MATRIX METALLOPROTEINASEINHIBITORS
Field of the Invention
The present invention relates to certain sulfonyl and oxy acetic acid derivatives and
to processes for their syntheses. This invention also relates to pharmacological
compositions containing the compounds of the present invention, and methods of treating
asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis,
pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome,
perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal
proliferation, which leads to restenosis and ischemic heart failure, stroke, renal diseases,
tumor metastasis, and other inflammatory disorders characterized by over-expression and
over-activation of matrix metalloproteinase using the compounds.
Background of the Invention
Metalloproteinases (MMPs) are a naturally occurring superfamily of proteinases
(enzymes) found in most mammals. The superfamily is composed of at least 26 members
of zinc-containing enzymes produced by many cell types and sharing structural and
functional features. Based on structural and functional considerations, proteinases have
been classified into different families and subfamilies (Vartak et al., J. Drug Targeting,
15, p. 1-20 (2007); and Hopper, FEBS, 354, p. 1-6 (1994)), such as collagenases (MMP-1,
-8 and -13), gelatinases (MMP-2, and -9), metalloelastases (MMP-12), the MT-MMPs
(MMP-14, -15, -16, -17, - 24 and 25), matrilysins (MMP-7 and -26), stromelysins (MMP-
3, -10 and - 11) and sheddases such as TNF-converting enzymes (TACE, and ACE).
Metalloproteinases are believed to be important in physiological disease processes
that involve remodelling such as embryonic development, bone formation and uterine
remodelling during menstruation. One major biological function of MMPs is to catalyze
the breakdown of connective tissues or extra-cellular matrix by their ability to hydrolyze
various components of tissue or matrix. Apart from their role in degrading connective
tissue, MMPs are involved in the activation of zymogen (pro) forms of other MMPs
thereby inducing MMP activation. They are also involved in the biosynthesis of TNFalpha
which is implicated in many pathological conditions.
MMP-12, also known as macrophage elastase or metallpelastase, is expressed in
activated macrophages and has been shown to be secreted from alveolar macrophages
from smokers as well as in foam cells in atherosclerotic lesions. MMP-12 knockout
mouse studies have shown the development of significant emphysema, thus supporting its
role in COPD. MMP-9 (gelatinase B, 92 kDa type IV collagenase) is one member of the
MMP family that is released as a proenzyme and subsequently activated via a protease
cascade in vivo.
The concentration of MMP-9 is increased in diseases like asthma, interstitial
pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS), and in chronic
obstructive pulmonary disease (COPD). Because of its proteolytic ability, MMP-9 has
been implicated in tissue remodelling of the airways and lungs in chronic inflammatory
diseases such as severe asthma and COPD. MMP-9 is also likely to be physiologically
important because of its ability to regulate the digestion of components of the extracellular
matrix as well as the activity of other proteases and cytokines. MMP-9 is secreted in
neutrophils, macrophages, osteoclasts, which are easily induced by cytokines and growth
factors, and plays a role in various physiological and pathological processes.
Over-expression or over-activation of an MMP, or an imbalance between an MMP
and a natural (i.e., endogenous) tissue inhibitor of a matrix metalloproteinase (TIMP) has
been linked to a pathogenesis of diseases characterized by the breakdown of connective
tissue or extracellular matrix.
Inhibition of the activity of one or more MMPs may be of benefit in treatment of
various inflammatory, autoimmue and allergic diseases such as inflammation of the joint,
inflammation of the GI tract, inflammation of the skin, collagen remodeling, wound
healing disorders, etc.
The design and therapeutic application of MMP inhibitors has revealed that the
requirement of a molecule to be an effective inhibitor of MMP class of enzymes is a
functional group (e.g. carboxylic acid, hydroxamic acid or sulphydryl) capable of
chelating to the active site Zn2+ ion (Whittaker et al, Chem. Rev., 99 p. 2735-76 (1999)).
WO 2004/0461 19 discloses substituted aralkyl derivatives that are useful as
antidiabetic, hypolipidaemic and hypocholesterolemic agents. EP 0 364 804 discloses
compounds that are non-peptide rennin inhibitors. U.S. Patent No. 4,833,161 discloses
carboxylic acid derivatives that are useful for the treatment of diabetes, adipositas or
atherosclerosis. WO 2004/096764 relates to a method of preparing a chiral compound
having a stereogenic carbon atom adjacent to a nonstereogenic quaternary carbon atom
bearing diastereotopic groups. WO 03/008380 relates to novel compound having a2b1
integrin inhibitory activity. WO 2004/1 10974 discloses compounds and their
physiologically functional derivatives described as inhibitors of matrix metalloproteinase
enzymes. WO 2004/1 13279 discloses alleged inhibitors of matrix metalloproteinase. WO
2005/026120 discloses compounds also described as inhibitors of matrix
metalloproteinase. U.S. Patent Application No. 2003/0139453 discloses diflourobutyric
acid compounds useful for treating diseases associated with zinc metalloprotease activity.
WO 2006/090235 describes 5-phenyl-pentanoic acid derivatives described as matrix
metalloproteinase inhibitors for the treatment of asthma and other diseases.
Research has been carried out into the identification of inhibitors that are selective,
e.g. , for a few of the MMP subtypes. An MMP inhibitor of improved selectivity would
avoid potential side effects associated with inhibition of MMPs that are not involved in the
pathogenesis of the disease being treated.
Further, use of more selective MMP inhibitors would require administration of a
lower amount of the inhibitor for treatment of disease than would otherwise be required
and, after administration, partitioned in vivo among multiple MMPs. Still further, the
administration of a lower amount of compound would improve the margin of safety
between the dose of the inhibitor required for therapeutic activity and the dose of the
inhibitor at which toxicity is observed.
Many drugs exist as asymmetric three-dimensional molecules, i.e., chiral, and will
therefore have several stereoisomers depending upon the number of chiral centers present.
The importance of evaluating new chemical entities having chiral centers as single isomers
is to understand their effect on pharmacological and toxicological aspects. There are often
pharmacodynamic, pharmacokinetic and/or toxicological differences between
enantiomers/diastereomers. Even if natural physiological mediators are achiral, based on
their target environment, their receptors/enzymes may demonstrate a preference for only
one optically pure enantiomer of agonists, antagonists or inhibitors. From a
pharmacokinetic point of view, chirality can have an influence on drug absorption,
distribution, metabolism and elimination. Pure single isomers may also offer advantages
in terms of these pharmacokinetic parameters thus enabling better developability of such
molecules as drug candidates. It is also known that chirality has a significant effect of the
physicochemical properties and crystallinity of a chiral molecule which in turn have
profound effects on the pharmacokinetics and developability of the molecule. Besides
those mentioned above, regulatory principles guide one to preferably develop single
isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and
toxicological problems that may arise due to interactions of an unwanted isomer with
undesirable molecular targets.
In this context, synthetic strategies to produce pure single isomers offer advantages
over analytical techniques of separation of isomer not only in terms of cost and efficiency
but larger amounts of compound can be prepared for elaborate pharmaceutical testing.
Thus, compounds of present invention, which are single chiral isomers, have improved
potency, improved pharmacokinetics and/or improved physicochemical properties as
compared to racemic compounds.
The present invention is directed to overcoming problems encountered in the art.
Summary of the Invention
The present invention provides some sulfonyl or oxy acetic acid derivatives which
act as matrix metalloprotease inhibitors, corresponding processes for their synthesis of and
pharmaceutical compositions containing the compounds of the present invention. The
present invention relates to matrix metalloproteinase inhibitors useful as effective
therapeutic or prophylactic agents in treatment of various inflammatory, autoimmune, and
allergic diseases and other inflammatory disorders characterized by the over-expression
and over-activation of a matrix metalloproteinase using the compounds.
The present invention discloses a novel class of compounds that are dual MMP-
9/12 inhibitors and have desirable activity profiles. The compounds of this invention have
beneficial potency and/or selectivity.
Pharmaceutical compositions containing such compounds are provided together
with the pharmaceutically acceptable carriers or diluents, which can be used for the
treatment or prevention of inflammatory or autoimmune diseases. These pharmaceutical
compositions may be administered or co-administered by a wide variety of routes
including, for example, oral, topical, rectal, intranasal or by parenteral route. The
composition may also be administered or co-administered in slow release dosage forms.
Although the specific enantiomers have been shown by way of examples, the
racemates, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts,
pharmaceutically acceptable solvates, co-crystals, prodrugs and metabolites having the
same type of activity, are also provided. The pharmaceutical compositions comprising the
compounds, their metabolites, racemates, enantiomers, N-oxides, polymorphs, solvates,
co-crystals, prodrugs or pharmaceutically acceptable salts thereof, in combination with a
pharmaceutically acceptable carrier and optionally included excipients are also included.
The therapeutically effective amounts of one or more compounds of the present
invention can be used in combination with one or more other therapeutic agents, for
example, other anti-inflammatory agents, beta agonists, antihypertensive agents,
immunosuppressive agents and anti-infective agents.
Other objects will be set forth in accompanying description and in the part will be
apparent from the description or may be learnt by the practice of the invention.
Detail Description of the Invention
In accordance with one aspect, there are provided compounds having the structure
of Formula I;
Formula I
including racemates, enantiomers and diastereomers thereof, or a pharmaceutically
acceptable salt thereof wherein,
represents (un)substituted aryl or heteroaryl;
— represents C -C12 aryl, C3-C12 cycloalkyl, C -C12 heteroaryl or C -C12
heterocyclyl each of which is optionally further substituted by one or more
substituents independently selected from R '
U represents bond, -NH-, -C(=0)- , -(CH2)n-, -C(=S>, -0-, -S0 2- or -S - wherein n
represents zero or an integer between 1 and 2 ;
V represents bond, -NH-, -C(=0)-, -C(=S)- or -S0 2-;
W represents bond, -NH-, -C(=0)- ,(CH2)n-, -C(=S)-, -0-, -S- or -S0 2.;
X1 represents -0-, -S-, -SO- or -S0 2-;
R represents H, alkyl or arylalkyl;
R represents alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno -C|-C alkyl,
halogeno-Ci-C 6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf, -C(=0)-R f, -COORf,
-NRfRq, -(CH2)n-C(=0)NR fRq, -(CH2)„-NHC(=0)-R f, -(CH2)n- O-C -NRfR ,
(CH2)„NHC(=0)NR fRq , -(CH2) -0 -C(=0)- Rf, -(CH2) -NH-C(=0)-R f or
-(CH2) nS(=0 )m-NRfRq {whereinRf and qeach independently represent hydrogen,
alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and
alkylheterocyclyl, n is as defined earlier, and m is an integer 0-2};
represents mono-, bi- or polycyclic heteroaryl or heterocyclyl selected from
the following:
wherein R is as defined earlier and v represents zero or an integer between 1-4.
In accordance with one aspect, there are provided compounds having the structure
of Formula la;
including racemates, enantiomers and diastereomers thereof, or a pharmaceutically
acceptable salt thereof wherein,
represents (un)substituted aryl or heteroaryl;
represents C6-C12 aryl, C3-C12 cycloalkyl, C6-C12 heteroaryl or C6-C12
heterocyclyl, each of which is optionally further substituted by one or more
substituents independently selected from R1;
L1 represents bond, -(CH2) -, -NHC(=0)(CH 2)„., -(CH2)nC(=0)NH-,
-NHC(=0)NH-, -S0 2NH-, -NHS0 2-, -S0 2-, -NHC(=0)(0)-, -0-(CH 2)n-, -(CH2)n-0-
, -(CH2)„OC(=0)NH-, -C(=S)NH-, -NHC(=S)- or -NHC(=S)NH- wherein n can be
zero or an integer between 1 and 2;
X1 represents -0-, -S-, -SO- or -S0 -;
R represents H, alkyl or arylalkyl;
R1 represents alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Cj-C 6 alkyl,
halogeno-d-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)„-OR -C(=0)-R f, -COORf, -
R Rq,
(CH2)n NHC(=0)NR^, -(CH )n-0-C(=0)- Rf, -(CH2)„-NH-C(=0)-R f or
-(CH2)nS(=0) m-NRfRq {whereinRf and Rqindependently represent hydrogen, alkyl,
alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and
alkylheterocyclyl, n is as defined earlier and m is an integer 0-2} ;
represents mono-, bi- or polycyclic heteroaryl or heterocyclyl selected from
the following:
wherein R is as defined earlier and v represents zero or an integer between 1-4.
The enantiomers, diastereomers, rotational isomers, N-oxides, polymorphs,
pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these
compounds, prodrugs and metabolites having the same type of activity are also provided,
as well as pharmaceutical compositions comprising the compounds, their metabolites,
enantiomers, diastereomers, conformational isomers, N-oxides, polymorphs, solvates or
pharmaceutically acceptable salts thereof, in combination with a pharmaceutically
acceptable carrier and optionally included excipients.
