discarded and the
organic layer is washed with water (250 ml). The organic layer is
concentrated under reduced pressure (20-100 mm) while exchanging
the solvent to toluene. After the more volatile components have
been removed, the batch volume is adjusted to 400-450 ml. This
mixture is warmed to 70.degree., clarified, concentrated to
one-half volume, and cooled to 0.degree.. After stirring at this
temperature for 2 hours, the product is collected and is washed
with toluene/heptane (10:90; 100 ml). The resulting solid is dried
under reduced pressure at 50-60.degree. for 4-8 hours to give
5-ethyl-2-(2', 3', 5', 6'-tetrafluoroanilino)phenylacetic acid of
Example 3.
[0171] The starting material is prepared as follows:
[0172] 4-Ethylaniline (242.36 g; 2.00 mol) is dissolved in dry
tetrahydrofuran (900 ml). A solution of n-BuLi (2.5 M in hexanes,
800 ml; 2.00 mol) is added under N.sub.2 with cooling maintaining
the reaction temperature below 15.degree.. After stirring for 1
hour at 10.degree., neat pentafluorobenzene (168.06 g; 1.00 mol) is
added with cooling to the mixture, keeping the temperature at
10-20.degree.. The reaction is stirred at ambient temperature for
1.5 hours, then aqueous HCl (6 N; 500 ml) is added slowly with
vigorous stirring and cooling, keeping the reaction temperature
below 350. The quenched reaction is stirred at ambient temperature
for 0.5-18 hours. The aqueous layer is separated, and the organic
phase is concentrated under reduced pressure (30-150 mm) to
one-fourth volume. The concentrate is diluted with heptane (300 ml)
and extracted with water (300 ml). The separated top organic layer
is stirred over 230-400 mesh silica gel (50 g) and filtered. The
filter cake is washed with heptane (4.times.50 ml). The combined
filtrate and washings are concentrated under reduced pressure
(20-30 mm) to give solid crude product. This material is
recrystallized from hot heptane (200 ml) and collected at
0.degree.. This solid is washed with cold heptane (100 ml) and
dried under reduced pressure at 40.degree. to give pure
N-(2',3',5',6'-tetrafluorophenyl)-4-ethylaniline.
[0173] The diphenylamine derivative (230.0 g; 0.854 mol; 1.0 eq) is
treated with chloroacetyl chloride (192.96 g; 1.709 mol; 2.0 eq) at
100-115.degree. for 2 hours (vigorous HCl evolution is controlled
by rate of heating). The mixture is cooled to ambient temperature,
then concentrated under reduced pressure (10-12 mm) to 80-90% of
the original volume. 1,2-Dichlorobenzene (80 ml) is added and the
diluted mixture is concentrated under reduced pressure (10-12 mm)
until no more chloroacetyl chloride is found by GC analysis (30-40
ml distilled) to give crude
N-(2',3',5',6'-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline in
solution.
[0174] Anhydrous AlCl.sub.3 (170.84 g; 1.281 mol; 1.5 eq) was
slurried with 1,2-dichlorobenzene (480 ml) under N.sub.2 and cooled
to 0.degree.. The crude product solution from the previous step
(theoretically containing 295.34 g; 0.854 mol; 1.0 eq) is added
slowly with vigorous stirring, keeping the temperature below
60.degree.. A solution of EtAlCl.sub.2 (1.8 M in toluene; 733 ml;
1.319 mol; 1.7 eq) is added, and the vigorously stirred reaction
mixture is heated to .about.160.degree., distilling toluene
(135-160.degree.) at ambient pressure. Upon cessation of the
distillation (.about.690 ml), the reaction temperature is held at
155-165.degree. for 3.5-5 hours. The mixture is cooled to ambient
temperature, then poured onto crushed ice (2.5 kg) with vigorous
stirring under N.sub.2. The reaction vessel is rinsed with
1,2-dichlorobenzene (50 ml). The cold quenched product slurry is
filtered and the filtercake is washed sequentially with 10%
1,2-dichlorobenzenelheptane (100 ml) and heptane (100 ml). The
material is dried under reduced pressure at 80-90.degree. for 12-16
hours to give N-(2',3',5',6'-tetrafluorophenyl)-5-
-ethyloxindole.
EXAMPLE 5
[0175] (a) N,N-Dimethyl
5-ethyl-2-(4'-chloro-2'-fluoro-6'-methylanilino)ph- enylacetamide
is converted as in the previous examples to
5-ethyl-2-(4'-chloro-2'-fluoro-6'-methylanilino)phenylacetic acid,
m.p. 153-156.degree..
