U.S. patent application number 10/006349 was filed with the patent office on 2002-08-08 for new benzofuran and benzothiophene derivatives as anti-inflammatory agents.
Invention is credited to McLaren, Kevin L., Smith, David Bernard, Tracy, Jahari Laurant.
Application Number | 20020107280 10/006349 |
Document ID | / |
Family ID | 22951260 |
Filed Date | 2002-08-08 |
United States Patent
Application |
20020107280 |
Kind Code |
A1 |
McLaren, Kevin L. ; et
al. |
August 8, 2002 |
NEW BENZOFURAN AND BENZOTHIOPHENE DERIVATIVES AS ANTI-INFLAMMATORY
AGENTS
Abstract
This invention relates to compounds, which are generally
anti-inflammatory and analgesic compounds, and which are
represented by Formula I: 1 wherein A is a --CH.sub.2--, --C(O)--,
--O--, --S--, --S(O)--, or --S(0).sub.2-- and the other
substituents are as defined in the specification; or prodrugs,
individual isomers, mixtures of isomers, and pharmaceutically
acceptable salts thereof. The invention further relates to
pharmaceutical compositions containing such compounds and methods
for their use as therapeutic agents.
Inventors: |
McLaren, Kevin L.; (Carmel,
IN) ; Smith, David Bernard; (San Mateo, CA) ;
Tracy, Jahari Laurant; (Redwood City, CA) |
Correspondence
Address: |
ROCHE BIOSCIENCE
3401 HILLVIEW AVENUE
INTELLECTUAL PROPERTY LAW DEPT., MS A2-250
PALO ALTO
CA
94304-9819
US
|
Family ID: |
22951260 |
Appl. No.: |
10/006349 |
Filed: |
December 3, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60251283 |
Dec 5, 2000 |
|
|
|
Current U.S.
Class: |
514/443 ;
514/469; 514/470; 549/466; 549/467; 549/49; 549/52; 549/57 |
Current CPC
Class: |
A61P 15/06 20180101;
A61P 19/04 20180101; A61P 25/28 20180101; C07D 333/70 20130101;
A61P 15/00 20180101; A61P 19/10 20180101; A61P 43/00 20180101; A61P
25/00 20180101; A61P 19/06 20180101; A61P 21/00 20180101; C07D
307/84 20130101; A61P 29/00 20180101; A61P 25/06 20180101; A61P
19/00 20180101; A61P 19/02 20180101 |
Class at
Publication: |
514/443 ;
514/469; 514/470; 549/52; 549/49; 549/57; 549/466; 549/467 |
International
Class: |
C07D 339/02; C07D
333/52; C07D 333/72 |
Claims
What is claimed is:
1. A compound selected from the group of compounds represented by
Formula I 9wherein Y is O or S; A is a --CH.sub.2--, --C(O)--,
--O--, --S--, --S(O)--, or --S(O).sub.2--; Ar is an optionally
substituted phenyl; R.sup.1 is hydrogen, alkyl, alkoxy, hydroxy,
halo, cyano, --C(O)NR.sup.4R.sup.5, --COOR.sup.4,
--NR.sup.4R.sup.5, wherein R.sup.4 and R.sup.5 are each
independently in each occurrence hydrogen or alkyl; R.sup.2 is
hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, nitro, cyano, or
--NR.sup.4R.sup.5, wherein R.sup.4 and R.sup.5 are as defined
previously; R.sup.3 is --SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
or --SO.sub.2NR.sup.4R.sup.5 wherein R.sup.6 is alkyl,
hydroxyalkyl, alkoxyalkyl, carboxyalkyl, or alkoxycarbonylalkyl;
and R.sup.4 and R.sup.5 are as defined previously; or prodrugs,
individual isomers, mixtures of isomers, and pharmaceutically
acceptable salts thereof.
2. The compound of claim 1 wherein Ar is phenyl optionally
substituted at one or two substitutents independently selected from
the group consisting of halo and alkoxy, and R.sup.3 is
--SO.sub.2R.sup.6, wherein R.sup.6 is alkyl.
3. The compound of claim 2 wherein Y is --O-- and A is --S--.
4. The compound of claim 3 wherein R.sup.1is alkyl or cyano.
5. The compound of claim 2 wherein Y is --S-- and A is --S--.
6. The compound of claim 5 wherein R.sup.1 is alkyl or cyano.
7. The compound of claim 2 wherein Y is --S-- and A is --O--.
8. The compound of claim 7 wherein R.sup.1 is alkyl or cyano.
9. The compound of claim 1 comprising:
3-(2-Chloro-phenylsulfanyl)-6-metha-
nesulfonyl-benzo[b]thiophene-2-carbonitrile;
3-(2,4-Dichloro-phenylsulfany-
l)-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile;
3-(4-Ethoxy-phenoxy)-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile;
3-(2-Fluoro-phenylsulfanyl)-6-methanesulfonyl-benzo[b]thiophene-2-carboni-
trile;
3-(4-Fluoro-phenylsulfanyl)-6-methanesulfonyl-benzo[b]thiophene-2-c-
arbonitrile; and
3-(4-Chloro-2-fluoro-phenoxy)-6-methanesulfonyl-benzo[b]t-
hiophene-2-carbonitrile.
10. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 and a pharmaceutically
acceptable excipient.
11. A method of treatment of a disease in a mammal treatable by
administration of a selective COX II inhibitor comprising
administration to the mammal a therapeutically effective amount of
a compound of claim 1.
12. The method of claim 11 wherein the disease is an inflammatory
disease selected from myositis, synovitis, arthritis (rheumatoid
arthritis and osteoarthritis), gout, back pain, dental pain, sports
injuries, sprains, strains, headache, tendonitis, ankylosing,
sponylitis, and bursitis.
13. The method of claim 11 wherein the disease is dysmenorrhoea or
premature labor.
14. The method of claim 11 wherein the disease is Alzheimer's.
15. A process for preparing a compound selected from the group of
compounds of claim 1, which comprises reacting a compound of
general Formula: 10wherein L is a leaving group, and R.sup.1,
R.sup.2, R.sup.3, and Y are as defined in claim 1 with a compound
of general formula ArAH, wherein Ar and A are as defined in Clliam
1, to provide a compound of Formula I: 11wherein R.sup.1, R.sup.2,
R.sup.3, Y, A and Ar are as defined in claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This Application claims benefit under Title 35 U.S.C. 119(e)
of U.S. Provisional Application No. 60/251,283 filed Dec. 05,
2000.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to anti-inflammatory and analgesic
compounds, especially to certain benzofuran and benzothiophene
derivatives, pharmaceutical compositions containing them, methods
for their use, and methods for preparing these compounds.
[0004] 2. Background of the Invention
[0005] Non-steroidal anti-inflammatory drugs (NSAIDs), have a
problem of causing serious side-effects such as gastrointestinal
tract distress or nephro-toxicity. NSAIDs inhibit the activity of
cyclooxygenase (COX), which is an enzyme involved in prostaglandin
G/H synthesis, resulting in the inhibition of the biosynthesis of
prostaglandins not only in inflammatory loci but also in stomach
and kidney. It has been found that COX exists in two forms: COX-1
and COX-2, Cell, 83, 345, (1995).
[0006] COX-1 is expressed in normal cells and controls the function
of stomach and kidney, while COX-2 is induced by mitogens or
cytokines in inflammatory sites where inflammation and other
immunoreactions occur, J. Biol. Chem., 271, 33157(1996).
[0007] To avoid the toxicity of NSAIDs due to the inhibition of
coexisting COX-1, selective inhibitors of COX-2 have been
investigated. The selective COX-2 inhibitors have anti-inflammatory
action, pain-relieving action, and/or antipyretic action; with less
side effects such as bleeding in the gastrointestinal tract. COX-2
inhibitors may show anticancer activity and lower the induction of
asthma in asthmatic patients who are sensitive to conventional
NSAIDs. These selective inhibitors of COX-2 may also be used in
treating Alzheimer's disease and osteoporosis of women after
menopause.
DESCRIPTION OF RELATED ART
[0008] U.S. Pat. No. 3,331,854 (American Cyanamid) refers to
certain novel furan and thiophene compounds.
[0009] U.S. Pat. No. 5,426,113 (Warner Lambert) refers to certain
tetrazol-benzothiophene carboxamides in preventing ulcer
formation.