In one embodiment, the invention encompasses compounds of Formula I/Ia, which
may include, but are not limited to the following, for example:
2-[(4-{[(4-Methylphenyl)carbonyl]amino}phenyl) sulfonyl]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 1),
2-[(3'-Methoxybiphenyl-4-yl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 2),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfonyl]-4-(6-niethyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 3),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 4),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfonyl}-4-(6-fluoro-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 5),
2-{[(4*-Chlorobiphenyl-4-yl)methyl]sulfonyl}-4-(7-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 6),
2-{[(4'-Chlorobiphenyl-4-yl)methyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 7),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 8),
2-{[(4"-Chlorobiphenyl-4-yl)methyl]sulfonyl} -4-[4-oxo-7-(trifluoromethyl> 1,2,3-
benzotriazin-3(4H)-yl]butanoic acid (Compound no. 9),
4-(6-Methyl-4-oxo- 1,2,3-benzotriazin-3(4H)-yl)-2- {[4'-(trifluoromethyl)biphenyl-
4-yl]sulfonyl}butanoic acid (Compound no. 10),
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 11),
2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 12),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 13),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfony]]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 14),
2-[(4'-Fluorobiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 15),
2-[(4'-Chlorobiphenyl-4-yl)sulfonyl]-4-(6-memyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 16),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 17),
2-[(4'-Methoxybiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 18),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 19),
2-{[4-(6-Methoxypyridin-3-yl)benzyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 20),
4-(4-Oxo- 1,2,3-benzotriazin-3(4H)-yl)-2-({ [4'-(trifluoromethoxy)biphenyl-4-yl]
methyl} sulfonyl)butanoic acid (Compound no. 21),
2-{[(3',4'-Dimethoxybiphenyl-4-yl)methyl] sulfonyl} -4-(4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 22),
2-{[(3'-Fluoro-4*-methylbiphenyl-4-yl)methyl]sulfonyl}-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 23),
2-{[(3',4'-Dimethylbiphenyl-4-yl)methyl] sulfonyl}-4-(4-oxo-1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 24),
2-{[(3^4*-Dichlorobiphenyl-4-yl)methyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 25),
2-{[(4'-Fluoro-3'-methylbiphenyl-4-yl)methyl]sulfonyl}-4-(4-oxo-l,2,3-
benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 26),
4-(4-Oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-({[4'-(trifluoromethyl)biphenyl-4-
yl]methyl}sulfonyl)butanoic acid (Compound no. 27),
2-{[(4'-Methoxybiphenyl-4-yl)methyl] sulfonyl}-4-(4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 28),
2-{[(4'-Fluorobiphenyl-4-yl)methyl]sulfonyl} -4-(4-oxo- 1,2,3-benzotriazin-3(4H)-
yl)butanoic acid (Compound no. 29),
2-({2-[4-(6-Methoxypyridin-3-yl)phenyl]ethyl}sulfonyl)-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 30),
2-{[2-(3'-Fluoro-4'-methylbiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 31),
2-{[2-(4'-Ethylbiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 32),
2-{[2-(3 ',4*-Difluorobiphenyl-4-yl)ethyl] sulfonyl}-4-(4-oxo-1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 33),
2-{ [2-(4'-Cyanobiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l ,2,3-benzotriazin-3(4H
yl)butanoic acid (Compound no. 34),
2-{[2-(3'-Fluoro-4'-methoxybiphenyl-4-yl)ethyl] sulfonyl}-4-(4-oxo-1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 35),
2-({2-[4-(l -Methyl-1H-pyrazol-4-yl)phenyl]ethyl }sulfonyl)-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 36),
2-{[2-(4*-Methylbiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 37),
4-(4-Oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2-({2-[4'-(trifluoromethoxy)biphenyl-4-
yl]ethyl}sulfonyl)butanoic acid (Compound no. 38),
4-(7-Methyl-4-oxo-l ,2,3-benzotriazin-3(4H)-yl)-2-{ [4'-
(trifluoromethoxy)biphenyl-4-yl] sulfonyl}butanoic acid (Compound no. 39),
4-(6-Methoxy-4-oxo- 1,2,3-benzotriazin-3(4H)-yl)-2- {[4 -
(trifluoromethoxy)biphenyl-4-yl] sulfonyl}butanoic acid (Compound no. 40),
4-(7-Methoxy-4-oxo- 1,2,3-benzotriazin-3(4H)-yl)-2- {[4'-(trifluoromethoxy)
biphenyl-4-yl]sulfonyl }butanoic acid (Compound no. 41),
2-[(4'-t rt-Butylbiphenyl-4-yl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 42),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic
acid (Compound no. 43),
4-(4-Oxo- 1,2,3-benzotriazin-3(4H)-yl)-2- {[4'-(propan-2-yl)biphenyl-4-yl] sulfonyl }
butanoic acid (Compound no. 44),
4-(4-Oxo- 1,2,3-benzotriazin-3(4H)-yl)-2-{ [4'-(trifluoromethoxy)biphenyl-4-yl]
sulfonyl}butanoic acid (Compound no. 45),
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2-({4-[(phenylcarbonyl)amino]phenyl }
sulfonyl)butanoic acid (Compound no. 46),
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 47),
4-(7-Methoxy-4-oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethyl)
biphenyl-4-yl]sulfonyl} butanoic acid (Compound no. 48),
2-[(4'-Methoxybiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 49),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 50),
2-[(3',4'-Dimethoxybiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 51),
2-[(4-{ [(3-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 52),
2-[(4-{[(3-Fluorophenyl)carbonyl] amino}phenyl)sulfonyl] -4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 53),
2-[(4- {[(4-Fluorophenyl)carbonyl] amino}phenyl)sulfonyl] -4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 54),
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 55),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 56),
2-[(4'-Chlorobiphenyl-4-yl)sulfonyl] -4-(7-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 57),
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 58),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 59),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 60),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 61),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 62),
2-[(3 ',4'-Dichlorobiphenyl-4-yl)sulfonyl] -4-(6-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 63),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 64),
2-{[4'-Chloro-3 ,-(trifluoromethyl)biphenyl-4-yl]sulfonyl}-4-(6-methoxy-4-oxo-
1,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 65),
2-[(4'-Emylbiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4 H )
yl)butanoic acid (Compound no. 66),
2-[(3',4'-Dimethylbiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 67),
4-(6-Methoxy-4-oxo-l,2,3-benzo1riazin-3(4 H)-yl)-2-[(4 ,-methylbiphenyl-4-yl)
sulfonyl]butanoic acid (Compound no. 68),
2-[(4'-Chlorobiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 69),
4-(6-Methoxy-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethyl)
biphenyl-4-yl] sulfonyl}butanoic acid (Compound no. 70),
2-[(4'-Methoxybiphenyl-4-yl)sulfonyl] -4-(6-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 71),
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2-( {2-[4-({[4-(trifluoromethyl)
phenyl]carbonyl}amino)phenyl]ethyl}sulfonyl)butanoic acid (Compound no. 72),
4-(4-Oxo- 1,2,3 -benzotriazin-3(4 H)-yl)-2-( {2-[4-( {[4-(trifluoromethoxy)
phenyl] carbonyl}amino)phenyl] ethyl }sulfonyl)butanoic acid (Compound no. 73),
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 74),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-[4-oxo-7-(trifluoromethyl)-
1,2,3 -benzotriazin-3 (4H)-yl]butanoic acid (Compound no. 75),
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(2- {4-[(phenylcarbonyl)
amino]phenyl}ethyl)sulfonyl]butanoic acid (Compound no. 76),
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(2- {4-[(thiophen-2-ylcarbonyl)amino]
phenyl}ethyl)sulfonyl]butanoic acid (Compound no. 77),
2-[(2-{4-[(Cyclopentylcarbonyl)amino]phenyl}ethyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 78),
2-[(2-{4-[(Cyclopropylcarbonyl)amino]phenyl}ethyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 79),
2-{[2-(4-{[(3-Methoxyphenyl)carbonyl] amino}phenyl)ethyl]sulfonyl}-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 80),
2-{[2-(4-{[(3-Chlorophenyl)carbonyl]amino}phenyl)ethyl]sulfonyl}-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 81),
2-{[2-(4-{[(3-Fluorophenyl)carbonyl]amino}phenyl)ethyl]sulfonyl}-4-(4-oxo-
1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 82),
2-{[2-(4- {[(4-Ethylphenyl)carbonyl] amino}phenyl)ethyl]sulfonyl} -4-(4-oxo- 1,2,3 -
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 83),
2-{[2-(4- {[(4-Methoxyphenyl)sulfonyl]amino }phenyljethyl] sulfonyl}-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 84),
2-[(4-{ [(3-Ethoxyphenyl)carbamoyl]amino}phenyl)sulfonyl]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 85),
2-{[4-({[2-Fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]sulfonyl}-
4-(4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 86),
2-[(4- {[(2,6-Dimethoxyphenyl)carbonyl] amino}phenyl)sulfonyl] -4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 87),
2-[(4- {[(4-Fluorophenyl)carbamoyl] amino}phenyl)sulfony 1] -4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 88),
2-[(4'-Fluorobiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 89),
2-[(3'-Ffluoro-4 ,-methylbiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 90),
2-[(4'-Fluoro-3'-metliylbiphenyl-4-yl)sulfony]]-4-(8-metliyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 91),
2-({2-[4-(Benzyloxy)pheny]]ethyl}sulfonyl)-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 92),
2-[(3',4'-Dimethylbiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 93),
2-[(4-{ [(3-Methylphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 94),
2-[(4-{[(2-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 95),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 96),
2-[(4'-Methylbiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 97),
2-{[4-(6-Methoxypyridin-3 -yl)phenyl] sulfonyl }-4-(8-methyl-4-oxo- 1,2,3 -
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 98),
2-( {4-[(Cyclohexylcarbonyl)amino]phenyl }sulfonyl)-4-(4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 99),
2-[(4-{[(2-Methylphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 100),
2-({4-[(Cyclopropylcarbonyl)amino]phenyl}sulfonyl)-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 101),
4-(4-Oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2-({4-[(thiophen-2-
ylcarbonyl)amino]phenyl}sulfonyl)butanoic acid (Compound no. 102),
2-({4-[(Cyclopentylcarbonyl)amino]phenyl}sulfonyl)-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 103),
-{[4-({[4-Fluoro-3-(trifluoromethyl)phenyl]carbonyl }amino)pheny]]sulfonyl }-4-
(4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 104),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(7-methyl-4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 105),
2-[(4,-Chlorobiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 106),
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 107),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 108),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 109),
4-(6-Methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4 ,-(trifluoromethyl)biphenyl-
4-yl] sulfanyl}butanoic acid (Compound no. 110),
2-[(3 ,,4 -Dichlorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. I l l),
2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 112),
2-[(3 ,,4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 113),
2-[(3 ,-Fluoro-4"-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 114),
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 115),
2-[(4'-E%lbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazm-3(4 H)-
yl)butanoic acid (Compound no. 116),
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl] -4-(6-methyl-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 117),
2-[(4'-Fluoro-3 '-methylbiphenyl-4-yl)sulfanyl] -4-(6-methyl-4-oxo- 1,2,3 -
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 118),
4-(4-Oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethyl)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 119),
4-(8-Methyl-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2-{ [4'-
(trifluoromethoxy)biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 120),
4-(7-Methyl-4-oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethoxy)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 121),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4'-(trifluoromethoxy)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 122),
4-(7-Methoxy-4-oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethoxy)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 123),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 124),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 125),
2-[(4'-Fluoro-3 '-methylbiphenyl-4-yl)sulfanyl] -4-(6-methoxy-4-oxo- 1,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 126),
2-[(3 ,,4'-Dichlorobiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 127),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 128),
2-{ [4,-chloro-3'-(trifluoromethyl)biphenyl-4-yl]sulfanyl} -4-(6-methoxy-4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 129),
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo- 1,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 130),
2-[(3',4'-Dimethylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 131),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(4'-methylbiphenyl-4-yl)
sulfanyl]butanoic acid (Compound no. 132),
4-(6-Methoxy-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4'-(trifluoromethyl)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 133),
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo- 1,2,3-benzotriazin-3(4 H
yl)butanoic acid (Compound no. 134),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 135),
2-{[4-(6-Methoxypyridin-3 -yl)phenyl] sulfanyl }-4-(8-methyl-4-oxo- 1,2,3 -
benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 136),
2-[(4,-Methylbiphenyl-4-yl)sulfanyl]-4-(8-me%l-4-oxo-l,2,3-benzotriazin-3(4/^
yl)butanoic acid (Compound no. 137),
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 138),
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl] -4-(8-methyl-4-oxo- 1,2,3 -benzotriazin-3 (4H
yl)butanoic acid (Compound no. 139),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 140),
2-[(3^4,-Difluorobiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 141),
2-[(3^4'-Dimethoxybiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 142),
2-[(3 ,,4'-Dimethylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l ,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 143),
4-(8-Methyl-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2-{ [4'-(trifluoromethyl)biphenyl-
4-yl]sulfanyl}butanoic acid (Compound no. 144),
2-[(3,-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 145),
4-(5-Chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(3 ,-fluoro-4'-methoxybiphenyl-
4-yl)sulfanyl]butanoic acid (Compound no. 146),