[0176] The starting material is prepared as follows:
[0177] Ullmann condensation of
N,N-dimethyl-5-ethyl-2-iodo-phenylacetamide with
2-bromo-4-chloro-6-fluoroaniline according to the procedure
described in Example 1 yields
N,N-dimethyl-5-ethyl-2-(2'-bromo-4'-chloro--
6'-fluoroanilino)phenylacetamide.
[0178]
N,N-Dimethyl-5-ethyl-2-(2'-bromo-4'-chloro-6'-fluoroanilino)phenyla-
cetamide (2.5 g, 6.0 mmol) is combined with DMF (10 ml),
triethylamine (10 ml), tri-o-tolylphosphine (0.5 g, 1.6 mmol),
tetramethyltin (4 ml, 5.16 g, 28.9 mmol) and palladium acetate
(0.25 g, 1.1 mmol), and the mixture heated in a sealed tube for 3
days at 95.degree.. The tube is allowed to cool and carefully
opened. Water and ethyl acetate are added to the reaction and the
mixture separated. The organic fraction is washed with a dilute
NaCl solution (2.times.50 ml). The combined aqueous fractions are
then washed with ethyl acetate and the combined organic fractions
are then dried (magnesium sulfate). The material is absorbed onto a
small amount of silica gel and purified by flash chromatography (on
silica, ethyl acetate:hexanes, 1:4 to 1:1) to give
N,N-dimethyl-5-ethyl-2-(4'-chl-
oro-2'-fluoro-6'-methylanilino)phenylacetamide.
[0179] Similarly prepared are:
[0180] (b) 5-ethyl-2-(2',4'-difluoro-6'-methylanilino)phenylacetic
acid, m.p. 143-145.degree.;
[0181] (c)
5-ethyl-2-(2'-chloro-4'-fluoro-6'-methylanilino)phenylacetic acid,
m.p. 151-154.degree.;
EXAMPLE 6
[0182] (a) 5-Ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetic
acid (1.0 g, 3.06 mmol) in THF (100 ml) is treated with 1 N sodium
hydroxide (3.06 ml, 3.06 mmol) for 1 hour. The mixture is
concentrated on a rotovap and then dried by evaporating first with
THF (2.times.100 ml) and then with benzene (2.times.100 ml). The
remaining off-white sodium salt of
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetic acid is
dried under high vacuum overnight. Sodium
5-ethyl-2-(2',3',5',6'-tetrafluoroani- lino)phenylacetate (0.5 g,
1.43 mmol) and benzyl 2-bromoacetate (272 .mu.l, 1.72 mmol) are
stirred at 50.degree. in dimethylformamide (50 ml) for 14 hours.
The reaction mixture is cooled to room temperature and partitioned
between EtOAc (200 ml) and water (200 ml). The organic layer is
washed again with water (2.times.200 ml), brine (100 ml), dried
(MgSO.sub.4) and concentrated on a rotovap. The crude benzyl ester
is flash chromatographed on silica (10-15% EtOAc/hexane) to provide
the benzyloxycarbonylmethyl ester of
5-ethyl-2-(2',3',5',6'-tetrafluoroanilin- o)phenylacetic acid as a
colorless oil. The oil is dissolved in HOAc (20 ml) and
hydrogenated (55 psi) with a 1 0% Pd/C (0.1 g) catalyst for 1 hour.
The catalyst is removed by filtration through Celite and the
filtrate poured into water (200 ml) and EtOAc (200 ml). The organic
layer is washed with water (250 ml) and brine (100 ml). Evaporation
on a rotovap and trituration with Et.sub.2O/hexanes gives the
ester, carboxymethyl
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetate, m.p.
151-153.degree., of the formula 12
[0183] Similarly prepared are:
[0184] (b) carboxymethyl
5-ethyl-2-(2',4'-dichloro-6'-methylanilino)phenyl- acetate, m.p.
123-125.degree.;
[0185] (c) carboxymethyl
5-ethyl-2-(2',6'-dichloroanilino)phenylacetate, m.p.
124-126.degree.;
[0186] (d) carboxymethyl
5-ethyl-2-(2',4'-difluoro-6'-chloroanilino)phenyl- acetate, m.p.