[0010] U.S. Pat. No. 5,731,342 (Eli Lilly) refers to certain
benzothiophenes, which are useful for the treatment of the medical
indications associated with post-menopausal syndrome and breast
cancer treatment and prevention.
[0011] U.S. Pat. Nos 4,663,347; 4,745,127; 4,822,803; 4,933,351;
and 4,621,091 (Merck) refer to certain benzofuran-2-carboxylic acid
derivatives as 5-lipoxygenase inhibitors.
[0012] U.S. Pat. No.4,621,091 (Merck) refers to certain
3-hydroxybenzothiophene-2-sulfide derivatives as 5-lipoxygenase
inhibitors.
[0013] DE Pat. No. 3,342,624 (Grote) refers to certain
3-hydroxybenzoyl-benzofuran derivatives.
[0014] PCT Published Application No. WO 95/02406 (Warner Lambert)
refers to certain use of benzothiophene and benzofuran compounds
for monitoring inflammation.
SUMMARY OF THE INVENTION
[0015] In a first aspect, this invention provides compounds
selected from the group of compounds represented by Formula I:
2
[0016] wherein:
[0017] Y is O or S;
[0018] A is a --CH.sub.2--, --C(O)--, --O--, --S--, --S(O)--, or
--S(O).sub.2--;
[0019] Ar is an optionally substituted phenyl;
[0020] R.sup.1 is hydrogen, alkyl, alkoxy, hydroxy, halo, cyano,
--C(O)NR.sup.4R.sup.5, --COOR.sup.4, --NR.sup.4R.sup.5, wherein
R.sup.4 and R.sup.5 are each independently in each occurrence
hydrogen or alkyl;
[0021] R.sup.2 is hydrogen, alkyl, alkoxy, hydroxy, halo,
haloalkyl, nitro, cyano, or --NR.sup.4R.sup.5, wherein R.sup.4 and
R.sup.5 are as defined previously;
[0022] R.sup.3 is --SR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, or
--SO.sub.2NR.sup.4R.sup.5 wherein R.sup.6 is alkyl, hydroxyalkyl,
alkoxyalkyl, carboxyalkyl, or alkoxycarbonylalkyl; and R.sup.4 and
R.sup.5 are as defined previously; or
[0023] prodrugs, individual isomers, mixtures of isomers, and
pharmaceutically acceptable salts thereof.
[0024] In a second aspect, this invention provides pharmaceutical
compositions containing a therapeutically effective amount of a
compound of Formula I or its pharmaceutically acceptable salt and a
pharmaceutically acceptable excipient.
[0025] In a third aspect, this invention provides a method of
treatment of a disease, in particular an inflammatory and
autoimmune disease, in a mammal treatable by administration of a
prostaglandin G/H synthase inhibitor, comprising administration of
a therapeutically effective amount of a compound of Formula I or
its pharmaceutically acceptable salt.
[0026] In a fourth aspect, this invention provides processes for
preparing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Definitions
[0028] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0029] "Alkyl" means a linear saturated monovalent hydrocarbon
radical of one to six carbon atoms or a branched saturated
monovalent hydrocarbon radical of three to six carbon atoms, e.g.,
methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the
like.
[0030] "Alkylene" means a linear saturated divalent hydrocarbon
radical of one to six carbon atoms or a branched saturated divalent
hydrocarbon radical of three to six carbon atoms, e.g., methylene,
ethylene, propylene, 2-methylpropylene, pentylene, and the
like.
[0031] "Alkoxy", "aryloxy", "aralkyloxy", or "heteroaralkyloxy"
means a radical --OR where R is an alkyl, aryl, aralkyl, or
heteroaralkyl respectively, as defined herein, e.g., methoxy,
phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
[0032] "Alkoxycarbonylalkyl" means a radical --R.sup.aC(O)R.sup.b
where R.sup.a is an alkylene group as defined above and R.sup.b is
an alkoxy group as defined above e.g., methoxycarbonylethyl,
ethoxycarbonylbutyl, and the like.
[0033] "Aryl" means a monovalent monocyclic or bicyclic aromatic
radical of 6 to 10 ring atoms which is substituted independently
with one to five substituents, preferably one, two, or three
substituents selected from alkyl, cycloalkyl, cycloalkylalkyl,
halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, alkylamino,
dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, --COR (where R is
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or
phenylalkyl), --(CR'R").sub.n--COOR (where n is an integer from 0
to 5, R' and R" are independently hydrogen or alkyl, and R is
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or
phenylalkyl) or --(CR'R").sub.n--CONR.sup.aR.sup.b (where n is an
integer from 0 to 5, R' and R" are independently hydrogen or alkyl,
and R.sup.a and R.sup.b are, independently of each other, hydrogen,
alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). More
specifically the term aryl includes, but is not limited to, phenyl,
biphenyl, 1-naphthyl, and 2-naphthyl, and the derivatives
thereof.
[0034] "Halogen" or "halo" means the radical fluoro, bromo, chloro,
and/or iodo.
[0035] "Haloalkyl" means alkyl substituted with one or more same or
different halo atoms, e.g., --CH.sub.2Cl, --CF.sub.3,
--CH.sub.2CF.sub.3, --CH.sub.2CCl.sub.3, and the like, and further
includes those alkyl groups such as perfluoroalkyl in which all
hydrogen atoms are replaced by fluorine atoms.
[0036] "Hydroxyalkyl" means an alkyl radical as defined herein,
substituted with one or more, preferably one, two or three hydroxy
groups, provided that the same carbon atom does not carry more than
one hydroxy group. Representative examples include, but are not
limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,
1-hydroxymethyl-2-methy- lpropyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl, 2,3-dihydroxypropyl,
1-hydroxymethyl-2-hydroxyethyl, 2,3-dihydroxybutyl,
3,4-dihydroxybutyl and 2-hydroxymethyl-3-hydroxypropyl, preferably
2-hydroxyethyl, 2,3-dihydroxypropyl and
1-hydroxymethyl-2-hydroxyethyl. Accordingly, as used herein, the
term "hydroxyalkyl" is used to define a subset of heteroalkyl
groups.
[0037] "Optionally substituted phenyl" means a phenyl ring which is
optionally substituted independently with one to four substituents,
preferably one or two substituents selected from alkyl, cycloalkyl,
cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,
acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy,
heteroalkyl, --COR (where R is hydrogen, alkyl, phenyl or
phenylalkyl, --(CR'R").sub.n --COOR (where n is an integer from 0
to 5, R' and R" are independently hydrogen or alkyl, and R is
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or
phenylalkyl), or --(CR'R").sub.n--CONR.sup.aR.sup.b (where n is an
integer from 0 to 5, R' and R" are independently hydrogen or alkyl,
and R.sup.a and R.sup.b are, independently of each other, hydrogen,
alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).
[0038] "Leaving group" has the meaning conventionally associated
with it in synthetic organic chemistry i.e., an atom or group
capable of being displaced by a nucleophile and includes halo (such
as chloro, bromo, iodo), alkanesulfonyloxy, arenesulfonyloxy,
alkylcarbonyloxy (e.g. acetoxy), arylcarbonyloxy, mesyloxy,
tosyloxy, trifluoromethanesulfonylox- y, aryloxy (e.g.,
2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the
like.
[0039] "Pharmaceutically acceptable excipient" means an excipient
that is useful in preparing a pharmaceutical composition that is
generally safe, non-toxic and neither biologically nor otherwise
undesirable, and includes an excipient that is acceptable for
veterinary use as well as human pharmaceutical use. A
"pharmaceutically acceptable excipient" as used in the
specification and claims includes both one and more than one such
excipient.
[0040] "Pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include:
[0041] (1) acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]-oct-- 2-ene-1-carboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
t-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or
[0042] (2) salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic base such as ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine, and the like.
[0043] "Prodrugs" means any compound which releases an active
parent drug, or any compound which changes its oxidation level,
according to Formula I in vivo when such prodrug is administered to
a mammalian subject. Prodrugs of a compound of Formula I are
prepared by modifying functional groups present in the compound of
Formula I in such a way that the modifications may be cleaved in
vivo to release the parent compound. Prodrugs may also be prepared
by incomplete oxidation of certain functional groups, such as
sulfur containing functional groups, in such a way that the
oxidation of said functional group may be effected in vivo to
release a compound according to Formula I. Prodrugs include
compounds of Formula I wherein a hydroxy, amino, or sulfhydryl
group in a compound of Formula I is bonded to any group that may be
cleaved in vivo to regenerate the free hydroxyl, amino, or
sulfhydryl group, respectively. Examples of prodrugs include, but
are not limited to esters (e.g., acetate, formate, and benzoate
derivatives) or carbamates (e.g., N,N-dimethylaminocarbonyl) of
hydroxy functional groups and thiol or sulfoxide groups in
compounds of Formula I, and the like.