4-(7-Chloro-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2-[(3 ,-fluoro-4'-methoxybiphenyl-
4-yl)sulfanyl]butanoic acid (Compound no. 147),
2-{[4-(6-Methoxypyridin-3 -yl)phenyl] sulfanyl} -4-(4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 148),
2-[(4,-Methoxybiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 149),
2-[(3 '-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl] -4-(4-oxo- 1,2,3 -benzotriazin-3 (4H
yl)butanoic acid (Compound no. 150),
2-[(3 ',4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo- 1,2,3 -benzotriazin-3 (4H
yl)butanoic acid (Compound no. 151),
2-[(3'-Methoxybiphenyl-4-yl)sulfany] ]-4-(4-oxo- 1,2,3 -benzotriazin-3 (4H)-
yl)butanoic acid (Compound no. 152),
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo- 1,2,3 -benzotriazin-3 (4H
yl)butanoic acid (Compound no. 153),
2-(Biphenyl-4-ylsulfanyl)-4-(4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid
(Compound no. 154),
2-[(2^3'-Difluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4/^
yl)butanoic acid (Compound no. 155),
2-{[(4'-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 156),
2-{[(4'-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(7-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 157),
2-{ [(4,-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(7-methoxy-4-oxo- 1,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 158),
2-{[(4'-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(6-fluoro-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 159),
2-{[(4 ,-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 160),
2-{ [(4'-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-[4-oxo-7-(trifluoromethyl)- 1,2,3-
benzotriazin-3(4 H)-y]]butanoic acid (Compound no. 161),
2-{[(4,-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(5-chloro-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 162),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfanyl}-4-(7-chloro-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 163),
2-{[2-(4*-Chlorobiphenyl-4-yl)ethyl]sulfanyl}-4-(7-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 164),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfanyl}-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 165),
2-[(4,-ter t-Butylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 166),
2-[(4*-Emylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic
acid (Compound no. 167),
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- {[4'-(propan-2-yl)biphenyl-4-
y]]sulfanyl}butanoic acid (Compound no. 168),
4-(4-Oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4'-(trifluoromethyl)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 169),
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H yl)-2- {[4'-(trifluoromethoxy)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 170),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 171),
4-(7-Memoxy-4-oxo-l,2,3-benzotriazin-3(4/^-yl)-2-{[4-(6-methoxypyridin-3-
yl)phenyl]sulfanyl}butanoic acid (Compound no. 172),
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4 *-
(trifluorometnyl)biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 173),
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl] -4-(7-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 174),
2-[(3,-Fluoro-4 ,-methylbiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 175),
4-(7-Methoxy-4-oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2- {[4-(1-methyl- 1H-pyrazol-4-
yl)phenyl]sulfanyl}butanoic acid (Compound no. 176),
2-[(3',4'-Dimethoxybiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 177),
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl] -4-(7-methoxy-4-oxo- 1,2,3 -benzotriazin-3 (4H
yl)butanoic acid (Compound no. 178),
2-[(4'-Fluoro-3 '-methylbiphenyl-4-yl)sulfanyl] -4-(7-methoxy-4-oxo- 1,2,3 -
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 179),
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 180),
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l ,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 181),
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 182),
2-[(4-{[(3-Methoxyphenyl)acetyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 183),
2-[(4-{[(2,5-Dimethoxyphenyl)acetyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 184),
4-(4-Oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-({4-(phenylacetyl)
amino]phenyl}sulfonyl)butanoic acid (Compound no. 185),
2-(4-Fluorobenzyl)-2-[(2-{4-[(4-fluorobenzyl)oxy]phenyl}ethyl)sulfonyl]-4-(4-
oxo- 1,2,3-benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 186),
4-(6-Methoxy-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2-[(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 187),
4-(8-Methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 188),
4-(6-Methoxy-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 189),
4-(8-Methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 190),
2-(3-Fluorobenzyl)-2-[(2-{4-[(3-fluorobenzyl)oxy]phenyl}ethyl)sulfonyl]-4-(4-
oxo- 1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 191),
4-(6-Methyl-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 192),
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 193),
4-(6-Fluoro-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 194),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfanyl}-4-(6-fluoro-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 195),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfanyl}-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 196),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfonyl} -4-(7-methyl-4-oxo- 1,2,3-
benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 197),
2-(2-Chlorobenzyl)-2-[(2-{4-[(2-chlorobenzyl)oxy]phenyl}ethyl)sulfonyl]-4-(4-
oxo- 1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 198),
2-{ [2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfonyl} -4-(6-methyl-4-oxo- 1,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 199),
4-(6-Methyl-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 200),
4-(7-Methyl-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 201),
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-
1,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 202),
2-[(4-{[(4-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-
1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 203),
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-
1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 204),
2-[(4-{[(4-Ethylphenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 205),
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-
1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 206),
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 207),
2-[(4-{[(4-Ethylphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-
1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 208),
2-[(4-{[(4-Fluorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-
1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 209),
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-
1,2,3 -benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 210),
2-[(4'-Chlorobiphenyl-4-yl)oxy] -4-(4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)butanoic
acid (Compound no. 2 11),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(6-fluoro-4-oxo- 1,2,3-benzotriazin-3(4H)-
yl)butanoic acid (Compound no. 212),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(7-chloro-4-oxo- 1,2,3-benzotriazin-3(4H
yl)butanoic acid (Compound no. 213),
2-[(4,-Chlorobiphenyl-4-yl)oxy]-4-[4-oxo-7-(trifluoromethyl)-l,2,3-benzotriazin-
3(4H)-yl]butanoic acid (Compound no. 214),
2-[(4'-Chlorobiphenyl-4-yl)oxy] -4-(5-fluoro-4-oxo- 1,2,3-benzotriazin-3(4H)-
yl)butanoic acid (Compound no. 215),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(5-chloro-4-oxo- 1,2,3-benzotriazin-3(4H)-
yl)butanoic acid (Compound no. 216),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 217),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(5-me%l-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 218),
(2/?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6-fluoro-4-oxo-l,2,3-ber^otriazin-3(4 H)-
yl)butanoic acid (Compound no. 219),
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(7-chloro-4-oxo-l,2,3-berLz:otriazin-3(4H)
yl)butanoic acid (Compound no. 220),
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 221),
(2R)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6,7-difluoro-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 222),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(7-chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 223),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(7-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 224),
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(2,4-dioxo-2H-l,3-benzoxazin-3(4 H)-
yl)butanoic acid (Compound no. 225),
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(l-oxophthalazin-2(l H)-yl)butanoic acid
(Compound no. 226),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 227),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(1-oxophthalazin-2( lH)-yl)butanoic acid
(Compound no. 228),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(2,4-dioxo-2H-1,3-benzoxazin-3(4H)-
yl)butanoic acid (Compound no. 229),
including racemates, enantiomers and diastereomers thereof, or a pharmaceutically
acceptable salt of any one thereof.
In another aspect, provided herein are pharmaceutical composition comprising
therapeutically effective amounts of one or more compounds described herein together
with one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, provided herein are compounds according to Formula I/Ia for
use in medicine.
In another aspect, provided herein are compounds according to Formula I/Ia for
use in treating or preventing various inflammatory and allergic diseases comprising
administering to a mammal in need thereof.
In another aspect, provided herein are compounds according to Formula I/Ia
wherein various inflammatory and allergic diseases are asthma, rheumatoid arthritis, COPD,
dry eye, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary
inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis,
gingivitis, atherosclerosis, dry eye, neointimal proliferation associated with restenosis and
ischemic heart failure, stroke, renal disease or tumor metastasis.
In yet another aspect, the present invention relates to the therapeutically effective
dose of a compound of Formula I/Ia in combination with one or more of other therapeutic
agents used for treating various inflammatory and allergic diseases. Examples of such
therapeutic agents include, but are not limited to:
1) Anti-inflammatory agents, experimental or commercial (i) such as
nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids,
fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin
inhibitors, CCR-3 antagonists, iNOS inhibitors, tryptase and elastase
inhibitors, beta-2 integrin antagonists, cell adhesion inhibitors (especially
ICAM), adenosine 2a agonists; (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-
Inhibitors, 5-lipoxygenase inhibitors and PAF- receptor antagonists; (iii)
Cox-2 inhibitors; (iv) other MMP inhibitors; (v) interleukin-I inhibitors; (vi)
corticosteroids such as alclometasone, amcinonide, amelometasone,
beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,
cloticasone, cyclomethasone, deflazacort, deprodone, dexbudesonide,
diflorasone, difluprednate, fluticasone, flunisolide, halometasone,
halopredone, hydrocortisone, methylprednisolone, mometasone,
prednicarbate, prednisolone, rimexolone, tixocortol, triamcinolone,
ulobetasol, rofleponide, GW 215864, KSR 592, ST-126, dexamethasone and
pharmaceutically acceptable salts, solvates thereof. Preferred corticosteroids
include, for example, flunisolide, beclomethasone, triamcinolone,
budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone; (vii)
Cathepsin-S inhibitors;
2) Beta-agonists, experimental or commercial (i) suitable p2-agonists include,
for example, one or more of albuterol, salbutamol, biltolterol, pirbuterol,
levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol,
fenoterol, salmeterol, carmoterol, arformoterol, formoterol, and their
pharmaceutically acceptable salts or solvates thereof. One or more b2-
agonists may be chosen from those in the art or subsequently discovered (ii)
the p2-agonists may include one or more compounds described in, for
example, U.S. Patent Nos. 3,705,233; 3,644,353; 3,642,896; 3,700,681;
4,579,985; 3,994,974; 3,937,838; 4,419,364; 5,126,375; 5,243,076;
4,992,474; and 4,01 1,258;
3) antihypertensive agents, (i) ACE inhibitors, e.g., enalapril, lisinopril,
valsartan, telmisartan and quinapril; (ii) angiotensin II receptor antagonists
and agonists, e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan;
(iii) b-blockers; and (iv) calcium channel blockers;
4) immunosuppressive agents, for example, cyclosporine, azathioprine and
methotrexate, anti-inflammatory corticosteroids; and
5) anti-infective agents (e.g. antibiotics, antivirals).
The following definitions apply to terms as used herein:
The term "alkyl" refers to a straight or branched fully saturated hydrocarbon chain
which is optionally substituted by one or more halo atoms, and which has 1 to 20 carbon
atoms unless otherwise specified. This term is exemplified by groups, such as methyl,
ethyl, n-propyl, wo-propyl, n-butyl, wo-butyl, t-butyl, n-hexyl, n-decyl, n-tetradecyl,
trifluoromethyl, chloroethyl, and the like.
The term "alkenyl", unless otherwise specified, refers to a branched or unbranched
unsaturated hydrocarbon group containing at least one double bond with cis or trans
geometry and preferably having 2 to 20 carbon atoms. Examples of alkenyl group include
ethenyl, 2-propenyl and isopropenyl.
The term "cycloalkyl" refers to a non-aromatic cyclic group having 3 to 20 ring
carbon atoms and forms one to three rings and may optionally contain one or more olefinic
bonds. Polycyclic ring systems may be a spiro, fused or bridged arrangement. Cycloalkyl
groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, adamantlyl, bicyclo[2.2J]heptanyl,
bicyclo[2.2.2]octane, tricycle [3.3.1.7]decane, and the like.
The term "aryl" refers to an aromatic system having from 6 to 14 carbon atoms and
up to three rings which may be fused or directly joined. Representative examples of such
aryl group include, but are not limited to, phenyl, biphenyl, naphthyl, phenanthrene,
anthracenyl, azulenyl, and indanyl. Aryl group may also comprise one or more rings
which are not fully aromatic and examples of such system are indane, indene, 2,3
dihydrobenzofuran and 1,2,3,4-tetrahydronaphthalene.
The term "heteroaryl" refers to an aromatic system having from 5 to 14 membered
carbon atoms and up to three rings, which may be fused or directly joined, and containing
from one to eight heteroatoms selected from N, O and S. Examples of heteroaryl groups
are yridinyl, quinolinyl, oxazolyl, imidazolyl, pyrrolyl, thiophenyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridazinyl,
pyrazinyl, thienyl, soxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl,
benzoxazolyl, and the like.