142-144.degree.;
[0187] (e) carboxymethyl
5-ethyl-2-(2',4'-dichloro-6'-fluoroanilino)phenyl- acetate, m.p.
132-134.degree.;
[0188] (f) carboxymethyl
5-ethyl-2-(2'-chloro-6'-fluoroanilino)phenylaceta- te, m.p.
106-108.degree.;
[0189] (g) carboxymethyl
5-methyl-2-(2'-fluoro-4',6'-dichloroanilino)pheny- lacetate, m.p.
148-150.degree.;
[0190] (h) carboxymethyl
5-methyl-2-(2',6'-dichloroanilino)phenylacetate, m.p.
125-126.degree.;
[0191] (i) carboxymethyl
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacet- ate, m.p.
96-98.degree..
[0192] (j) carboxymethyl
5-methyl-2-(2',4'-difluoro-6'-chloroanilino)pheny- lacetate.
EXAMPLE 7
[0193] 5-Ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetic acid
(1.0 g, 3.06 mmol) in THF (100 ml) is treated with 1 N sodium
hydroxide (3.06 ml, 3.06 mmol) for 1 hour. The mixture is
concentrated on a rotovap and the residue is then treated and
evaporated to dryness first with THF (2.times.100 ml) and then with
benzene (2.times.100 ml). The remaining off-white sodium salt of
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenyl- acetic acid is
dried under high vacuum overnight.
[0194] The sodium
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetate ( 2.0 g,
6.2 mmol) is dissolved in DMF (70 ml) and treated with
1-bromo-4-chlorobutane (1.2 g, 6.9 mmol) at room temperature
overnight. The reaction mixture is concentrated under high vacuum
(35-50 mbar) on a rotovap. The resulting oil is partitioned between
water (200 ml) and Et.sub.2O (200 ml). The organic layer is washed
with brine (100 ml), dried (MgSO.sub.4) and concentrated on a
rotovap to give the chlorobutyl ester as a light-brown oil. The
chlorobutyl ester is dissolved in CH.sub.3CN (100 ml) and treated
with silver nitrate (8.7 g, 50 mmol) at reflux temperature for 18
hours. The reaction is cooled to room temperature and the solvent
removed on a rotovap. The residue is partitioned between
CH.sub.2Cl.sub.2 (200 ml) and water (200 ml). The organic layer is
dried (MgSO.sub.4), concentrated and flash-chromatographed (5%
EtOAc/hexane) to give nitrooxybutyl
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetate as a clear
oil.
EXAMPLE 8
[0195] Sodium
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetate (7.3 g,
20.9 mmol) is dissolved in DMF (100 ml) and treated with benzyl
2-methyl-2-bromopropionate (6.2 g, 24.2 mmol) at 50.degree. for 96
hours. The reaction mixture is cooled to room temperature, and
concentrated under high vacuum (35-50 mbar) on a rotovap. The
resulting oil is partitioned between water (200 ml) and Et.sub.2O
(200 ml). The organic layer is washed with brine (100 ml), dried
(MgSO.sub.4) and concentrated on a rotovap to give a light-brown
oil. Flash chromatography (0-10% EtOAc/hexane) on silica-gel gives
the ester as a light-red oil. The ester (1.5 g, 3.0 mmol) is
dissolved in EtOAc (150 ml) and hydrogenated (55 psi) with a 10%
Pd/C (0.3 g) catalyst for 1 hour. The catalyst is removed by
filtration through Celite (500 ml). Evaporation on a rotovap
followed by trituration with hexanes gives 1-carboxy-1-methylethyl
5-ethyl-2-(2',3',5',6'-tetrafluoroanilino)phenylacetate as a
crystalline white solid, m.p. 104-108.degree..
EXAMPLE 9
[0196] (a) Isopropyl
5-methyl-2-(2'-fluoro-6'-trifluoromethylanilino)pheny- lacetate
(2.9 g, 8.4 mmol) is dissolved in methanesulfonic acid (25 ml) and
stirred at room temperature for 8 hours. The reaction mixture is
slowly added to 200 ml of ice in a beaker. After the ice has
melted, the solution is stirred to produce a white solid which is
isolated by filtration. The solid is flash chromatographed on
silica-gel using 35% EtOAc as an eluant to give
5-methyl-2-(2'-fluoro-6'-trifluoromethylanilin- o)phenylacetic acid
as a white solid, m.p. 155-156.degree..