[0044] "Protecting group" refers to a grouping of atoms that when
attached to a reactive group in a molecule masks, reduces or
prevents that reactivity. Examples of protecting groups can be
found in T. W. Greene and P. G. Wuts, Protective Groups in Organic
Chemistry, (Wiley, 2nd ed. 1991) and Harrison and Harrison et al.,
Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and
Sons. 1971-1996). Representative amino protecting groups include
formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),
tert-butoxycarbonyl (Boc), trimethylsilyl (TMS),
2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted
trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl
(FMOC), nitro-veratryloxycarbonyl (NVOC) and the like.
Representative hydroxy protecting groups include those where the
hydroxy group is either acylated or alkylated such as benzyl and
trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers,
trialkylsilyl ethers, and allyl ethers.
[0045] "Treating" or "treatment" of a disease includes:
[0046] (1) preventing the disease, i.e. causing the clinical
symptoms of the disease not to develop in a mammal that may be
exposed to or predisposed to the disease but does not yet
experience or display symptoms of the disease,
[0047] (2) inhibiting the disease, i.e., arresting or reducing the
development of the disease or its clinical symptoms, or
[0048] (3) relieving the disease, i.e., causing regression of the
disease or its clinical symptoms.
[0049] "A therapeutically effective amount" means the amount of a
compound that, when administered to a mammal for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the mammal to be treated.
[0050] "Optional" or "optionally" in the above definitions means
that the subsequently described event or circumstance may but need
not occur, and that the description includes instances where the
event or circumstance occurs and instances in which it does not.
For example, "heterocyclo group optionally mono- or di-substituted
with an alkyl group" means that the alkyl may but need not be
present, and the description includes situations where the
heterocyclo group is mono- or di-substituted with the alkyl group
and situations where the heterocyclo group is not substituted with
the alkyl group.
[0051] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers". Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers". Stereoisomers that are not mirror images of one
another are termed "diastereomers" and those that are
non-superimposable mirror images of each other are termed
"enantiomers". When a compound has an asymmetric center, for
example, it is bonded to four different groups, a pair of
enantiomers is possible. An enantiomer can be characterized by the
absolute configuration of its asymmetric center and is described by
the R- and S-sequencing rules of Cahn, Ingold and Prelog, (Cahn et
al. Angew. Chem. Inter. Edit., 5, 385; (1966) errata 511; Cahn et
al. Angew. Chem., 78, 413;(1966) Cahn and Ingold J. Chem. Soc.
(London), 612; (1951) Cahn et al. Experientia, 12, 81;(1956), Cahn,
J. Chem.Educ., 41, 116, (1964)) or by the manner in which the
molecule rotates the plane of polarized light and designated as
dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers
respectively). A chiral compound can exist as either individual
enantiomer or as a mixture thereof. A mixture containing equal
proportions of the enantiomers is called a "racemic mixture".
[0052] The compounds of this invention may exist in stereoisomeric
form if they possess one or more asymmetric centers or a double
bond with asymmetric substitution and, therefore, can be produced
as individual stereoisomers or as mixtures. Unless otherwise
indicated, the description is intended to include individual
stereoisomers as well as mixtures. The methods for the
determination of stereochemistry and the separation of
stereoisomers are well-known in the art (see discussion in Chapter
4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley
and Sons, New York, 1992).
[0053] Throughout the application the following abbreviations are
used with the following meanings:
1 DBN 1,5-Diazabicyclo[4.3.0]non-5-ene DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene DMF N,N-Dimethylformamide DMSO
Dimethylsulfoxide EtOAc Ethyl acetate Et.sub.2O Ethyl ether EtOH
Ethanol HMPA Hexamethylphosphoric triamide HPLC High pressure
liquid chromatography KHMDS Potassium hexamethyldisilazide MCPBA
m-Chloroperbenzoic acid MHz Megahertz MS Mass Spectrum NMR Nuclear
Magnetic Resonance OXONE .TM. Potassium peroxymonosulfate p-TsOH
p-Toluenesulfonic acid TFAA Trifluoroacetic anhydride THF
Tetrahydrofuran TLC Thin layer chromatography
[0054] Nomenclature
[0055] The naming and numbering of the compounds of this invention
is illustrated below. 3
[0056] In general, the nomenclature used in this Application is
based on AUTONOM.TM. v.4.0, a Beilstein Institute computerized
system for the generation of IUPAC systematic nomenclature.
[0057] Representative Compounds of this Invention are as
Follows:
[0058] Compounds of Formula I wherein R.sup.1, R.sup.2, R.sup.3, Y,
A, and Ar are as defined below:
2 Formula I 4 Cpd MS. # R.sup.1 R.sup.2 R.sup.3 A Y Ar [m +
H].sup.+ 15 CN H methylsulfonyl --O-- --S-- 4-methoxyphenyl 360 16
CN H methylsulfonyl --S-- --S-- 4-methoxyphenyl 376 17 CN H
methylsulfonyl --S-- --S-- 2-chlorophenyl 381 18 CN H
methylsulfonyl --S-- --S-- 4-methylphenyl 360 19 CN H
methylsulfonyl --S-- --S-- 2,4- 415 dichlorophenyl 20 CN H
methylsulfonyl --O-- --S-- 4-fluorophenyl 348 21 CN H
methylsulfonyl --S-- --S-- phenyl 346 22 CN H methylsulfonyl --S--
--S-- 4-methylphenyl 344 23 CN H methylsulfonyl --S-- --S--
4-chlorophenyl 381 24 CN H methylsulfonyl --O-- --S-- phenyl 330 25
CN H methylsulfonyl --O-- --S-- 2-chloro-4- 394 methoxyphenyl 26 CN
H methylsulfonyl --S-- --S-- 4-fluorophenyl 364 27 CN H
methylsulfonyl --S-- --S-- 2-fluorophenyl 348 28 CN H
methylsulfonyl --S-- --S-- 2,6- 415 dichlorophenyl 29 CN H
methylsulfonyl --O-- --S-- 2-methoxyphenyl 360 30 CN H
methylsulfonyl --S-- --S-- 2-fluorophenyl 364 31 CN H
methylsulfonyl --O-- --S-- 4-ethoxyphenyl 374 32 CN H
methylsulfonyl --S-- --S-- 2,4-difluorophenyl 382 33 CN H
methylsulfonyl --O-- --S-- 4-chloro-2- 383 fluorophenyl 34 CN H
methylsulfonyl --O-- --S-- 2,4-difluorophenyl 366 35 CN H
methylsulfonyl --S-- --O-- 4-methoxyphenyl 360 36 CN H
methylsulfonyl --S-- --O-- 2,4-difluorophenyl M+ = 366
[0059] Preferred Embodiments
[0060] While the broadest definition of this invention is set forth
in the Summary of the Invention, certain compounds of Formula I are
preferred.
[0061] In certain preferred embodiments Ar is a phenyl optionally
substituted at one or more positions, preferably with one to two
substitutents independently selected from the group consisting of
halo and alkoxy, and R.sup.3 is --SO.sub.2R.sup.6, wherein R.sup.6
is alkyl.
[0062] In another embodiment, another preferred group of compounds
is that wherein Ar is phenyl optionally substituted at one or more
positions, preferably with one to two substituents independently
selected from the group consisting of halo and alkoxy; R.sup.3 is
--SO.sub.2R.sup.6, wherein R.sup.6 is alkyl; Y is --O--; and A is
--S--; and yet a more preferred group of compounds is that wherein
Ar is phenyl optionally substituted at one or more positions,
preferably with one to two substitutents independently selected
from the group consisting of halo and alkoxy; R.sup.3 is
--SO.sub.2R.sup.6, wherein R.sup.6 is alkyl; Y is O; A is S; and
R.sup.1 is alkyl or cyano.