The term "heterocyclyl" refers to a non-aromatic monocyclic or polycyclic ring
system, which may be fused, spiro or bridged having 3 to 12 ring atoms and up to eight
heteroatoms selected from N, O and S. Examples of heterocyclyl ring systems include
piperidine, morpholine, piperazine, isoquinoline, oxazolidine, tetrahydrofuran,
dihydrofuran, dihydropyridine, dihydroisoxazole, dihydrobenzofuran, azabicyclohexane,
dihydroindole, tetrahydroquinoline, pyrrolidine, azepine, azetidine, aziridine,
tetrahydropyridine, benzthiazine, benzoxazinyl, isoindoline, azabicycle[3.i .0]hexyl,
phenoxazine, tetrahydropyran, 1,4-dioxane, and the like.
The terms "cycloalkylalkyl", "arylalkyl", "heteroarylalkyl", "heterocyclylalkyl"
refer respectively to cycloalkyl, aryl, heteroaryl or heterocyclyl group linked the remainder
of the molecule via an alkyl group.
The term "amino" refers to -NH2.
The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined
above.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
The term "halogeno-d -C6 alkyl" refers to C C6 alkyl of which one or more
hydrogen(s) is/are replaced by halogen.
The term "halogeno Ci-C alkoxy" refers to as halogen atom bonded to -C
alkoxy group. Examples of such groups include trifiuoromethoxy, trichloromethoxy,
difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy, etc.
The term "hydroxyl" or "hydroxy" refers to -OH.
The term "thiol" refers to the group -SH.
The term "alkylthiol" refers to a thiol group when hydrogen is replaced by alkyl,
for example, methylthio, ethylthio, propylthio, t-butylthio, cyclopropylthio, and the like.
The term "cyano" refers to CºN.
The term "azido" refers to N=N=N
The term "leaving group" refers to groups that exhibit or potentially exhibit the
properties of being labile under the synthetic conditions and also of being readily
separated from synthetic products under defined conditions. Examples of leaving groups
include, but are not limited to, halogen (e.g., F, CI, Br, I), triflates, tosylate, mesylates,
alkoxy, thioalkoxy, or hydroxy radicals, and the like.
The term "protecting groups" refers to moieties that prevent chemical reaction at a
location of a molecule intended to be left unaffected during chemical modification of such
molecule. Unless otherwise specified, protecting groups may be used on groups, such as
hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and
P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons,
New York, N.Y. The species of the carboxylic protecting groups, amino protecting groups
or hydroxy protecting groups employed are not critical, as long as the derivatised
moiety/moieties is/are stable to conditions of subsequent reactions and can be removed
without disrupting the remainder of the molecule.
Compounds described herein can contain one or more asymmetric carbon atoms
and thus occur as diastereomers. These compounds can also exist as conformers/rotamers.
All such isomeric forms of these compounds are included herein. Each stereogenic carbon
may be of the R S configuration. Although the specific compounds exemplified in this
application may be depicted in a particular stereochemical configuration, compounds
having either the opposite stereochemistry at any given chiral center or mixtures thereof
are envisioned.
The term "pharmaceutically acceptable salts" forming part of this invention
includes the salts of carboxylic acid moiety, which may be prepared by reacting the
compound with an appropriate base to provide corresponding base addition salts.
Examples of such bases are alkali metal hydroxide including potassium hydroxide, sodium
hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as magnesium
hydroxide and calcium hydroxide. Further, the salts of organic bases, such as lysine,
arginine, guanidine, ethanolamine, choline, and the like; inorganic bases, e.g., ammonium
or substituted ammonium salts are also included. Wherever appropriate, compounds of
the present invention may also form the acid addition salts by treating the said compounds
with pharmaceutically acceptable organic and inorganic acids, e.g., hydrohalides, such as
hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding
salts, such as sulphate, nitrate, phosphate, etc.; and alkyl and mono-arylsulphonates, such
as ethane sulphonate, toluene sulphonate and benzene sulphonate; and other organic acids
and their corresponding salts, such as acetate, tartarate, maleate, succinate, citrate, etc.
The salt forms differ from the compound described herein in certain physical properties,
such as solubility, but the salts are otherwise equivalent for the purpose of this invention.
The term "pharmaceutically acceptable solvates" refers to solvates with water (i.e.,
hydrates) or pharmaceutically acceptable solvents, for example, solvates with ethanol, and
the like. Such solvates are also encompassed within the scope of the disclosure.
Furthermore, some of the crystalline forms for compounds described herein may exist as
polymorphs and as such are intended to be included in the scope of the disclosure.
The term "polymorphs" includes all crystalline forms as well as amorphous forms
for compounds described herein and as such are included in the present invention.
The term "pharmaceutically acceptable carriers" is intended to include non-toxic,
inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation
auxiliary of any type.
The term "pharmaceutically acceptable" means approved by a regulatory agency of
the federal or a state government or listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly in humans.
Examples of inflammatory conditions and autoimmune disorders in which the
compounds of the invention have potentially beneficial effects in treatment methods may
include, but are not limited to, diseases of the respiratory tract, such as asthma (including
allergen-induced asthmatic reactions), cystic fibrosis, bronchitis (including chronic
bronchitis), chronic obstructive pulmonary disease (COPD), adult respiratory distress
syndrome (ARDS), chronic pulmonary inflammation, rhinitis and upper respiratory tract
inflammatory disorders (URID), ventilator induced lung injury, silicosis, pulmonary
sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, arthritis, e.g.,
rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, traumatic
arthritis, rubella arthritis, Reiter's syndrome, gouty arthritis and prosthetic joint failure,
gout, acute synovitis, spondylitis and non-articular inflammatory conditions, e.g.,
herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis, tendonitis,
tenosynovitic, fibromyalgic syndrome and other inflammatory conditions associated with
ligamentous sprain and regional musculoskeletal strain, inflammatory disorders of the
gastrointestinal tract, e.g., ulcerative colitis, diverticulitis, Crohn's disease, inflammatory
bowel diseases, irritable bowel syndrome and gastritis, multiple sclerosis, systemic lupus
erythematosus, scleroderma, autoimmune exocrinopathy, autoimmune encephalomyelitis,
diabetes, tumor angiogenesis and metastasis, cancer including carcinoma of the breast,
colon, rectum, lung, kidney, ovary, stomach, uterus, pancreas, liver, oral, laryngeal and
prostate, melanoma, acute and chronic leukemia, periodontal disease, neurodegenerative
disease, Alzheimer's disease, Parkinson's disease, epilepsy, muscle degeneration, inguinal
hernia, retinal degeneration, diabetic retinopathy, macular degeneration, ocular
inflammation, bone resorption diseases, osteoporosis, osteopetrosis, graft vs. host reaction,
allograft rejections, sepsis, endotoxemia, toxic shock syndrome, tuberculosis, usual
interstitial and cryptogenic organizing pneumonia, bacterial meningitis, systemic cachexia,
cachexia secondary to infection or malignancy, cachexia secondary to acquired immune
deficiency syndrome (AIDS), malaria, leprosy, leishmaniasis, Lyme disease,
glomerulonephritis, glomerulosclerosis, renal fibrosis, liver fibrosis, pancreatitis, hepatitis,
endometriosis, pain, e.g., that associated with inflammation and/or trauma, inflammatory
diseases of the skin, e.g., dermatitis, dermatosis, skin ulcers, psoriasis, eczema, systemic
vasculitis, vascular dementia, thrombosis, atherosclerosis, restenosis, reperfusion injury,
plaque calcification, myocarditis, aneurysm, stroke, pulmonary hypertension, left
ventricular remodeling and heart failure. It will be appreciated by those skilled in the art
that reference herein to treatment extends to prophylaxis as well as the treatment of
established conditions.
Compounds disclosed herein may be prepared, for example, by techniques well
known in the organic synthesis and familiar to a practitioner ordinarily skilled in art of this
invention. In addition, the processes described herein may enable the synthesis of the
compounds of the present invention. However, these may not be the only means by which
the compounds described in the invention may be synthesized. Further, the various
synthetic steps described herein may be performed in alternate sequences in order to
furnish the desired compounds.
Accordingly, compounds of FormulaX can be prepared by following Scheme I.
Compounds of Formula II can react through two pathways.
Path A: The ring opening of compound of Formula II (wherein G is O or S), gives a
compound of Formula III (wherein Rp is carboxy protecting group such as methyl, ethyl,
allyl, benzyl, t-butyl and silyl) which reacts with a compound of Formula IV (wherein
_ / is as defined earlier where the heterocycle is N-attached) to give a compound of
Formula V, which then undergoes coupling with a compound of Formula VI (wherein R
is H, halo, alkyl, alkoxy, cyano, halogeno-C -C6 alkyl, halogeno-CrCe alkoxy) to give a
compound of Formula VII.
Path B : The compound of Formula II can undergo coupling with a compound of Formula
VI to give a compound of Formula VIII. The ring opening of compound of Formula VIII
gives a compound of Formula EX, which then reacts with a compound of Formula IV to
give a compound of Formula VII.
The compound of Formula VII can then undergo hydrolysis to give a compound of
Formula X.
The reaction of a compound of Formula II (Path A) to give a compound of
Formula III is carried out intially in the presence of a base, for example, sodium
hydroxide, potassium hydroxide, lithium hydroxide or mixtures thereof, in a solvent, for
example, N,N-dimethylformamide, water, dioxane, dimethylsulphoxide, tetrahydrofuran or
mixtures followed by reaction with alkyl halides, for example, methyl iodide, ethyl iodide,
allyl bromide in the presence of a base, for example, sodium bicarbonate optionally in the
presence of a catalyst, for example, 18-crown-6, dibenzo-18-crown-6,
trimethylbenzylammonium chloride, or tetrabutyl ammonium iodide.
The reaction of a compound of Formula III with a compound of Formula IV to
give a compound of Formula V can be carried out in the presence of Mitsunobu reagents,
for example, diisopropylazodicarboxylate (DIAD), dibenzylazodicarboxylate (DBAD),
azodicarbonyldipiperidide (ADDP) or diethylazodicarboxylate (DEAD) in the presence of
phosphines, for example, triphenyl phosphine, tributylphosphine or trimethylphosphine in
a solvent, for example, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dioxane, or
mixtures thereof.
The coupling of a compound of Formula V with a compound of Formula VI to
give a compound of Formula VII can be carried out in the presence of bis-(diphenylphosphino)
ferrocene palladium II dichloride (Pd(dppf)Cl2), tetrakistriphenylphosphine
palladium (0) [Pd (Ph3P) ], palladium acetate or dichlorobistriphenylphosphine palladium
(II), with a suitable base, for example, potassium carbonate, sodium acetate or potassium
acetate, potassium fluoride in one or more solvent, for example, acetonitrile,
dimethylformamide, toluene, tetrahydrofuran, acetone, water or dioxane.
The coupling of a compound of Formula II with a compound of Formula VI to give
a compound of Formula VIII (Path B) can be carried out in the same way as the coupling
of a compound of Formula V with a compound of Formula VI to give a compound of
Formula VII.
The reaction of a compound of Formula VIII to give a compound of Formula IX
can be carried out in a similar way as that of a compound of Formula II to give a
compound of Formula III.
The reaction of a compound of Formula IX with a compound of Formula IV to
give a compound of Formula VII can be carried out in the same way as reaction of a
compound of Formula III with a compound of Formula IV to give a compound of Formula
V.
The hydrolysis of a compound of Formula VII to give a compound of Formula X
can be carried out in lithium hydroxide, potassium hydroxide or sodium hydroxide in one
or more solvents, for example, tetrahydrofuran, water, methanol, dichloromethane,
acetone, acetonitrile or dioxane.
The compound of Formula XI can be prepared by following Scheme II.
Scheme II
The compound of Formula X (when G is S) is oxidized to give a compound of Formula
XI.
The oxidation of a compound of Formula X to give a compound of Formula XI can
be carried out with an oxidizing agent, for example, metachloroperbenzoic acid or oxone
in a solvent, for example, chloroform, dichoromethane, methanol, water,
tetrachloromethane, or mixtures thereof.
The compound of Formula XVII can be prepared by following Scheme III.
Scheme III
Formula XIV Formula XV
Accordingly, the compound of Formula XIV (wherein Rm is Br or N0 2 and Rp is as
defined earlier) can undergo oxidation to give a compound of Formula XV. The
compound of Formula XV can react with a compound of Formula XVI (wherein X is a
leaving group, for example, halogen, mesylate, triflate, etc.,) to give a compound of
Formula XVII.