[0197] The starting material is prepared as follows:
[0198] 2-Iodo-5-methylphenylacetic acid (20.0 g, 72 mmol) and a
catalytic amount of 98% sulfuric acid (0.2 ml) are dissolved in
isopropyl alcohol (200 ml) and heated to reflux temperature for 48
hours. The solvent is removed on a rotovap and the residual oil
partitioned between EtOAc (500 ml) and saturated NaHCO.sub.3
solution (500 ml). The organic layer is separated, dried
(MgSO.sub.4) and concentrated on a rotovap. The residual oil is
distilled using a kugelrohr apparatus to give a clear, colorless
oil which solidifies on standing at room temperature to give
isopropyl 2-iodo-5-methylphenylacetate, m.p. 48-50.degree..
[0199] Isopropyl 2-iodo-5-methylphenylacetate (10.0 g, 31 mmol),
2-amino-3-fluorobenzotrifluoride (20.0 g, 111 mmol), copper powder
(1.1 g, 16 mmol), copper (I) iodide (3.1 g, 16 mmol) and
K.sub.2CO.sub.3 (4.3 g, 31 mmol) are stirred together in xylenes
(200 ml). The reaction mixture is heated to reflux temperature for
48 hours. While still slightly warm (40.degree.) the brown
suspension is filtered through a pad of Celite, which in turn is
rinsed with toluene (100 ml). The filtrate is evaporated on a
rotovap and then flash chromatographed on silica-gel using 3-4%
EtOAc in hexanes as the eluant. The product, isopropyl
5-methyl-2-(2'-fluoro-6'-trifluoromethylanilino)phenyl acetate, is
isolated as a pale yellow oil.
[0200] (b) Similarily prepared is
5-methyl-2-(2',4'-dichloro-6'-trifluorom- ethylanilino)phenylacetic
acid, m.p. 157-158.degree..
EXAMPLE 10
[0201] (a) To a degassed solution of 1500 ml of absolute ethanol
and 510 ml of 2N NaOH (1.02 mol) is added 150 g (0.51 mol) of
N-(2'-chloro-4',6'-difluorophenyl)-5-methyloxindole. The resultant
mixture is degassed and heated to 60-65.degree. for 2 hours. Most
of the ethanol is removed under reduced pressure and then 4500 ml
of water is added to the residue which is then washed three times
with 1500 ml of toluene. The aqueous layer is cooled to 0.degree.
and adjusted to pH 6 using 1.2 N HCl. The solid is filtered off and
washed with 100 ml of water and dried. Recrystallization from ethyl
acetate and heptane gives
5-methyl-2-(2',4'-difluoro-6-chloroanilino)phenylacetic acid of
Example 1(g).
[0202] The starting material is prepared in the following
manner:
[0203] 2-Bromo-4,6-difluoroaniline (26.00 g; 0.13 mol) is added to
78 ml (0.71 mol) of acetic anhydride and stirred at room
temperature for 5 hours. The reaction is quenched by the addition
of 104 ml of water over a 10 minute period, causing the temperature
to rise to 43.degree.. The reaction is allowed to cool to room
temperature and then cooled to 5.degree. in ice water. The solids
are collected by suction filtration, washed with 104 ml of water,
and dried to give 2-bromo-4,6-difluoroacetan- ilide, m.p.
156.degree..
[0204] Cuprous chloride (11.9 g, 0.12 mol) and cupric chloride
(16.14 g, 0.12 mol) are dissolved in 100 ml of DMF.
2-Bromo-4,6-difluoroacetanilide (20 g, 0.08 mol) is added and the
solution is heated to 130.degree. C. for 20 hours. The reaction is
cooled to room temperature and then added dropwise over 30 minutes
to 400 ml of 3N HCl. The solid is filtered off, washed with 200 ml
of water, and dried to give 2-chloro-4,6-difluoroaceta- nilide,
m.p. 144-150.degree..
[0205] To a slurry of 110.36 g (0.54 mol) of
2-chloro-4,6-difluoroacetanil- ide in 735 ml of absolute ethanol is
added 100.36 ml (1.32 mol) of concentrated HCl. The mixture is
heated to reflux for 20 hours and then cooled to room temperature.
The mixture is concentrated under reduced pressure to give a
residue which is dissolved in 1105 ml of water, and 1N NaOH is
added to adjust the pH to 12. The basic mixture is extracted twice
with ethyl acetate and the combined organic layers are washed with
735 ml of water. The solvents are evaporated under reduced pressure
to give 2-chloro-4,6-difluoroaniline as an oil.