[0063] In another embodiment another preferred group of compounds
is that wherein Ar is phenyl optionally substituted at one or more
positions, preferably with one to two substituents independently
selected from the group consisting of halo and alkoxy; R.sup.3 is
--SO.sub.2R.sup.6; wherein R.sup.6 is alkyl; Y is --S--; and A is
--S--; and yet a more preferred group of compounds is that wherein
Ar is phenyl optionally substituted at one or more positions,
preferably with one to two substitutents independently selected
from the group consisting of halo and alkoxy; R.sup.3 is
--SO.sub.2R.sup.6, wherein R.sup.6 is alkyl; Y is S; A is S; and
R.sup.1 is alkyl or cyano.
[0064] Within the foregoing preferred embodiment another preferred
group of compounds is that wherein Ar is phenyl optionally
substituted at one or more positions, preferably with one to two
substitutents independently selected from the group consisting of
halo and alkoxy; R.sup.3 is --SO.sub.2R.sup.6.sub.5 wherein R.sup.6
is alkyl; Y is --S--; and A is --O--; and yet a more preferred
group of compounds is that wherein Ar is phenyl optionally
substituted at one or more positions, preferably with one to two
substitutents independently selected from the group consisting of
halo and alkoxy; R.sup.3 is --SO.sub.2R.sup.6, wherein R.sup.6 is
alkyl; Y is S; A is O; and R.sup.1 is alkyl or cyano.
[0065] While the broadest definition of the invention is set forth
in the Summary of the Invention, certain compounds of Formula I are
preferred. For example, preferred compounds of Formula I are those
in which R.sup.1 is cyano or alkyl, R.sup.2 is hydrogen or alkyl,
R.sup.3 is alkylsulfonyl, A is --S-- or --O--, Y is --S-- or --O--,
and Ar is unsubstituted, monosubstituted, or disubstituted phenyl.
Even more preferred compounds of Formula I are those in which A is
--S-- or --O--, Y is --S--, R.sup.1 is cyano, R.sup.2 is hydrogen,
R.sup.3 is alkylsulfonyl, and Ar is a phenyl mono or disubstituted
with halo or alkoxy.
[0066] General Synthetic Scheme
[0067] Compounds of this invention can be made by the methods
depicted in the reaction schemes shown below.
[0068] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.),
or Sigma (St. Louis, Mo.) or are prepared by methods known to those
skilled in the art following procedures set forth in references
such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes
1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon
Compounds, Volumes 1-5 and Supplementals (Elsevier Science
Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and
Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and
Sons, 4.sup.th Edition) and Larock's Comprehensive Organic
Transformations (VCH Publishers Inc., 1989). These schemes are
merely illustrative of some methods by which the compounds of this
invention can be synthesized, and various modifications to these
schemes can be made and will be suggested to one skilled in the art
having referred to this disclosure.
[0069] The starting materials and the intermediates of the reaction
may be isolated and purified if desired using conventional
techniques, including but not limited to filtration, distillation,
crystallization, chromatography, and the like. Such materials may
be characterized using conventional means, including physical
constants and spectral data.
[0070] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure over a temperature range
from about -78.degree. C. to about 150.degree. C., more preferably
from about 0.degree. C. to about 125.degree. C. and most preferably
at about room (or ambient) temperature, e.g., about 20.degree.
C.
[0071] A person of ordinary skill in the art will have no
difficulty, having regard to that skill and this disclosure, in
determining how to synthesize compounds of this invention.
Preparation of Compounds of Formula I
[0072] Schemes A, and B, describe methods to prepare the compounds
of Formula I. 5
[0073] Scheme A describes the synthesis of a compound of Formula I
wherein A is --S-- or --O--; Y is --S--; R and R.sup.1 are alkyl;
R.sup.1 is cyano; n is one or two, R.sup.29, R.sup.3 and Ar are as
defined in the Summary of the Invention.
[0074] In Step 1, a certain aldehyde of Formula 1, wherein R is
alkyl, preferably wherein R is methyl, can be protected by
treatment with an alcohol such as methyl alcohol, in the presence
of an acid catalyst such as p-TsOH, to give an acetal of Formula 2,
preferably-1-(1,1-dimethoxy-me- thyl)-4-methylsulfanyl-benzene. In
general, the compounds of Formula 1 are commercially available or
can be readily synthesized by those of ordinary skill in the art,
see e.g., Watabe, et al, J.Chem.Soc.Chem.Commun.; 10; 1983;
585-586.
[0075] In Step 2, the --SR group of a certain compound of Formula 2
wherein R and R' are alkyl, preferably wherein R and R' are methyl,
can be oxidized with MCPBA, OXONE.TM., and the like to provide a
sulfoxide or sulfone of Formula 3, wherein R and R' are alkyl,
preferably R and R' are methyl. Suitable solvents for the reaction
are alcohols (such as methanol and ethanol) or halogenated solvents
(such as dichloromethane, chloroform and the like). Sulfoxides of
Formula 3 may be similarly converted to the corresponding sulfones.
It is appreciated that this second oxidation may be performed at
various points in Scheme A as may be required by the skilled
artisan.
[0076] In Step 3, a certain acetal of Formula 3, wherein R and R'
are alkyl, preferably wherein R and R' are methyl, can be
hydrolyzed with a suitable amount of acid, such as diluted
hydrochloric acid or sulfuric acid in a suitable inert solvent such
as THF, to give an aldehyde of Formula 4, wherein R is alkyl,
preferably wherein R is methyl.
[0077] In Step 4, a certain aldehyde of Formula 4, wherein R is
alkyl, preferably wherein R is methyl, can be condensed with
malonic acid in the presence of pyridine or an alkoxide as a
catalyst, preferably pyridine to give a
3-(4-alkylsulfonyl-phenyl)-acrylic acid of Formula 5, wherein R is
alkyl, preferably wherein R is methyl, according to the method of
Wiley, R. H.; Smith, N. R. Org. Synth. Coll. Vol IV, 731-734.
Suitable solvents are inert solvents such as THF and the like.
[0078] In Step 5, a certain intermediate acid chloride of Formula
6, wherein R is alkyl, preferably wherein R is methyl, can be
prepared according to the method of Connor, D. T., et al. J. Med.
Chem. 1992, 35, 958-65; wherein the acrylic acid of Formula 5,
wherein R is alkyl, preferably wherein R is methyl, can then be
converted to the benzothiophene of Formula 6, wherein R is alkyl,
preferably wherein R is methyl, by treatment with SOCl.sub.2 in the
presence of pyridine in suitable solvents such as polar aprotic
solvents, e.g. DMF, DMSO, chlorobenzene and the like.
[0079] In Step 6, a certain acid chloride of Formula 6, wherein R
is alkyl, preferably wherein R is methyl, can be
amino-de-halogenated with ammonia in THF or an halogenated solvent
such as dichloromethane, chloroform, and the like, to give a
certain amide of Formula 7, wherein R is alkyl, preferably wherein
R is methyl.
[0080] In Step 7, a certain amide of Formula 7, wherein R is alkyl,
preferably wherein R is methyl, can be dehydrated preferably in the
presence of an anhydride such as trifluoroacetic anhydride,
trifluoromethanesulfonic anhydride, and the like in an halogenated
solvent, such as dichloromethane, chloroform, and the like to give
the nitrile of Formula 8, wherein R is alkyl, preferably wherein R
is methyl.
[0081] In Step 8, a nucleophilic displacement of the chlorine atom
of a certain compound of Formula 8, wherein R is alkyl, preferably
wherein R is methyl, by a certain phenol or thiophenol of Formula
Ar--AH wherein A is --O-- or --S--, in the presence of a base such
as potassium hydroxide, potassium hexamethyldisilazide and the
like, in an inert solvent such as DMF can give the
3-substituted-2-cyano-6-alkylsulfoxy-benzothiophene of Formula I,
wherein R is alkyl, preferably wherein R is methyl. 6
[0082] In Step 1, a certain acid of Formula 9 can be esterified by
conditions well known in the art, i.e. with an alcohol under acidic
conditions. Subsequently the --SR group can be oxidized with MCPBA,
OXONE.TM., and the like to provide a sulfoxide or sulfone of
Formula 10. Sulfoxides of Formula 10 may be similarly converted to
the corresponding sulfones. It is appreciated that this second
oxidation may be performed at various points in Scheme B as may be
required by the skilled artisan.