Oxidation of a compound of Formula XIV to give a compound of Formula XV can
be carried out in a similar way as the oxidation of a compound of Formula X to a
compound of Formula XI.
Reaction of a compound of Formula XV with a compound of Formula XVI to give
a compound of Formula XVII can be carried out in a solvent, for example, N,Ndimethylformamide,
N,N -dimethylacetaniide in the presence of a base, for example,
potassium carbonate, sodium carbonate, triethylamine, N,N -diisopropylethylamine or
mixtures thereof. The reaction can be carried out in the presence of a catalyst, for
example, t-butyl ammonium iodide, t-butyl ammonium bromide,
trimethylbenzylammonium chloride, benzethonium chloride, cetrimonium bromide or
cetylpyridinium chloride.
The compound of Formula XXIV can be prepared by following Scheme IV.
Scheme IV
Accordingly, the compound of Formula XIX can be O-protected to give a
compound of Formula XX (wherein Rp is as defined earlier). The compound of Formula
XX can be N-protected to give a compound of Formula XXI (wherein Rp is an amino
protecting group selected from di- rt-butyl dicarbonate, t-Boc, F-moc, benzyl, tosyl or
carbobenzyloxy). The compound of Formula XXI can be oxidized to give a compound of
Formula XXII. The compound of Formula XXII reacts with a compound of Formula XVI
(wherein X is as defined earlier) to give a compound of Formula XXIII, which then
undergoes N-deprotection to give a compound of Formula XXIV.
O-protection of a compound of Formula XIX to give a compound of Formula XX
can be carried out the presence of methanol and sulfuric acid.
N-protection of a compound of Formula XX to give a compound of Formula XXI
can be carried out with an amino protecting group, for example, benzylchloroformate, dirt-
butyl dicarbonate, Boc anhydride or Fmoc chloride in the presence of a base, for
example, triethylamine, sodium bicarbonate, N,N -diisopropylethylamine or potassium
carbonate in a solvent, for example, dichloromethane, dioxane, dichloroethane,
chloroform, carbon tetrachloride, t-butanol, or tetrahydrofuran.
Oxidation of a compound of Formula XXI to give a compound of Formula XXII
can be carried out in a similar way as the oxidation of a compound of Formula X to a
compound of Formula XI.
The reaction of a compound of Formula XXII with a compound of Formula XVI to
give a compound of Formula XXIII can be carried out in a similar way as the reaction of
compound of Formula XV with a compound of Formula XVI to give a compound of
Formula XVII.
The N-deprotection of a compound of Formula XXIII to give a compound of
Formula XXIV can be carried out in one or more solvent, for example, dichloromethane,
dichloroethane, chloroform, tetrahydrofuran, water or carbon tetrachloride in the presence
of an acid such as trifluoroacetic acid or hydrochloric acid.
The compounds of Formulae XXVI, XXIX, XXXII can be prepared by following
Scheme V.
Accordingly, a compound of Formula XVII (wherein Rm is as defined earlier) can
react through two pathways.
Path C: The compound of Formula XVII (when Rm is Br) undergoes coupling with a
compound of Formula VI to give a compound of Formula XXV, which then undergoes
hydrolysis to give a compound of Formula XXVI.
Path D: The compound of Formula XVII (when Rm is N0 2) undergoes reduction to give a
compound of Formula XXIV.
Path E: The compound of Formula XXIV couples with a compound of Formula XXVII
(wherein Rkand z are as defined earlier) to give a compound of Formula XXVIII, which
can then be hydrolyzed to give a compound of Formula XXIX.
Path F: The compound of Formula XXIV couples with a compound of Formula XXX
(wherein Rj is -(CH2)0-1-CO-, -C(0)0-, -S0 - and R and X are as defined earlier), to give
a compound of Formula XXXI. The compound of Formula XXXI can then be hydrolyzed
to give a compound of Formula XXXII.
Coupling of a compound of Formula XVII with a compound of Formula VI (Path
C) to give a compound of Formula XXV can be carried out in the similar way as coupling
of a compound of Formula V with a compound of Formula VI to give a compound of
Formula VII.
Hydrolysis of a compound of Formula XXV to give a compound of Formula XXVI
can be carried out in a similar way as the hydrolysis of a compound of Formula VII to a
compound of Formula X.
The reduction of a compound of Formula XVII to give a compound of Formula
XXIV (Path D) can be carried out in the presence of one or more reducing agent, for
example, Palladium-carbon/hydrogen, Raney nickel/hydrogen, platinum/hydrogen or
mixture thereof in a solvent, for example, methanol, tetrahydrofuran, ethanol, propanol,
isopropanol, or mixtures thereof.
The coupling of a compound of Formula XXIV with a compound of Formula
XXVII to give a compound of Formula XXVIII (Path E) can be carried out with a base,
for example, triethylamine (TEA), N-methyl-morpholine (NMM), N,Ndimethylaminopyridine
(DMAP) or N,N -diisopropylethylamine (DIEA) in a solvent, for
example, tetrahydrofuran, dichloromethane, dimethylformamide, dioxane, acetonitrile or
acetone.
Hydrolysis of a compound of Formula XXVIII to give a compound of Formula
XXIX can be carried out in a similar way as the hydrolysis of a compound of Formula VII
to a compound of Formula X.
Coupling of a compound of Formula XXIV with a compound of Formula XXX
(Path F) to give a compound of Formula XXXI can be carried out in a similar way as the
coupling of a compound of Formula XXIV with a compound of Formula XXVII to give a
compound of Formula XXVIII.
Hydrolysis of a compound of Formula XXXI to give a compound of Formula
XXXII can be carried out in a similar way as the hydrolysis of compound of FormulaVII
to a compound of Formula X.
The compound of Formula XLI can also be prepared by following Scheme VI.
Scheme VI
Accordingly, the compound of Formula XXXIII can react through two pathways.
Path G: The compound of Formula XXXIII can undergo reduction to give a compound of
Formula XXXIV. The compound of Formula XXXIV can react with a compound of
Formula XXX to give a compound of Formula XXXV. The compound of Formula
XXXV reacts to give a compound of Formula XXXVI which undergoes reaction with a
compound of Formula IV to give a compound of Formula XXXVII.
Path H: The compound of Formula XXXIII reacts to give a compound of Formula
XXXVIII. The compound of Formula XXXVIII can react with a compound of Formula
IV to give a compound of Formula XXXIX. The compound of Formula XXXIX can
undergo reduction to give a compound of Formula XL. The compound of Formula XL
can couple with compound of Formula XXX to give a compound of Formula XXXVII.
The compound of Formula XXXVII can then undergo hydrolysis to give a
compound of Formula XLI.
The reduction of a compound of Formula XXXIII to give a compound of Formula
XXXIV (Path G) can be carried out in similar way as the reduction of a compound of
Formula XVII to a compound of Formula XXIV.
The coupling of a compound of Formula XXXIV with a compound of Formula
XXX to give a compound of Formula XXXV can be carried out in a similar way as the
coupling of compound of Formula XXIV with a compound of Formula XXVII to give a
compound of Formula XXVIII.
The reaction of a compound of Formula XXXV to give a compound of Formula
XXXVI can be carried out in a similar way as that of compound of Formula II to give a
compound of Formula III.
The reaction of a compound of Formula XXXVI with a compound of Formula IV
to give a compound of Formula XXXVII can be carried out in a similar way as the
reaction of a compound of Formula III with compound of Formula IV to give a compound
of Formula V.
The reaction of a compound of Formula XXXIII (Path H) to give a compound of
Formula XXXVIII can be carried out in a similar way as that of a compound of Formula II
to give a compound of Formula III.
The reaction of a compound of Formula XXXVIII with a compound of Formula IV
to give a compound of Formula XXXIX can be carried out in a similar way as the reaction
of a compound of Formula III with compound of Formula IV to give a compound of
Formula V.
The reduction of a compound of Formula XXXIX to give a compound of Formula
XL can be carried out in a similar way as the reduction of compound of Formula XVII to a
compound of Formula XXIV.
The coupling of a compound of Formula XL with a compound of Formula XXX to
give a compound of Formula XXXVII can be carried out in a similar way as the coupling
of a compound of Formula XXIV to give a compound of Formula XXVIII.
The hydrolysis of a compound of Formula XXXVII to give a compound of
Formula XLI can be carried out in a similar way as the hydrolysis of a compound of
Formula VII to give a compound of Formula X.
The compound of Formula XXXII can also be prepared by following Scheme VII.
Scheme VII
Accordingly, the compound of Formula XLI undergoes oxidation to give a
compound of Formula XXXII.
The oxidation of a compound of Formula XLI to give a compound of Formula
XXXII can be carried out in a similar way as the oxidation of a compound of Formula X
to give a compound of Formula XI.
The compound of Formula XLV can be prepared by following Scheme VIII.
Formula XLV
Accordingly, the compound of Formula XLII undergoes oxidation to give a
compound of Formula XLIII. The compound of Formula XLIII reacts with a compound
of Formula XVI to give a compound of Formula XLIV. The compound of Formula XLIV
undergoes hydrolysis to give a compound of Formula XLV.
Oxidation of a compound of Formula XLII to give a compound of Formula XLIII
can be carried out in the same way as the oxidation of a compound of Formula X to a
compound of Formula XL
Reaction of a compound of Formula XLIII with a compound of Formula XVI to
give a compound of Formula XLIV can be carried out in the same way as the reaction of a
compound of Formula XXII with a compound of Formula XVI to give a compound of
Formula XXIII.
Hydrolysis of a compound of Formula XLIV to give a compound of Formula XLV
can be carried out in the same way as the hydrolysis of a compound of Formula VII to
give a compound of Formula X.
The compound of Formula XLVIII can be synthesized be following Scheme IX.
Formula XLVIII
Accordingly, the compound of Formula XLIV undergoes deprotection to give a
compound of Formula XLVI. The compound of Formula XLVI can be benzylated to give
a compound of Formula XLVII. The compound of Formula XLVII can be hydrolyzed to
give a compound of Formula XLVIII.
The deprotection of a compound of Formula XLIV to give a compound of Formula
XLVI can be carried out in the presence of an acid, for example, boron trifluoride or
aluminium trichloride in a solvent, for example, diethylether, dichloromethane,
tetrahydrofuran, dioxane, chloroform, or mixtures thereof.
Alternatively, benzyl deprotection can be carried out (i) in hydrogenation
conditions, for example, H2/Pd-C in the presence of a solvent, for example,
tetrahydrofuran, ethyl acetate, methanol or mixtures thereof; or (ii) with transfer
hydrogenation, for example with ammonium formate/Pd-C in a solvent, for example,
methanol, ethanol, isopropanol or mixtures thereof; or (iii) with 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) in a solvent, for example, tetrahydrofuran.
Reaction of a compound of Formula XLVI to give a compound of Formula XLVII
can be carried out in the presence of a base, for example, potassium carbonate, sodium
hydrogen carbonate, cesium carbonate, sodium hydride, pyridine, sodium acetate, sodium
thiosulfate or diisopropyl ethylamine or triethylamine in a solvent, for example, N,Ndimethylformamide,
water, dioxane, dimethylsulphoxide, tetrahydrofuran or mixtures
thereof.
Hydrolysis of a compound of Formula XLVII to give a compound of Formula
XLVIII can be carried out in a similar way as the hydrolysis of a compound of Formula
VII to give a compound of Formula X.
In the above schemes, where specific reagents, for example, bases, acids, solvents,
condensing agents, hydrolyzing agents, catalysts, etc., as mentioned, it is to be understood
that other reagents, e.g., other acids, bases, solvents, condensing agents, reducing agents,
deprotecting agents, hydrolyzing agents, catalysts, etc., known to one of ordinary skill in
the art may be used. Similarly, reaction temperatures and durations may be adjusted
according to the desired needs without undue experimentation and well within the abilities
of one of ordinary skill in the art.
The compounds described herein may be administered to an animal for treatment
orally, topically, rectally, internasally, or by parenteral route. Pharmaceutical
compositions disclosed herein comprise pharmaceutically effective amounts of
compounds described herein formulated together with one or more pharmaceutically
acceptable carriers, excipients or diluents.
Solid form preparations for oral administration include capsules, tablets, pills,
powders, granules, lozenges, troches, cachets and suppositories. For solid form preparations,
active compounds can be mixed with one or more inert, pharmaceutically acceptable
excipients or carrier; tablets and capsules for oral administration may contain conventional
excipients such as binding agents and/or dissolution enhancers, for example, polyvinyl
pyrrolidine, cellulose, mucilage of starch, gelatin, sorbitol, syrup, acacia or tragacanth;
fillers or bulking agents, for example, microcrystalline cellulose, sugar, maize-starch,
calcium phosphate, sorbitol or lactose; lubricants, for example, talc, silica,
polyethyleneglycol, magnesium stearate or stearic acid; disintegrating agents and binder,
for example, croscarmellose sodium, pregelatinized starch, sodium starch gylcollate or
potato starch; glidants, for example, colloidal silicon dioxide or talc; antiadherants, for
example, magnesium stearate or sodium lauryl sulfate; and coating materials.