[0206] A mixture of 4-iodotoluene (210 g, 0.96 mol),
2-chloro-4,6-difluoroaniline (204 g, 1.25 mol), copper powder (36
g, 0.57 mol), cuprous iodide (130 g, 0.68 mol), and potassium
carbonate (118 g, 0.86 mol) in 500 ml of xylene is stirred
vigorously and heated to reflux in a flask fitted with a Dean-Stark
trap for 26 hours. After cooling to room temperature, the solids
are filtered off, and the filter cake is washed with 100 ml of
xylene. The solvents are evaporated under reduced pressure to give
an oil which is dissolved in a mixture of 50 g of silica gel in 750
ml of heptane. The solids are filtered off and the solvents are
evaporated under reduced pressure to give
N-(2'-chloro-4',6'-difluoro- phenyl)-4-methylaniline as an oil.
[0207] A mixture of 230 g (0.9 mol)
N-(2'-chloro-4',6'-difluorophenyl)-4-m- ethylaniline and 325 ml
(4.06 mol) of chloroacetyl chloride is heated under a nitrogen
atmosphere for one hour at 50.degree.. The solvent is evaporated
under reduced pressure to give an oil to which 200 ml of
chlorobenzene is added. The solvent is evaporated under reduced
pressure to completely remove the chloroacetyl chloride, giving
N-(2'-chloro-4',6'-difluorophenyl)-N-chloroacetyl-4-methylaniline
as an oil.
[0208] To a mixture of 100 g (0.3 mol) of
N-(2'-chloro-4',6'-difluoropheny- l)-N-chloroacetyl-4-methylaniline
and 103 g (0.78 mol) of aluminum chloride is added 400 ml of
1,2-dichlorobenzene. The reaction is heated to 140.degree. for 2
hours. The reaction is cooled to room temperature and added to a
mixture of 100 ml of concentrated HCl and 700 ml water (cooled to
0-5.degree. in a dry ice/acetone bath). The mixture is extracted
twice with 400 ml of methylene chloride. The combined organic
layers are washed with 600 ml of 3N HCl. The organic layer is
stirred with 66 g of magnesium sulfate and 33 g of charcoal (DARCO
G-60). The solids are filtered off and the solvents are evaporated
under reduced pressure to give a tan solid which is recrystallized
from ethanol to give
N-(2'-chloro-4',6'-difluorophenyl)-5-methyloxindole, mp
137-140.degree..
[0209] b) Similarly prepared is
5-methyl-2-(2'-chloro-6'-fluoroanilino) phenylacetic acid of
example 1(d).
[0210] The preparation of the starting material,
N-(2-chloro-6-fluoro) aniline from 2-chloro-6-fluorobenzamide is
described in Rec. Trav. Chim. Pays-Bas, 97, 51-56 (1978).
EXAMPLE 11
[0211] A solution of 1300 ml of ethanol, 130 ml of water and 43.5 g
of sodium hydroxide is degassed. To the solution is added 100.0 g
of N-(2'-chloro-6'-fluorophenyl)-5-methyloxindole and the mixture
is heated to 700 for 2 hours. The reaction is cooled to 50.degree.
and 90.7 ml of 37% HCl in 453.3 ml of water is added slowly. The
suspension is cooled slowly to room temperature and filtered. The
filter cake is washed three times with 80 ml of 1:1 ethanol and
water and dried to give
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid,
m.p.152-154.degree..
[0212] The starting material,
N-(2'-chloro-6'-fluorophenyl)-5-methyloxindo- le, is prepared in
the following manner:
[0213] A solution of 261.1 g (2.0 mol) of 1-chloro-3-fluorobenzene
in 2000 ml of dry tetrahydrofuran under nitrogen is cooled to
-78.degree.. To the solution is added 960 ml (2.4 mol) of 2.5 M
n-butyllithium in hexanes over a period of 40 minutes. After
stirring for 2.5 hours, a slurry of 155 ml of bromine cooled to
-78.degree. is added over 30 minutes and the mixture is stirred for
40 minutes before warming to -10.degree.. The reaction is quenched
with an aqueous solution of 151.3 g (1.2 mol) of sodium sulfite and
16.0 g (0.4 mol) of sodium hydroxide in 500 ml of water. The
organic layer is separated, the solvents are removed at ambient
pressure, and the product is distilled at 92-96.degree. (20 mm Hg)
to obtain 2-bromo-3-fluoro-chlorobenzene as a colorless oil.