[0083] Suitable solvents are alcohols such as methanol or ethanol
or halogenated solvents such as dichloromethane, chloroform, and
the like.
[0084] In Step 2, the ether and ester groups of a certain compound
of Formula 10 can be hydrolyzed with acid reagents such as
pyridinium hydrochoride, boron trichloride, hydrobromic acid, and
the like, preferably pyridinium hydrochloride, and the acid group
can be further esterified by conditions well known in the art to
give a compound of Formula 11.
[0085] In Step 3, the phenol group of a certain compound of Formula
11 can be alkylated with chloroacetonitrile under basic conditions,
in a suitable inert solvent such as DMF, DMSO, benzene, toluene,
and the like. A suitable base can be sodium carbonate, potassium
carbonate, triethylamine, and the like.
[0086] In Step 4, a certain compound of Formula 13 can be obtained
by internal cyclization to form a benzofuran ring. Such cyclization
can be effected with potassium tert-butoxide in an inert solvent
such as toluene.
[0087] In Step 5, the hydroxyl group of a certain compound of
Formula 13 can be protected by mesylation with methane sulfonyl
chloride under basic conditions to provide a certain compound of
Formula 14.
[0088] In Step 6, a nucleophilic displacement of the mesylate group
of a certain compound of Formula 14 by a certain optionally
substituted benzenethiol of Formula Ar-AH in the presence of sodium
hydride in an inert solvent or a mixture of solvents such as THF or
DMF, can give a compound of Formula I, wherein A is S or O, and Y
is O.
[0089] General Utility
[0090] The compounds of the invention are inhibitors of
prostaglandin G/H Synthase I and II (COX I and COX II), especially
COX II, in vitro, and as such are expected to possess both
anti-inflammatory and analgesic properties in vivo. See, for
example, Goodman and Gilmans's "The Pharmacological Basis of
Therapeutics", Ninth Edition, McGraw Hill, New York, 1996, Chapter
27. The compounds and compositions containing them are therefore
useful as anti-inflammatory and analgesic agents in mammals,
especially humans. They find utility in the treatment of fever,
inflammation, and pain caused by conditions such as rheumatic
fever, symptoms associated with influenza or other viral
infections, low back and neck pain, dysmenorrhoea, headache, dental
pain, sprains, strains, sports injuries, bursitis, tendonitis,
myositis, synovitis, arthritis (rheumatoid arthritis and
osteoarthritis), gout, ankylosing spondylitis, burns, or injuries.
They may be used to inhibit prostanoid-induced smooth muscle
contractions (e.g., in the treatment of dysmenorrhoea, premature
labor, and asthma) and to treat autoimmune disorders (such as
systemic lupus erythematosus and type I diabetes).
[0091] As inhibitors of prostaglandin G/H Synthase, the compounds
of this invention are also expected to be useful in the prevention
and treatment of cancer, in particular colon cancer. It has been
shown that COX-2 gene expression is upregulated in human colorectal
cancers and that drugs that inhibit prostaglandin G/H Synthase are
effective in animal models of cancer (Eberhart, C. E., et. al.,
Gastroenterology, 107, 1183-1188, (1994), and Ara, G. and Teicher,
B. A., Prostaglandins, Leukotrienes and Essential Fatty Acids,
54,3-16, (1996)). In addition, there is epidemiological evidence
that shows a correlation between use of drugs that inhibit
prostaglandin G/H synthase and a reduced risk of developing
colorectal cancer (Heath, C. W. Jr., et. al., Cancer, 74, No.10,
2885-8, (1994)).
[0092] The compounds of this invention are also expected to be
useful in the prevention and treatment of Alzheimer's disease.
Indomethacin, an inhibitor of prostaglandin G/H synthase, has been
shown to inhibit the cognitive decline of Alzheimer's patients
(Rogers, J., et. al., Neurology, 43, 1609, (1993)). Also, the use
of drugs which inhibit prostaglandin G/H synthase has been linked
epidemiologically with a delayed onset of Alzheimer's disease
(Breitner, J. C. S., et. al., Neurobiology of Aging, 16, No. 4,
523, (1995) and Neurology, 44, 2073, (1994)).
[0093] Testing
[0094] The anti-inflammatory activity of the compounds of this
invention may be assayed by measuring the ability of the compound
to inhibit COX I and COX II, especially COX II, in vitro, using a
radiometric assay, as described in more detail in Example 4. It may
also be assayed by in vivo assays such as the Rat Carrageenan Paw
and Rat Air-Pouch assays, as described in more detail in Examples 5
and 6. The analgesic activity of the compounds of this invention
may be assayed by in vivo assays such as the Randall-Selitto assay
and the rat arthritis pain model, as described in Example 7.
[0095] Administration and Pharmaceutical Composition
[0096] In general, the compounds of this invention will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. The actual amount of the compound of this invention,
i.e., the active ingredient, will depend upon numerous factors such
as the severity of the disease to be treated, the age and relative
health of the subject, the potency of the compound used, the route
and form of administration, and other factors.
[0097] Therapeutically effective amounts of compounds of Formula I
may range from approximately 0.005-10 mg per kilogram body weight
of the recipient per day, preferably about 0.05-1 mg/kg/day. Thus,
for administration to a 70 kg person, the dosage range would
preferably be about 3.5 mg to 400 mg per day.
[0098] In general, compounds of this invention will be administered
as pharmaceutical compositions by any one of the following routes:
oral, systemic (e.g., transdermal, intranasal or by suppository),
or parenteral (e.g., intramuscular, intravenous or subcutaneous)
administration. The preferred manner of administration is oral
using a convenient daily dosage regimen, which can be adjusted
according to the degree of affliction. Compositions can take the
form of tablets, pills, capsules, semisolids, powders, sustained
release formulations, solutions, suspensions, elixirs, aerosols, or
any other appropriate compositions.
[0099] The choice of formulation depends on various factors such as
the mode of drug administration (e.g., for oral administration,
formulations in the form of tablets, pills or capsules are
preferred) and the bioavailability of the drug substance. Recently,
pharmaceutical formulations have been developed especially for
drugs that show poor bioavailability based upon the principle that
bioavailability can be increased by increasing the surface area
i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes a pharmaceutical formulation having particles
in the size range from 10 to 1,000 nm in which the active material
is supported on a crosslinked matrix of macromolecules. U.S. Pat.
No. 5,145,684 describes the production of a pharmaceutical
formulation in which the drug substance is pulverized to
nanoparticles (average particle size of 400 nm) in the presence of
a surface modifier and then dispersed in a liquid medium to give a
pharmaceutical formulation that exhibits remarkably high
bioavailability.
[0100] The compositions are comprised of, in general, a compound of
Formula I in combination with at least one pharmaceutically
acceptable excipient. Acceptable excipients are non-toxic, aid
administration, and do not adversely affect the therapeutic benefit
of the compound of Formula I. Such excipient may be any solid,
liquid, semi-solid or, in the case of an aerosol composition,
gaseous excipient that is generally available to one of skill in
the art.
[0101] Solid pharmaceutical excipients include starch, cellulose,
talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk, and the like.
Liquid and semisolid excipients may be selected from glycerol,
propylene glycol, water, ethanol, and various oils, including those
of petroleum, animal, vegetable or synthetic origin, e.g., peanut
oil, soybean oil, mineral oil, sesame oil. Preferred liquid
carriers, particularly for injectable solutions, include water,
saline, aqueous dextrose, and glycols.
[0102] Compressed gases may be used to disperse a compound of this
invention in aerosol form. Inert gases suitable for this purpose
are nitrogen, carbon dioxide, etc.
[0103] Other suitable pharmaceutical excipients and their
formulations are described in Remington's Pharmaceutical Sciences,
edited by E. W. Martin (Mack Publishing Company, 18th ed.,
1990).
[0104] The level of the compound in a formulation can vary within
the full range employed by those skilled in the art. Typically, the
formulation will contain, on a weight percent (wt %) basis, from
about 0.01-99.99 wt % of a compound of Formula I based on the total
formulation, with the balance being one or more suitable
pharmaceutical excipients. Preferably, the compound is present at a
level of about 1-80 wt %. Representative pharmaceutical
formulations containing a compound of Formula I are described in
Example 3.
EXAMPLES
[0105] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and to practice
the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and
representative thereof.