Capsules, tablets or pills may also comprise buffering agents.
Tablets, capsules, pills or granules can be prepared using one or more coatings or
shells to modulate the release of active ingredients, for example, enteric coatings or other
coatings known to one of ordinary skill in the art.
General Example
A formulation of a tablet could typically contain from 0.01 mg to 500 g of active
compound while tablet fill weight may range from 50 mg to 1000 mg. An example is
illustrated below.
Ingredients Amount % w/w
Active Compound 0.01 to 20 mg
Microcrystalline Cellulose about 50% to about 90%
Croscarmellose Sodium about 1% to about 10%
Pregelatinized Starch about 1% to about 15%
Polyvinyl Pyrrolidone (K-30) about 5% to about 12%
Talc about 0.1% to about 2%
Magnesium Stearate about 0.1% to about 2%
Colloidal Silicon Dioxide about 0.1% to about 2%
Liquid form preparations for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form
preparations, active compounds can be mixed with water or one or more non-toxic
solvents, solubilizing agents or emulsifiers, for example, water, ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,
1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn,
germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan or mixtures
thereof. Oral compositions can also include one or more adjuvants, for example, wetting
agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents,
perfuming agents, or mixtures thereof.
Injectable preparations, for example, sterile injections, and aqueous suspensions
may be formulated according to methods known to one of ordinary skill in the art, and in
particular, using one or more suitable dispersing or wetting and suspending agents.
Acceptable vehicles and solvents that may be employed include one or more of water,
Ringer's solution, isotonic sodium chloride, or mixtures thereof.
Suppositories for rectal administration of the compound of this invention can be
prepared by mixing the drug with suitable nonirritating excipients such as cocoa butter and
polyethylene glycols, which are solid at ordinary temperatures but liquid at body
temperature and which therefore melt in the rectum and release the drug.
Dosage forms for topical or transdermal administration of a compound of the
present invention include ointments, pastes, creams, lotions, gels, powders, solutions,
sprays, inhalants or patches. Active compounds can be admixed under sterile conditions
with one or more pharmaceutically acceptable carriers and optionally any preservatives or
buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders
and solutions are also encompassed within the scope of this invention.
Pharmaceutical preparations may be in unit dosage form. In unit dosage form, the
preparations can be subdivided into unit doses containing appropriate quantities of active
components. Unit dosage forms can be packaged preparations containing discrete
capsules, powders, in vials or ampules, ointments, capsules, sachets, tablets, gels, creams
or any combination and number of such packaged forms.
The following examples are set forth to demonstrate general synthetic procedures
for the preparation of representative compounds of the present invention. The examples
are provided to illustrate a particular aspect of the disclosure and do not limit the scope of
the present invention.
Experimental Procedures
Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc.,
were dried using various drying reagents according to procedure as described in the
literature.
Synthesis of starting materials
Example A: Synthesis of 3-[(4-bromophenvnsulfanyl1dihvdrofuran-2(3 H)-one
To a solution of -bromothiophenol (30.0 g, 0.157 mol) in dichloromethane (200
mL) under argon atmosphere at 0°C, triethyl amine (48.0 g, 0.476 mol) and then a solution
of bromolactone (27.4g, 0.1666 mol) in dichloromethane (200 mL) were added drop wise.
This reaction mixture was stirred for about 30 minutes. The reaction was worked up by
adding water and extracted in dichloromethane, dried the organic layer with sodium
sulphate and concentrated, purified by 60-120 silica gel column, compound eluted at 10%
ethyl acetate/hexane.
Yield: 16 g
Example B: Synthesis of 3-(4-bromophenoxy)dihvdrofuran-2(3 H)-one
To a solution of 4-bromophenol (5 g, 0.028 mol) in dry N,N-dimethylformamide
(50 mL), at 0°C, 60% sodium hydride ( 1.38 g, 0.05 mol) was added. This was stirred for
about 30 minutes at about 0°C. Afterwards, ά-bromobutyrolactone (7.19 g, 0.043 mol)
was added and the reaction mixture was stirred for about 2 hours at 0°C and subsequently
stirred at room temperature for about 1 hour. The reaction mixture was heated to about
100°C for ~4 hours. Finally, the reaction mixture was quenched with water and extracted
in ethyl acetate, the organic layer was washed with brine and water and dried over
anhydrous sodium sulphate; 15g of crude product was obtained which was purified in 100-
200 mesh size silica gel column chromatography by using 25% ethyl acetate-hexane as
eluent to get the desired product
Yield: 8 g
Mass: 256.69 (M-l)
Example C: Synthesis of 3-IY4-bromobenzyr)sulfanyl1dihvdrofuran-2(3 HVone
To a solution of 3-mercapto-dihydrofuran-2-one ( 1l.lg, 0.042 mol) in ethanol (127
mL) was added potassium carbonate ( 11.7 g, 0.084 mol). 4-Bromobenzylbromide ( 11.1
mL, 0.0423 mol) was added to this resulting solution drop wise through a period of about
ten minutes. This reaction mixture was stirred at room temperature for about 2 hours.
Ethanol was removed under reduced pressure and the compound was extracted in ethyl
acetate and water. This was purified using silica gel column chromatograph wherein pure
compound was obtained in 6% ethyl acetate and hexane.
Yield: 9.2g
Mass: 287.21 (M+l)
Example D: Synthesis of 3-[(4-bromobenzvDoxy1dihydrofuran-2n H)-one
Sodium hydride (1.4g, 0.058 g) was added to a solution of 2-hydroxybutyrolactone
(5 g, 0.049 mol) in dimethylformamide (50 mL) at about 0°C. The reaction
mixture was stirred at same temperature for about 15 minutes and 4-bromobenzylbromide
(12.2 g, 0.049 mol) was added to it. The reaction mixture was stirred at room temperature
overnight and quenched with water (50 mL), extracted with ethyl acetate. Combined
organic extract was washed with water and brine, dried (Na2S0 4) and concentrated to get
crude compound, which was purified on column using 20% ethyl acetate :hexane to obtain
the title compound.
Yield: 6.7 g
Example E: Synthesis of methyl ( \2-(4-nitrophenyl)ethyl1sulfanyl} acetate
Step 1: Synthesis of 2-(4-nitrophenyl)ethyl methanesulfonate
To a solution of 4-nitrophenyl ethanol (20 g, 0.1 9 mol) in dichloromethane,
triethylamine (50 mL, 0.358 mol) and methane sulfonyl chloride ( 11.1 1 mL, 0.143 mol)
were added at about 0°C. The reaction mixture was stirred at room temperature for about
2 hours. Subsequently, as workup, the reaction mixture was extracted in dichloromethane
and washed with water and saturated brine sulution. The solvent was evaporated to obtain
the title compound.
Yield: 15.6 g
Mass: 246.33 (M+l)
Step 2: Synthesis of methyl {[2-(4-nitrophenyl)ethyl]sulfanyl}acetate
In a solution of 2-(4-nitrophenyl)ethyl methanesulfonate (28 g, 0.1 14 mol) in
methanol (571 mL), methyl thioglycolate ( 11.2 mL) and potassium carbonate (31.5 g)
were added. This reaction mixture was stirred at room temperature for about 4 hours.
After completion of reaction, the solvent was evaporated under reduced pressure and the
crude reaction mixture was extracted in ethyl acetate and washed with water and brine.
The organic layer was dried over anhydrous sodium sulphate and concentrated. This was
purified using silica gel column chromatograph in 5% ethyl acetate-hexane to obtain the
title compound.
Yield: 30 g
Mass: 255.47 (M+l)
The following intermediate was prepared using the above synthetic procedure:
Methyl [(4-nitrobenzyl)sulfanyl]acetate
Example F: Synthesis of methyl {[4-(benzyloxy)benzyl1sulfanyl>acetate
Step 1: Synthesis of [4-(benzyloxy)phenyl]methanol
Potassium carbonate (40 g, 0.289 mol) and benzyl bromide (22.5 mL, 0.188 mol)
were added to a solution of 4-(2-hydroxyethyl)phenol (20 g, 0.144 mol) in N,Ndimethylformamide
(434 mL) at room temperature and this was stirred at ~25°C
conditions for about 20 hours. After completion of reaction, the reaction mixture was
extracted in ethyl acetate and washed with water and saturated brine solution. The crude
compound was purified on silica gel column chromatograph with 20% ethyl acetate in
hexane as elutent to give the title compound.
Yield: 24 g
Mass: 246.55 (M+18)
Step 2 : Synthesis of 4-(benzyloxy)benzyl methanesulfonate
The synthesis of the said compound was carried out following the same procedure
as stated in step 1 of Example E using [4-(benzyloxy)phenyl] methanol as starting material.
Yield: 32 g
Step 3: Synthesis of meth l{[4-(benzyloxy)benzyl]sulf ny1} acetate
The synthesis of the said compound was carried out following the similar
procedure as stated in step 2 of Example E using 4-(benzyloxy)benzyl methanesulfonate
as starting material.
Yield: 27 g
Example G: Synthesis of ethyl [(4-nitrophenyl)sulfanyl1acetate
To a solution of p-nitro thiophenol (5.0 g, 0.0322 mol) in dichloromethane (50
mL), triethyl amine (9.7 g, 0.0967 mol) was added under argon atmosphere at about 0°C
and then added a solution of ethyl bromo acetate (6.4 g, 0.0387 mol) drop wise. The
reaction mixture was stirred for about 5 hours. The resultant mixture was extracted in
dichloromethane, dried the organic layer with sodium sulphate and concentrated, purified
on silica gel column using 10% ethyl acetate/hexane as eluent to give the title compound.
Yield: 6.5g
Example H: Synthesis of ethyl IY4-bromobenzyl)sulfanyl1acetate
To a solution of ethyl-2-mercapto acetate ( 1 g, 0.0083 mol) in ethanol (125ml),
potassium carbonate (2.3 g, 0.016 mol) and 4-bromobenzyl bromide (2.63 g, 0.01 mol)
were added at about 0°C. The reaction was stirred at room temperature for about 2 hours.
Subsequently, ethanol was removed under reduced pressure and the compound was
extracted in ethyl acetate, washing with water. This was purified on silica gel column
chromatograph using 6% ethyl acetate/hexane as eluent to give the title compound.
Yield: 0.85 g
Mass: 287.3 (M-l)
The following intermediates were prepared by following the above synthetic
procedure:
Ethyl {[2-(4-bromophenyl)ethyl] sulfanyl }acetate
Mass: 325.40 (M+Na)
Ethyl[(4-bromophenyl)sulfanyl]acetate
Example I : Synthesis of 3-[(4-nitrophenvnsulfanyl1dihvdrofuran-2(3H)-one
To a solution of p-nitro thiophenol (10.0 g, 0.0645 mol) in dichloromethane (75
mL) under argon atmosphere at about 0°C, was added triethyl amine (19.4 g, 0.1935 mol)
and then added a solution of bromolactone ( 11.1 g, 0.067 mol) in dichloromethane (75
mL) drop wise. The reaction mixture was stirred for about 30 minutes. Subsequently, the
crude compound was obtained by adding water to the reaction mixture and extracting in
dichloromethane. The organic layer was dried with sodium sulphate and concentrated,
purified by silica gel column, using 30% ethyl acetate/hexane as eluent to obtain the title
compound.
Yield: 1 1 g
Synthetic procedure for Scheme I :
Example 1
Path A:
Synthesis of 2- (3'-fluoro-4'-methoxybiphenyl-4- sulfan l -4-(6-methoxy-4-oxo- 1,2.3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 171)
Step 1: Synthesis of methyl 2-[(4-bromophenyl)sulfanyl]-4-hydroxybutanoate
To a solution of 3-[(4-bromophenyl)sulfanyl]dihydrofuran-2(3H)-one (10.0 g,
0.0366 mol) in dimethylformamide (40 mL) and water (10 mL), sodium hydroxide (1.75
g, 0.0439 mol) was added and the reaction mixture was stirred for about 30 minutes. To
the resultant mixture, sodium bicarbonate (3.6 g, 0.043 mol), 18 crown 6 (0.96 g, 0.0036
mol) and methyl iodide (7.7 g, 0.054 mol) were added and stirred overnight. The reaction
mixture was extracted in ethyl acetate, the organic layer was dried with sodium sulphate
and concentrated, purified by silica gel column using 8% ethyl acetate/hexane as eluent to
obtain the title compound.