[0214] A mixture of 146.1 g (1.36 mol) of p-toluidine, 12.6 g (0.02
mol) of (.+-.)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 261.9 g
(2.73 mol) of sodium t-butoxide, 314.1 g (1.50 mol) of
2-bromo-3-fluoro-chlorobenzen- e and 6.3 g (0.0069 mol) of
tris(dibenzylideneacetone)dipalladium(0) in 3000 ml of toluene is
heated to 110.degree. over 30 minutes and stirred an additional 4
hours at this temperature. The mixture is cooled to room
temperature and a solution of 680 ml 37% hydrochloric acid and 680
ml of water is added over 15 minutes. The mixture is stirred for 20
minutes and filtered through a pad of Celite. The layers are
separated and the organic phase is washed twice with 680 ml of
water and once with a solution of 225 g of sodium chloride in 680
ml of water. The solvents are evaporated under reduced pressure to
give N-(2'-chloro-6'-fluorophenyl)-4- -methylaniline as an oil,
b.p. 129-131.degree./0.5 mm Hg.
[0215] A mixture of 25 g (0.11 mol)
N-(2'-chloro-6'-fluorophenyl)-4-methyl- aniline and 40 ml (0.5 mol)
of chloroacetylchloride is heated under a nitrogen atmosphere for
15 minutes at 60.degree.. The solvent is evaporated under reduced
pressure to give an oil which is dissolved in 25 ml of ethyl
acetate. Pentane (250 ml) is added dropwise over 15 minutes to
precipitate the product. The mixture is cooled to -15.degree. C.
and the solid is filtered and washed with pentane to give
N-(2'-chloro-6'-fluorophenyl)-N-chloroacetyl-4-methylaniline, m.p.
80-83.degree..
[0216] A mixture of 100 g (0.32 mol) of
N-(2'-chloro-6'-fluorophenyl)-N-ch- loroacetyl-4-methylaniline and
110 g (0.82 mol) of aluminum chloride in 400 ml of 1
,2-dichlorobenzene is stirred vigorously and heated to 140.degree.
for 7.5 hours. The reaction is cooled to room temperature and added
to a mixture of 100 ml of 12N HCl and 700 ml of water (cooled to
0-5.degree. in a dry ice/acetone bath). The mixture is extracted
twice with 400 ml of methylene chloride and the combined organic
layers are washed with 600 ml of 3N HCl. The organic layer is
stirred with 66 g of magnesium sulfate and 33 g of charcoal (DARCO
G-60). The solids are filtered through a pad of Celite and the
solvents are evaporated under reduced pressure to give a tan solid
which is recrystallized from ethanol to give
N-(2'-chloro-6'-fluorophenyl)-5-methyloxindole, m.p.
137-140.degree..
[0217] Alternatively, a mixture of 169.8 g of crude
N-(2'-chloro-6'-fluorophenyl)-4-methylaniline, 172 ml (2.15 mol) of
chloroacetyl chloride in 580 ml of toluene is heated under a
nitrogen atmosphere for 2 hours at 70.degree.. The reaction is
cooled to room temperature, 450 ml of decane is added, and the
volatiles are distilled off under 200 mbar pressure at
62-72.degree.. To the mixture is added 150 ml of toluene and 385 g
of aluminum chloride (2.87 mol) slowly at 20-40.degree.. The
mixture is heated at 120.degree. for 5 hours, cooled to 20.degree.,
and added over 30 minutes to 800 ml of ethyl acetate. The mixture
is quenched by addition to a pre-cooled solution of 67 ml of 37%
hydrochloric acid in 800 ml of water at 20.+-.100, and the
resultant mixture is filtered through a pad of Celite. The organic
layer is separated and the volatiles are distilled off. To the
residue is added 100 ml of heptane and the mixture is cooled to
0.degree. over a 30 minute period and stirred for one hour. The
mixture is filtered and the filter cake is washed three times with
45 ml of heptane. To the crude product is added 90 g of charcoal
(DARCO G-60) and 4500 ml of methanol. The mixture is heated to
reflux for two hours, cooled to room temperature, and filtered
through a pad of Celite. After distilling off 4390 ml of methanol,
the mixture is cooled to 15.degree.. The product is collected by
filtration, washed three times with 30 ml of methanol, and dried to
give N-(2'-chloro-6'-fluorophenyl)-5-methyloxindole.
* * * * *