Example 1
[0106]
6-Methanesulfonyl-3-(4-methoxy-phenoxy)-benzo[b]thiophene-2-carboni-
trile 7
[0107] Steps 1-3
[0108] A solution of 4-methylsulfanylbenzaldehyde 1 (10 g, 66
mmol), (MeO).sub.3CH (8.6 mL, 79 mmol) and pTsOH (0.25 g, 1.3 mmol)
in MeOH (130 mL) was stirred for 18 h. The remaining pTsOH was
decomposed by addition of NaOMe. After 5 min, the mixture was
evaporated in vacuo, and passed through a pad of SiO.sub.2 (95:5
hexane/Et.sub.2O) to afford
1-(1,1-dimethoxy-methyl)-4-methylsulfanyl-benzene 2. The residue
after evaporation was dissolved into CH.sub.2Cl.sub.2 (360 mL) and
treated with MCPBA (41 g, 240 mmol). After 18 h, the mixture was
filtered and the filtrate evaporated. The residue was partitioned
between EtOAc and 1 M NaOH. The organic layer was washed with 1 M
NaOH (2.times.), washed with brine, dried (MgSO.sub.4), filtered
and evaporated to afford
1-(1,1-dimethoxy-methyl)-4-methanesulfonyl-benzene 3. The residue
was dissolved into THF (130 mL) and treated with 2% H.sub.2SO.sub.4
(3.4 mL). After 2 h, the solvent was evaporated, and the residue
was partitioned between EtOAc and NaHCO.sub.3. The organic layer
was dried (MgSO.sub.4), filtered and evaporated to afford 12 g (98%
for three steps) of 4-methylsulfonylbenzaldehyde 4 as a white
solid; .sup.1H NMR .delta. 3.11 (s, 3H), 8.09 (d, 2H,
J=8.6),8.14(d,2H,J=8.6), 10.15 (s, 1H).
[0109] Step 4
[0110] A solution of aldehyde 4-methylsulfonylbenzaldehyde 4 (1.0
g, 5.9 mmol) and malonic acid (0.63 g, 6.0 mmol) in 10:1
EtOH/pyridine (12.1 mL) was heated at a gentle reflux for 24 h.
After cooling to 0.degree. C., the resulting precipitate was
collected and rinsed with cold Et.sub.2O. The solid was resuspended
in EtOH (13 mL) and heated at reflux for an additional 2 h. After
cooling to 0.degree. C., the resulting precipitate was collected
and dried in vacuo to afford 0.63 g (51%) of
3-(4-methanesulfonyl-phenyl)-acrylic acid 5 as a white solid;
.sup.1H NMR (DMSO) .delta. 3.18 (s, 3H), 6.65 (d, 1H, J=16.1), 7.60
(d, 1H, J=16.1), 7.89 (m, 4H).
[0111] Steps 5-6
[0112] A stirring slurry of 3-(4-methanesulfonyl-phenyl)-acrylic
acid 5 (3.7 g, 16 mmol), pyridine (0.13 mL, 0.13 g, 1.6 mmol), and
DMF (1.2 mL, 1.1 g, 15 mmol) in phenylchloride (23 mL) was treated
with SOCl.sub.2 (6.1 mL, 9.9 g, 84 mmol). The resulting mixture was
heated at reflux for 24 h. All volatile material was removed in
vacuoto afford the intermediate acid chloride 6 as an orange solid;
.sup.1H NMR .delta. 3.15 (s, 3H), 8.06 (dd,1H, J=1.5, 8.6), 8.23
(dd,1H, J=0.6, 8.7), 8.53 (m,1H). The solid was dissolved into
CH.sub.2Cl.sub.2 (50 mL), cooled to 0.degree. C., and treated with
0.5 m solution of NH.sub.3 in 1,4 dioxane(12 mL). After 30 min, the
resulting solid was collected to afford 3.5 g (74%) of
3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carboxylic acid
amide 7; .sup.1H NMR (DMSO) .delta. 3.31 (s, 3H), 8.00 (brs, 1H),
8.06 (dd, 1H, J=1.6, 8.6), 8.13 (dd, 1H, J=0.7, 8.6), 8.24 (br s,
1H), 8.80 (dd, 1H, J=0.7,1.6).
[0113] Step 7
[0114] A stirring 0.degree. C. slurry of
3-chloro-6-methanesulfonyl-benzo[- b]thiophene-2-carboxylic acid
amide 7 (2.8 g, 9.7 mmol) in CH.sub.2Cl.sub.2 (50 mL) was treated
by sequential addition of TFAA (4.0 mL, 5.9 g, 28 mmol) then
pyridine (4.0 mL, 3.9 g, 49 mmol). After 2 h, the resulting
solution was washed with 0.1 M HCl, dried (Na.sub.2SO.sub.4),
filtered, and evaporated. Chromatography gave 2.1 g (81%) of
3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile 8;
.sup.1H NMR .delta. 3.15 (s, 3H), 8.09 (dd, 1H, J=1.5, 8.6), 8.15
(dd, 1H, J=0.7, 8.6), 8.52 (dd, 1H, J=0.7,1.5).
[0115] Step 8
[0116] A solution of KHMDS (0.18 g, 0.90 mmol) in DMF (7 mL) was
treated by sequential addition of 4-methoxyphenol (0.12 g, 0.99
mmol) then
3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile 8 (0.20
g, 0.75 mmol). After 2 h, the mixture was partitioned between EtOAc
and brine. The organic layer was washed with brine (2.times.),
dried (Na.sub.2SO.sub.4), filtered, and evaporated. Chromatography,
followed by recrystallization (EtOAc/hexane) gave 0.20 g (74%) of
6-methanesulfonyl-3-(4-methoxy-phenoxy)-benzo[b]thiophene-2-carbonitrile
15 as white needles; (m+H).sup.+ 360.
[0117] Similarly, following the procedure described above, but
replacing, in Step 8, 4-methoxyphenol with the appropriate
substituted phenols or thiophenols the additional compounds of
Formula I wherein Y is --S-- and A is --O-- or --S--, were
prepared:
[0118] 4-Methoxythiophenol gave
6-methanesulfonyl-3-(4-methoxy-phenylsulfa-
nyl)-benzo[b]thiophene-2-carbonitrile 16; (m+H).sup.+ 376;
[0119] 2-Chlorothiophenol gave
3-(2-chloro-phenylsulfanyl)-6-methanesulfon-
yl-benzo[b]thiophene-2-carbonitrile 17; (m+H).sup.+ 380;
[0120] 4-Methylthiophenol gave
6-Methanesulfonyl-3-p-tolyIsulfanyl-benzo[b-
]thiophene-2-carbonitrile 18; (m+H).sup.+ 360;
[0121] 2,4-Dichlorothiophenol gave
3-(2,4-dichloro-phenylsulfanyl)-6-metha-
nesulfonyl-benzo[b]thiophene-2-carbonitrile 19; (m+H).sup.+
415;
[0122] 4-Fluorophenol gave
3-(4-fluoro-phenoxy)-6-methanesulfonyl-benzo[b]-
thiophene-2-carbonitrile 20; (m+H).sup.+ 348;
[0123] Thiophenol gave
6-methanesulfonyl-3-phenylsulfanyl-benzo[b]thiophen-
e-2-carbonitrile 21; (m+H).sup.+ 345;
[0124] 4-Methylphenol gave
6-methanesulfonyl-3-p-tolyloxy-benzo[b]thiophen- e-2-carbonitrile
22; (m+H).sup.+ 344;
[0125] 4-Chlorothiophenol gave
3-(4-chloro-phenylsulfanyl)-6-methanesulfon-
yl-benzo[b]thiophene-2-carbonitrile 23; (m+H).sup.+ 380;
[0126] Phenol gave
6-methanesulfonyl-3-phenoxy-benzo[b]thiophene-2-carboni- trile 24;
(m+H).sup.+ 330;
[0127] 2-Chloro-4-methoxyphenol
gave3-(2-chloro-4-methoxy-phenoxy)-6-metha-
nesulfonyl-benzo[b]thiophene-2-carbonitrile 25; (m+H).sup.+
394;
[0128] 4-Fluorothiophenol gave
3-(4-fluoro-phenylsulfanyl)-6-methanesulfon-
yl-benzo[b]thiophene-2-carbonitrile 26; (m+H).sup.+ 364;
[0129] 2-Fluorophenol gave
3-(2-fluoro-phenoxy)-6-methanesulfonyl-benzo[b]-
thiophene-2-carbonitrile 27; (m+H).sup.+ 348;
[0130] 2,6-Dichlorothiophenol gave
3-(2,6-dichloro-phenylsulfanyl)-6-metha-
nesulfonyl-benzo[b]thiophene-2-carbonitrile 28; (m+H).sup.+
415;
[0131] 2-Methoxyphenol gave
6-methanesulfonyl-3-(2-methoxy-phenoxy)-benzo[-
b]thiophene-2-carbonitrile 29; (m+H).sup.+ 360;
[0132] 2-Fluorothiophenol gave
3-(2-fluoro-phenylsulfanyl)-6-methanesulfon-
yl-benzo[b]thiophene-2-carbonitrile 30; (m+H).sup.+ 364;
[0133] 4-Ethoxyphenol gave
3-(4-ethoxy-phenoxy)-6-methanesulfonyl-benzo[b]-
thiophene-2-carbonitrile 31; (m+H).sup.+ 374;
[0134] 2,4-Difluorothiophenol gave
3-(2,4-difluoro-phenylsulfanyl)-6-metha-
nesulfonyl-benzo[b]thiophene-2-carbonitrile 32; (m+H).sup.+
382;
[0135] 4-Chloro-2-fluorophenol gave
3-(4-chloro-2-fluoro-phenoxy)-6-methan-
esulfonyl-benzo[b]thiophene-2-carbonitrile 33; (m+H).sup.+ 382;
[0136] 2,4-Difluorophenol gave
3-(2,4-difluoro-phenoxy)-6-methanesulfonyl--
benzo[b]thiophene-2-carbonitrile 34; (m+H).sup.+ 366.