Yield: 8.0gm
Step 2 : Synthesis of methyl 2-[(4-bromophenyl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoate
To a solution of the methyl 2-[(4-bromophenyl)sulfanyl]-4-hydroxybutanoate (8 g,
0.0262 mol) in tetrahydrofuran (90 mL) under argon atmosphere, 7-methoxy-l,2,3-
benzotriazin-4(3H)-one (5.5 g, 0.031 mol) and triphenyl phosphine (10.3 g, 0.039 mol)
were added and cooled to about 0°C and then DIAD (7.9 g, 0.039 mol) was added. This
reaction mixture was stirred for about 30 minutes. The resultant reaction mixute was
extracted in ethyl acetate, dried with sodium sulphate and concentrated, purified by silica
gel column with 15% ethyl acetate/hexane to obtain the title product.
Yield: 2 g
LCMS: 465.97 (M+l)
Step 3 : Synthesis of methyl 2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(6-
methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoate
To a solution of methyl 2-[(4-bromophenyl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoate (0.5 g, 0.0010 mol) in dimethylformamide (10 mL) under
argon atmosphere, potassium carbonate (0.446 g, 0.00323 mol) and phenyl boronic acid
(0.366 g, 0.0021 mol) were added and the reaction mass was heated at about 100°C for
about 3 hours. The resultant mixture was extracted in ethyl acetate, dried the organic layer
with sodium sulphate and concentrated, purified by silica gel column with 15% ethyl
acetate/hexane to obtain the title product.
Yield: 0.3 g
LCMS: 510.11 (M+l)
Step 4: Synthesis of 2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)sulfany]]-4-(6-methoxy-4-
oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid
To a solution of methyl 2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(6-
methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoate (0.3 g, 0.0005 mol) in
tetrahydrofuran (5 mL) and methanol (5 mL), a solution of lithium hydroxide (0.037 g,
0.0008 mol) in water was added and the reaction mixture was stirred for about 1 hour. To
the resultant mixture, sodium bisulphite solution was added to acidify and then extracted
in ethyl acetate. The organic layer was dried with sodium sulphate and concentrated and
purified by preperative TLC with 10% methanol/dichloromethane to obtain the title
product.
Yield: 0.080 g
LCMS: 496.06 (M+l)
NMR (DMSO- , 400 MHz)-d 8.1 1 - 8.14 (lH, d, J = 12Hz), 7.46 - 7.60 (8H, d, J = 8 Hz),
7.23 - 7.25 (1H, d, J = 8 Hz), 4.52 (2H, m), 3.87 - 3.97 (6H, m), 3.3 (1H, s), 2.34 (1H, m),
2.18 (lH, m).
The following compounds were prepared by following the above synthetic route
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-[4-oxo-7-(trifluoromethyl)-
l,2,3-benzotriazin-3(4 H)-yl]butanoic acid (Compound no. 75)
Mass: 551.03(M+NH4+)
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(7-methyl-4-oxo- ,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 105)
Mass: 480.22
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl] -4-(6-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 106)
Mass: 482.13
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 107)
Mass: 466.20
2-[(3 -Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl] -4-(6-methyl-4-oxo- 1,2,3 -
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 108)
Mass: 480.22
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 109)
Mass: 465.75 (M+l)
4-(6-Methyl-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4'-(trifluoromethyl)biphenyl-
4-yl]sulfanyl}butanoic acid (Compound no. 110)
Mass: 500.22
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfany]]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. I l l )
Mass: 502.17 (M+2)
2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 112)
Mass: 476.28
2-[(3,,4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 113)
Mass: 468.22
2-[(3 ,-Fluoro-4*-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 114)
Mass: 464.25
2-[(4'-Florobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 115)
Mass: 450.20
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 116)
Mass: 460.22
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 117)
Mass: 462.23
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 118)
Mass: 464.25
4-(4-Oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4'-(trifluoromethyl)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 119)
Mass: 486.22
4-(8-Methyl-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4'-
(trifluoromethoxy)biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 120)
Mass: 516.19
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4'-
(trifluoromethoxy)biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 121)
Mass: 516.29 (M+l)
4-(6-Methoxy-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4'-
(trifluorometiioxy)biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 122)
Mass: 532.20
4-(7-Methoxy-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4 -
(trifluoromethoxy)biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 123)
Mass: 532.20
2-[(3',4 ,-Difluorobiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 124)
Mass: 484.17
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo- 1,2,3 -
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 125)
Mass: 480.25
2-[(4'-Fluoro-3 '-methylbiphenyl-4-yl)sulfanyl] -4-(6-methoxy-4-oxo- 1,2,3 -
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 126)
Mass: 480.16
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 127)
Mass: 518.14
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 128)
Mass: 496.20
2- {[4'-Chloro-3 '-(trifluoromethyl)biphenyl-4-yl] sulfanyl }-4-(6-methoxy-4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 129)
Mass: 550.12
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl] -4-(6-methoxy-4-oxo- 1,2,3 -benzotriazin-3 (4H)-
yl)butanoic acid (Compound no. 130)
Mass: 476.22
2-[(3',4'-Dimethylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 13 1)
Mass: 476.22
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(4'-methylbiphenyl-4-
yl)sulfanyl]butanoic acid (Compound no. 132)
Mass: 462.1 1
4-(6-Methoxy-4-oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethyl)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 133)
Mass: 515.99
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 134)
Mass: 460.30
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 135)
2-{[4-(6-Methoxypyridin-3 -yl)phenyl] sulfariyl} -4-(8-methyl-4-oxo- 1,2,3 -
benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 136)
Mass: 463.23
2-[(4'-Methylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)
yl)butanoic acid (Compound no. 137)
Mass: 446.28
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 138)
Mass: 466.25
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl]-4-(8-memyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 139)
Mass: 450.42
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 140)
Mass: 464.39
2-[(3',4 ,-Difluorobiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 141)
Mass: 468.38
2-[(3',4'-Dimethoxybiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 142)
Mass: 492.40
2-[(3 ',4'-Dimethylbiphenyl-4-yl)sulfanyl] -4-(8-methyl-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 143)
Mass: 460.55
4-(8-Methyl-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4'-(trifluoromethyl)biphenyl-
4-yl]sulfanyl}butanoic acid (Compound no. 144)
Mass: 499.39
2-[(3,-Fluoro-4 ,-methoxybiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 145)
Mass: 515-96 (M+K)
4-(5-Chloro-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- [(3'-fluoro-4'-methoxybiphenyl
4-yl)sulfanyl]butanoic acid (Compound no. 146)
Mass: 499.55 (M+l)
4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(3'-fluoro-4'-methoxybiphenyl-
4-yl)sulfanyl]butanoic acid (Compound no. 147)
Mass: 499.75 (M+l)
2-{[4-(6-Methoxypyridin-3 -yl)phenyl] sulfanyl }-4-(4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 148)
Mass: 449.20 (M+l)
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl]-4-(4-oxo- 1,2,3 -benzotriazin-3 (4H)-
yl)butanoic acid (Compound no. 149)
Mass: 448.25 (M+l)
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 150)
Mass: 450.27 (M+l)
2-[(3^4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 151)
Mass: 454.26 (M+l)
2-[(3'-Methoxybiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 152)
Mass: 448.31 (M+l)
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 153)
Mass: 436.29 (M+l)
2-(Biphenyl-4-yl)sulfanyl-4-(4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)butanoic acid
(Compound no. 154)
Mass: 418.26(M+l)
2-[(2',3 -Difluorobiphenyl-4-yl)sulfanyl] -4-(4-oxo- 1,2,3 -benzotriazin-3 (4H)-
yl)butanoic acid (Compound no. 155)
Mass: 454.26 (M+l)
2-[(4'-te r t-Butylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 166)
Mass: 474.26 (M+l)
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic
acid (Compound no. 167)
Mass: 446.23 (M+l)
4-(4-Oxo- 1,2,3-benzotriazin-3 (4H)-yl)-2- {[4'-(propan-2-yl)biphenyl-4-
yl] sulfanyl }butanoic acid (Compound no. 168)
Mass: 460.28 (M+l)
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethyl)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 169)
Mass: 486.15 (M+l)
4-(4-Oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- {[4'-(trifluoromethoxy)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 170)
Mass: 486.22 (M+l)
4-(7-Methoxy-4-oxo- 1,2,3 -benzotriazin-3(4H)-yl)-2- {[4-(6-methoxypyridin-3 -
yl)phenyl]sulfanyl}butanoic acid (Compound no. 172)
Mass: 479.18
4-(7-Methoxy-4-oxo- ,2,3-benzotriazin-3(4//)-yl)-2-{ [4'-(trifluoromethyl)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 173)
Mass: 516.28
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 174)
Mass: 478.31
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 175)
Mass: 480.34
4-(7-Methoxy-4-oxo- 1,2,3 -benzotriazin-3 (4H)-yl)-2- {[4-(1-methyl- 1H-pyrazol-4-
yl)phenyl]sulfanyl}butanoic acid (Compound no. 176)
Mass: 452.19
2-[(3',4'-Dimethoxybiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 177)
Mass: 508.36
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl] -4-(7-methoxy-4-oxo- 1,2,3 -benzotriazin-3 (4H)-
yl)butanoic acid (Compound no. 178)
Mass: 476.19
2-[(4 -Fluoro-3 '-methylbiphenyl-4-yl)sulfanyl] -4-(7-methoxy-4-oxo- 1,2,3 -
benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 179)
Mass: 480.31
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl] -4-(7-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 180)
Mass: 482.18
2-[(3 ',4'-Dichlorobiphenyl-4-yl)sulfanyl] -4-(7-methoxy-4-oxo- 1,2,3 -benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 181)
Mass: 516.06
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 2 11)
Mass: 436.26
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(6-fluoro-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 212)
Mass: 468.48 (M-l)
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(7-chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 213)
Mass: 470.21 & 472.16 (M+l) (Cl=35 or Cl=37)
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-[4-oxo-7-(trifluoromethyl)-l,2,3-benzotriazin-
3(4H)-yl]butanoic acid (Compound no. 214)
Mass: 504.29
2-[(4'-Chlorobiphenyl-4-yl)oxy] -4-(5-fluoro-4-oxo- 1,2,3-benzotriazin-3(4H)-
yl)butanoic acid (Compound no. 215)
Mass: 454.21
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(5 -chloro-4-oxo- 1,2,3-benzotriazin-3(4H
yl)butanoic acid (Compound no. 216)
Mass: 472.22
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 217)
Mass: 466.24
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(5-memyl-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 218)
Mass: 450 (M+l)
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6-fluoro-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 219)
Mass: 454.21
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(7-chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 220)
Mass: 472.16
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 221)
Mass: 466.31
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6,7-difluoro-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 222)
Mass: 470.41 (ES -ve)
2-[(4'-Chlorobiphenyl-4-yl)methoxy] -4-(7-chloro-4-oxo- 1,2,3 -benzotriazin-3 (4H)-
yl)butanoic acid (Compound no. 223)
Mass: 484.19
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 224)
Mass: 478.51 (ES -ve)
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(2,4-dioxo-2 H-l,3-benzoxazin-3(4 H)-
yl)butanoic acid (Compound no. 225)
Mass: 452.19
(27?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(l-oxophthalazin-2(l H)-yl)butano
(Compound no. 226)
Mass: 435.25
Path B:
Example 2 : Synthesis of 2-{[(4'-chlorobiphenyl-4-yl)methyl1sulfanyl>-4-(4-oxo-l,2,3-
benzotriazin-3 4H)-vDbutanoic acid (Compound no. 156)
Step 1: Synthesis of 3-{[(4'-chlorobiphenyl-4-yl)methyl]sulfanyl}dihydrofuran-2(3fl)-
one
To a solution of 3-[(4-bromobenzyl)sulfanyl]dihydrofuran-2(3 H)-one (1.5 g,
0.00522 mmol) in N,N-dimethylformamide (26 mL), potassium carbonate (2.16 g, 0.0156
mol) was added. To this mixture, 4-chlorobenzeneboronic acid (1.63 g, 1.0104 mol) and
tetrakis triphenylphosphine palladium (0) (0.6 g, 0.522 mmol) were added. The resulting
solution was heated at about 110°C for about 6 hours. Further, the reaction mixture was
cooled to room temperature by added water and extracted twice in ethyl acetate (40 mL).