Example 2
6-Methanesulfonyl-3-(4-methoxy-phenylsulfanyl)-benzofuran-2-carbonitrile
[0137] 8
[0138] Step 1
[0139] A stirring solution of 2-methoxy-4-methylthiobenzoic acid 9
(50.0 g) in methanol (400 mL) was treated with concentrated
H.sub.2SO.sub.4 (5 mL) under an inert atmosphere. After 1 day at
50.degree. C., the mixture was cooled and the solvent was
evaporated. The resulting oil was passed through a pad of silica
gel (EtOAc) to afford, after concentration, 60 g of an oil. A
portion of the oil (20 g) was dissolved into 10:1 MeOH/H.sub.2O
(385 mL) and treated at 0.degree. C. with Oxone.TM. (110 g, added
in three portions) with vigorous stirring. After 2 h, the mixture
was partitioned between EtOAc and H.sub.2O . The organic layer was
dried (MgSO.sub.4) and passed through a pad of silica gel. The
solvent was evaporated giving 21 g of
4-methanesulfonyl-2-methoxybenzoic acid methyl ester 10.
[0140] Step 2
[0141] A mixture of 10 (15 g) and pyridinium hydrochloride (45 g)
was heated under an inert atmosphere at 180.degree. C. for 1.5 h
and cooled. The mixture was partitioned between EtOAc and aqueous
HCl (5%). The organic layer was washed with aqueous HCl (5%),
dried, filtered, and concentrated. A solution of the resulting
residue in EtOH (400 mL) was treated with concentrated
H.sub.2SO.sub.4 (10 mL) and heated overnight at 75.degree. C. After
cooling, the mixture was concentrated and partitioned between EtOAc
and saturated aqueous NaHCO.sub.3. The organic layer was extracted
with 1 M NaOH (4 times). This combined aqueous layer was brought to
acidic pH by addition of aqueous HCl (5%) and was extracted with
EtOAc. This organic layer was dried (MgSO.sub.4), filtered, and
evaporated giving 8.5 g of 2-hydroxy-4-methanesulfonyl-benzoic acid
ethyl ester 11 as a solid.
[0142] Step 3
[0143] A stirring solution of 11 (6.0 g) in DMF (200 mL) was
treated with K.sub.2CO.sub.3 (6 g) and chloroacetonitrile (6 mL)
and heated at 75.degree. C. overnight. The mixture was cooled and
partitioned between 1:1 EtOAc/hexanes and H.sub.2O . The organic
layer was washed with 1 M NaOH, washed with brine, dried
(MgSO.sub.4), filtered, and evaporated. The residue was triturated
with Et.sub.2O/hexanes. The resulting solid was collected by
filtration giving 6.6 g of 2-cyanomethoxy-4-methanesulfo-
nyl-benzoic acid ethyl ester 12.
[0144] Step 4
[0145] A suspension of 12 (4.0 g) in toluene was treated with
potassium tert-butoxide (30 mL, 1 M in tert-butanol) under an inert
atmosphere. After heating at 110.degree. C. for 1 h, the mixture
was cooled and the resulting precipitate was collected by
filtration. The precipitate was washed with Et.sub.2O (3 times)
giving 5 g of 3-hydroxy-6-methanesulfonyl-
-benzofuran-2-carbonitrile 13 as a yellow solid.
[0146] Step 5
[0147] A suspension of 13 (3.9 g) in CH.sub.2Cl.sub.2 (200 mL) was
treated with pyridine (10 mL), methanesulfonyl chloride (4 mL), and
a catalytic amount of dimethylaminopyridine at 0.degree. C., under
an N.sub.2 atmosphere, for 2 h. The reaction was allowed to warm to
ambient temperature overnight. The reaction was partitioned between
1:1 Et.sub.2O/hexanes and brine. The organic layer was dried
(MgSO.sub.4), filtered, and evaporated. The residue was purified by
chromatography (silica gel, 1:1 EtOAc/hexanes) giving 1.05 g of
methanesulfonic acid 2-cyano-6-methanesulfonyl-benzofuran-3-yl
ester 14.
[0148] Step 6
[0149] A stirring solution of 14 (0.25 g) and 4-methoxybenzenethiol
(0.4 g) in THF (20 mL) and DMF (5 mL) was treated with NaH (0.080
g). After 3 h, the reaction was quenched by careful addition of
H.sub.2O , then diluted with 1:1 EtOAc/hexanes. The organic layer
was washed with saturated aqueous NaHCO.sub.3, washed with water,
washed with brine, dried (MgSO.sub.4), filtered, and evaporated.
Chromatography (silica gel, 20:80 to 33:67 EtOAc/hexanes) gave 0.11
g of 6-methanesulfonyl-3-(4-metho-
xy-phenylsulfanyl)-benzofuran-2-carbonitrile 35 as a solid;
(m+H).sup.+ 360.
[0150] Similarly, following the procedure described above, but
replacing, in Step 6, 4-methoxybenzenethiol with
2,4-difluorobenzenethiol, the additional compound of Formula I
wherein Y is --O-- and A is --S-- was prepared:
[0151]
3-(2,4-Difluoro-phenylsulfanyl)-6-methanesulfonyl-benzofuran-2-carb-
onitrile 36; (M).sup.+=366.
Example 3
[0152] The following are representative pharmaceutical formulations
containing a compound of Formula I.
Tablet Formulation
[0153] The following ingredients are mixed intimately and pressed
into single scored tablets.
3 Quantity per Ingredient tablet, mg compound of this invention 400
cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium
stearate 5
Capsule Formulation
[0154] The following ingredients are mixed intimately and loaded
into a hard-shell gelatin capsule.
4 Quantity per Ingredient capsule, mg compound of this invention
200 lactose, spray-dried 148 magnesium stearate 2
Suspension Formulation
[0155] The following ingredients are mixed to form a suspension for
oral administration.
5 Ingredient Amount compound of this invention 1.0 g fumaric acid
0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben
0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg
distilled water q.s. to 100 mL
Injectable Formulation
[0156] The following ingredients are mixed to form an injectable
formulation.
6 Ingredient Amount compound of this invention 0.4 mg sodium
acetate buffer solution, 0.4 M 2.0 mL HCl (1N) or NaOH (1N) q.s. to
suitable pH water (distilled, sterile) q.s. to 20 mL
Example 4
Inhibition of COX I and COX II in Vitro
[0157] The COX I and COX II inhibitory activity of compounds of
this invention in vitro was determined using partially purified COX
I and COX II enzymes, prepared as described in J. Barnett et al.,
Biochim. Biophys. Acta, 1209,130-139 (1994).
[0158] COX I and COX II samples were diluted with Tris-HCl buffer
(5OmM Tris-HCl, pH 7.9) containing 2 mM EDTA and 10% glycerol and
reconstituted by incubating first with 2 mM phenol for 5 minutes
and then with 1 micromolar hematin for an additional 5 minutes. 125
.mu.L of the reconstituted COX I or COX II enzyme were preincubated
for 10 minutes at room temperature in a shaking water bath with the
compounds of the invention dissolved in 2-15 .mu.L of DMSO or the
carrier vehicles (control samples). The enzyme reaction was
initiated by adding 25 .mu.L of 1-[14 C] arachidonic acid
(80,000-100,000 cpm/tube; 20 micromolar final concentration) and
the reaction was allowed to continue for an additional 45 seconds.
The reaction was terminated by adding 100 .mu.L of 2N HCl and 750
.mu.L water. An aliquot (950 .mu.L) of the reaction mixture was
loaded onto a 1 mL C.sub.18 Sep-Pak column (J. T. Baker,
Phillipsburg, N.J.) which had been previously washed with 2-3 mL
methanol and equilibrated with 5-6 mL distilled water. Oxygenated
products were quantitatively eluted with 3 mL of
acetonitrile/water/acetic acid (50:50:0.1, v/v) and the
radioactivity in the eluate determined in a scintillation
counter.
[0159] Compounds of this invention were active in this assay for
COX II.
[0160] The COX inhibitory activities (expressed as IC.sub.50, the
concentration causing 50% inhibition of the COX enzyme being
assayed) of some exemplary compounds of the invention were:
7 CPD COX I COX II # IC.sub.50, .mu.M IC.sub.50, .mu.M 17 >120
<1.0 19 >120 <1.5 26 >120 <1.5 30 >120 <1.2 31
>120 <1.5
Example 5
Anti-Inflammatory Activity
[0161] The anti-inflammatory activity of compounds of this
invention was determined by measuring the inhibition of
carrageenan-induced paw edema in the rat, using a modification of
the method described in Winter C. A. et al., "Carrageenan-Induced
Edema in Hind Paw of the Rat as an Assay for Anti-inflammatory
Drugs" Proc. Soc. Exp. Biol. Med. 111, 544-547, (1962). This assay
has been used as a primary in vivo screen for anti-inflammatory
activity of most NSAIDs, and is considered predictive of human
efficacy. Briefly, test materials were administered orally to
female rats in a volume of 1 mL prepared as solutions or
suspensions in an aqueous vehicle containing 0.9% sodium chloride,
0.5% sodium carboxymethyl-cellulose, 0.4% polysorbate 80, 0.9%
benzyl alcohol and 97.3% distilled water. Control rats received
vehicle alone. After 1 h 0.05 mL of a 0.5% solution of Carrageenan
(Type IV Lambda, Sigma Chemical Co.) in 0.9% saline was injected
into the subplantar region of the right hind paw. Three hours later
the rats were euthanized in a carbon dioxide atmosphere; hind paws
were removed by severing at the tatso-crural joint; and the left
and right paws were weighed. The increase in weight of the right
paw over the left paw was obtained for each animal and the mean
increases were calculated for each group. The anti-inflammatory
activity of the test materials is expressed as the percent
inhibition of the increase in hind paw weight of the test group
relative to the vehicle dosed control group. Compounds of this
invention were active in this assay.
Example 6
Inhibition of Eicosanoid Synthesis in Vivo
[0162] The activity of compounds of this invention in inhibiting in
vivo eicosanoid (prostaglandin E.sub.2) synthesis in inflamed
tissues was determined by the carrageenan-induced inflammation
(air-pouch model) in rats, using a modification of the method
described in Futaki, M., et al., "Selective Inhibition of NS-398 on
prostanoid production in inflamed tissue in rat Carrageenan
Air-pouch Inflammation" J. Pharm. Pharmacol. 45, 753-755, (1993)
and Masferrer, J. L., et al.; "Selective Inhibition of inducible
cyclooxygenase 2 in vivo is Antiflammatory and Nonulcerogenic"
Proc. Natl. Acad. Sci. USA. 91, 3228-3232, (1994). In this assay,
an air-pouch is created in the rat and the PGE.sub.2 levels in the
air-pouch exudate are measured by enzyme immunoassay. Briefly, male
rats were anesthetized using a 60:40 CO.sub.2: O.sub.2 mixture and
subsequently injected subcutaneously with 20 mL of sterilized air,
under aseptic conditions, in the proximal area of the dorsum. This
injection of sterile air causes the creation of a subcutaneous "air
pouch". The next day, a further 10 mL of sterile air was injected
into the previously formed pouch using the same technique. The test
materials were administered orally in a volume of 1 mL/100 g body
weight as solutions or suspensions in an aqueous vehicle containing
0.9% sodium chloride, 0.5% sodium carboxymethyl-cellulose, 0.4%
polysorbate 80, 0.9% benzyl alcohol and 97.3% water. Control rats
received vehicle alone. After 30 minutes, 5 mL of a 0.5% solution
of carrageenan (Sigma, Lambda Type IV) was injected into the air
pouch. The rats were euthanized 3 or 6 h after the compound
administration. 10 mL of a solution containing 10 .mu.g/l of
indomethacin and 5.4 mM EDTA in 0.9% sterile saline was injected
into the air pouch; the air pouch was cut open; and the exudate was
harvested. The total exudate volume was recorded, and the samples
were analyzed for PGE.sub.2 and 6-keto PGF.sub.1 by ELISA
(Titerzyme.RTM., PerSeptive Diagnostics, Boston, Mass.) and
TxB.sub.2 by radioimmuno assay (New England Nuclear Research,
Boston Mass., Catalog No. NEK-037), according to the manufacturer's
directions.
[0163] The mean concentrations of PGE.sub.2 were calculated for
each group. The anti-inflammatory activity of test materials is
expressed as the percent inhibition of PGE.sub.2 formation in the
test group relative to the control group.
[0164] Compounds of this invention were active in this assay.
Example 7
Analgesic Activity
[0165] The analgesic activity of the compounds of this invention
may be determined by using a modification of the method described
in Randall, L. O., and Selitto, J. J.,"A Method for Measurement of
Analgesic Activity on Inflamed Tissue", Arch. Int. Pharmacodyn.,
CXI, 4, 409, (1957) and Gans, et. al., "Anti-inflammatory and
Safety Profile of DuP 697, a Novel Orally Effective Prostaglandin
Synthesis Inhibitor", J. Pharmcol. Exp. Ther., 254, No. 1,180,
(1990). In this assay, the male Sprague Dawley rats were injected
with 0.1 mL of 20% brewer's yeast in deionized water (Sigma, St.
Louis) in the subplantar region of the left hind foot. After 2 h,
the test materials were administered orally in a volume of 1 mL/1
Og body weight as solutions or suspensions in an aqueous vehicle
containing 0.9% sodium chloride, 0.5% sodium
carboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol
and 97.3% water. Control rats received vehicle alone. After 1 h,
the hindpaw was placed on the platform of a Basile Analgesy-Meter
(Ugo Biological Research Apparatus, Italy, Model # 7200) and
mechanical force was applied to the dorsum of the rat's hindpaw.
Compounds of the invention were active in this assay.
[0166] The analgesic activity of compounds of this invention may
also be determined by using an adjuvant-induced arthritis pain
model in the rat, where pain is assessed by the animal's vocal
response to the squeezing or flexing of an inflamed ankle joint, as
described in Winter C. A. and Nuss, G. W., "Treatment of Adjuvant
Arthritis in rats with Anti-inflammatory Drugs", Arthritis Rheum.,
9, 394-403, (1966) and Winter, C. A., Kling P. J., Tocco, D. J.,
and Tanabe, K., "Analgesic activity of Diflunisal [MK-647;
5-(2,4-Difluorophenyl)salicylic acid] in Rats with Hyperalgesia
Induced by Freund's Adjuvant", J. Pharmacol. Exp. Ther., 211,
678-685, (1979).
[0167] The foregoing invention has been described in some detail by
way of illustration and example, for purposes of clarity and
understanding. It will be obvious to one of skill in the art that
changes and modifications may be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
[0168] All patents, patent applications, and publications cited in
this application are hereby incorporated by reference in their
entirety for all purposes to the same extent as if each individual
patent, patent application, or publication were so individually
denoted.
* * * * *