The organic layer was separated and dried under sodium sulphate and concentrated in
reduced pressure. Purification of the crude compound was performed through 60-120
mesh size silica gel column chromatograph with 20% ethyl acetate-hexane to obtain the
title compound. (Yield: 2.1g)
Step 2 : Synthesis of (2-{[(4'-chlorobiphenyl-4-yl)methyI]sulfanyl}-4-hydroxy
butanoyl)sodium
To a solution of 3-{[(4'-chlorobiphenyl-4-yl)methyl]sulfanyl}dihydrofuran-2(3H)-
one (2 g, 0.00628 mol) in N, AP-dimethylformamide:water (15 mL:4 mL) was added
sodium hydroxide (0.327 g, 0.00817 mol) at 0°C. The reaction mixture was stirred at
room temperature for 2 hours. This reaction mixture was directly taken for next step
without any work up.
Step 3: Synthesis of 2-(4'-chloro-biphenyl-4-ylmethylsulfanyl)-4-hydroxy-butyric
acid allyl ester
To a solution of (2-{[(4'-chlorobiphenyl-4-yl)methyl]sulfanyl}-4-hydroxy
butanoyl)sodium (2 g, 0.00628 mol) in N, V-dimethylformamide:water (15 mL:4 mL)
was added sodium bicarbonate (634 mg, 0.00075 mol), 18-Crown-6 (0.166 g, 0.628
mmol) and allyl bromide (0.815 mL, 0.00943 mol) and stirred overnight at room
temperature. This was extracted in ethyl acetate and washed with water and taken directly
for next step without purification.
Yield: 1.2 g
MS - 375.41 (M-l)
Step 4: Synthesis of prop-2-en-l-yl-2-{[(4'-chlorobiphenyl-4-yl)methyl]sulfanyl}-4-
(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoate
To a solution of 2-(4'-chloro-biphenyl-4-ylmethylsulfanyl)-4-hydroxy-butyric acid
allyl ester (0.216 g, 0.574 mmol) in tetrahydrofuran (5 mL), triphenyl phosphine (0.301 g,
0.001 1 mol) and benzotriazinone ( 0.101 g, 0.689 mmol) were added at room temperature.
At ~0°C, diisopropyl azodicarboxylate (0.174 mL, 0.00088 mol) was added to it. This
reaction mixture was stirred at room temperature for about one hour. After completion,
the reaction mixture was concentrated under reduced pressure and was directly purified
through silica gel column chromatograph with 10% ethyl acetate in hexane to obtain the
title compound.

WE CLAIM:
1. A compound of Formula I
including racemates, enantiomers and diastereomers thereof, or a pharmaceutically acceptable salt
thereof; wherein,
V_y represents (un)substituted aryl or heteroaryl;
G~)
V_y represents Ce-Ciiaryl, Cs-Cucycloalkyl, C6-C12 heteroaryl or C6-Ci2heterocyclyl each
of which is optionally further substituted by one or more substituents independently selected
fromR';
U represents bond, -NH-, -C(=0)-, -(CH2)n-, -C(=S)-, -0-, -SO2- or -S- wherein n represents
zero or an integer between 1 and 2;
V represents bond, -NH-, -C(=0)-, -C(=S)- or -SO2.;
W represents bond, -NH-, -C(=0)-,(CH2)n-, -C(=S)-, -0-, -S- or -SO2.;
X' represents-0-, -S-, -SO- or -SO2-;
R represents H, alkyl or arylalkyl;
R* represent salkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl, halogeno-
Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfRq, -(CH2)n-
C(=0)NRfR^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(-0)-NR{Rq, (CH2)n NHC(=0)NRfR<,,, -
(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0)n,-NR,Rq {wherein Rf and Rq each
independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl,
alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined earlier and m is an integer 0-2};
0
^^—y represents mono-, bi- or polycyclic heteroaryl or heterocyclyl selected from the
following:
68
o
0 0 O
I O I H
-^ ..p6-^' s^ .a^
0
o o 0
I (R )v
wherein R ' is as defined earlier and v represents zero or an integer between 1-4.
2. A compound according to claim 1, having the structure of Formula la
r E j
Formula la
including racemates, enantiomers and diastereomers thereof, or a pharmaceutically acceptable salt
thereof wherein,
V / represents (un)substituted aryl or heteroaryl;
( ^
V_y represents C6-C12 aryl, C3-C12 cycloalkyl, C6-C12 heteroaryl or C6-C12 heterocyclyl each
of which is optionally further substituted by one or more substituents independently selected
fromR';
L' represents bond, -(CH2)n-, -NHC(=0)(CH2)n-, -(CH2)nC(=0)NH-,
NHC(=0)NH-, -SO2NH-, -NHSO2., -S02.,.NHC(=0)(0)-, -0-(CH2)n-, -(CH2)n-0-, -
69
9 (CH2)nOC(=0)NH-, -C(=S)NH-, -NHC(=S)- or -NHC(=S)NH- wherein n represent zero or an
integer between 1 and 2;
X' represents -0-, -S-, -SO- or -SO2-;
R represents H, alkyi or arylalkyl;
R' represents alkyl, aikenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce aikyl, halogeno-
C, -C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfR^, -(CH2)n-
C(=0)NR,R^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NR,R^, (CH2)n NHC(=0)NR,Rq,, -
(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0)n,-NRfR<, {wherein Rf and R<, each
independently represent hydrogen, alkyl, aikenyl, cycloalkyl aryl, heteroaryl, heterocyclyl,
alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined earlier and m is an integer 0-2};
G)
^^-^ represents mono-, hi- or polycyclic heteroaryl or heterocyclyl selected from the
following
( R ^ v ^ ^ \\ (R ) v ^ ^ "" O^ / ^ J_
O '
0 0 n
// II
I U H
:A s^ s^. X'•
o
o o o
(R )v ^^ ^O (R )v j ^ O^ \ 1 (R )v
I '-' (R )v
wherein R* is as defined earlier and v represents zero or an integer between 1-4.
3. A compound of Formula!, which is:
2- [(4- {[(4-Methylphenyl)carbonyl]amino} phenyl)sulfonyl] -4-(4-oxo-1,2,3 -benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 1),
70
9 2-[(3'-Methoxybiphenyl-4-yl)sulfony 1]-4-(4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 2),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 3),
2- {[2-(4'-Chlorobiphenyl-4-yl)ethyl] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-yl)butanoic
acid (Compound no. 4),
2- {[2-(4'-Chlorobiphenyl-4-yl)ethyl] sulfonyl} -4-(6-fluoro-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 5),
2- {[(4'-Chlorobiphenyl-4-yl)methyl] sulfonyl} -4-(7-methyl-4-oxo-1,2,3 -benzotriazin-3 (4/:/)-
yl)butanoic acid (Compound no. 6),
2- {[(4'-Chlorobiphenyl-4-yl)methyl] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-yl)butanoic
acid (Compound no. 7),
2- [(3 ',4'-Difluorobiphenyl-4-yl)sulfonyl] -4-(6-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 8),
2- {[(4'-Chlorobiphenyl-4-yl)methyl] sulfonyl} -4- [4-oxo-7-(trifluoromethyl)-1,2,3-benzotriazin-
3(4//)-yl]butanoic acid (Compound no. 9),
4-(6-Methyl-4-oxo-1,2,3-benzotriazin-3 (4//)-yl)-2- {[4'-(trifluoromethyl)biphenyl-4-
yl]sulfonyl}butanoic acid (Compound no. 10),
2-[(3 ',4'-Dichlorobiphenyl-4-yl)sulfonyl] -4-(6-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 11),
2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 12),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4/:/)-
yl)butanoic acid (Compound no. 13),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 14),
2-[(4'-Fluorobiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 15),
2-[(4'-Chlorobiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 16),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4/:/)-y0butanoic
acid (Compound no. 17),
2-[(4'-Methoxybiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 18),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4ii/)-
yl)butanoic acid (Compound no. 19),
2-{[4-(6-Methoxypyridin-3-yl)benzyl]sulfonyl}-4-(4-oxo-1,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 20),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-({[4'-(trifluoromethoxy)biphenyl-4-yl]
methyl }sulfonyl)butanoic acid (Compound no. 21),
2-{[(3',4'-Dimethoxybiphenyl-4-yl)methyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 22),
2- {[(3 '-Fluoro-4'-methylbiphenyl-4-yl)methyl] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 23),
71
0 2- {[(3 ',4'-Dimethylbiphenyl-4-y l)methyl] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 24),
2-{[(3',4'-Dichlorobiphenyl-4-yl)methyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 25),
2-{[(4'-Fluoro-3'-methylbiphenyl-4-yl)methyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4/f)-
yl)butanoic acid (Compound no. 26),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-({[4'-(trifluoromethyl)biphenyl-4-
yl]methyl}sulfonyl)butanoic acid (Compound no. 27),
2- {[(4'-Methoxybiphenyl-4-yl)methyi] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 28),
2- {[(4'-Fluorobiphenyl-4-yl)methy 1] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-yl)butanoic
acid (Compound no. 29),
2-( {2- [4-(6-Methoxypyridin-3 -yl)phenyl] ethyl} sulfonyl)-4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 30),
2- {[2-(3 '-Fluoro-4'-methylbiphenyl-4-yl)ethyl] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 31),
2- {[2-(4'-Ethylbiphenyl-4-yl)ethyl] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4^-yl)butanoic
acid (Compound no. 32),
2-{[2-(3',4'-Difluorobiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 33),
2-{[2-(4'-Cyanobiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 34),
2- {[2-(3 '-Fluoro-4'-methoxybiphenyl-4-yl)ethyl] sulfonyl} -4-(4-oxo-1,2,3 -benzotriazin-3 {4H)-
yl)butanoic acid (Compound no. 35),
2-({2-[4-(l-Methyl-l//-pyrazol-4-yl)phenyl]ethyl}sulfonyl)-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 36),
2-{[2-(4'-Methylbiphenyl-4-yl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-benzotriazin-3(4/0-yl)butanoic
acid (Compound no. 37),
4-(4-Oxo-1,2,3 -benzotriazin-3 (4i7)-yl)-2-( (2- [4'-(trifluoromethoxy)biphenyl-4-
yl]ethyl}sulfonyl)butanoic acid (Compound no. 38),
4-(7-Methyl-4-oxo-1,2,3 -benzotriazin-3 {4H)-y\)-2- {[4'-(trifluoromethoxy)biphenyl
-4-yl]sulfonyl}butanoic acid (Compound no. 39),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethoxy)
biphenyl-4-yl] sulfonyl }butanoic acid (Compound no. 40),
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethoxy)
biphenyl-4-yl]sulfonyl}butanoic acid (Compound no. 41),
2-[(4'-/ert-Butylbiphenyl-4-yl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-3(4/f)-yl)butanoic acid
(Compound no. 42),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 43),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(propan-2-yl)biphenyl-4-yl]sulfonyl}butanoic
acid (Compound no. 44),
4-(4-Oxo-l ,2,3-benzotriazin-3 (4//)-yl)-2- {[4'-(trifluoromethoxy)biphenyl-4-yl]
sulfonyl jbutanoic acid (Compound no. 45),
72
9 4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-({4-[(phenylcarbonyl)amino]
phenyl}sulfonyl)butanoic acid (Compound no. 46),
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 47),
4-(7-Methoxy-4-oxo-1,2,3-benzotriazin-3(4//)-yl)-2- {[4'-(trifluoromethyl)
biphenyl-4-yl]sulfonyl}butanoic acid (Compound no. 48),
2-[(4'-Methoxybiphenyl-4-yl)sulfonyi]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 49),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 50),
2-[(3',4'-Dimethoxybiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 51),
2-[(4-{[(3-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 52),
2- [(4- {[(3 -Fluorophenyl)carbonyl]amino} phenyl)sulfonyl] -4-(4-oxo-1,2,3 -benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 53),
2-[(4-{[(4-Fluorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 54),
2- [(4- {[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfonyl]-4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 55),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 56),
2-[(4'-Chlorobiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 57),
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 58),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfonyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-
3(4/:/)-yl)butanoic acid (Compound no. 59),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 60),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 61),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4/;/)-
yl)butanoic acid (Compound no. 62),
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 63),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4/f)-yl)butanoic acid (Compound no. 64),
2- {[4'-Chloro-3 '-(trifluoromethyl)biphenyl-4-yl] sulfonyl} -4-(6-methoxy-4-oxo-1,2,3 -
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 65),
2-[(4'-Ethylbiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 66),
2- [(3 ',4'-Dimethylbiphenyl-4-yl)sulfonyl] -4-(6-methoxy-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 67),
73
9 4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(4'-methylbiphenyl-4-yl)
sulfonyljbutanoic acid (Compound no. 68),
2- [(4'-Chlorobiphenyl-4-yl)sulfonyl] -4-(6-methoxy-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 69),
4-(6-Methoxy-4-oxo-1,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethyl)
biphenyl-4-yl]sulfonyl}butanoic acid (Compound no. 70),
«
2-[(4'-Methoxybiphenyl-4-yl)sulfonyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 71),
4-(4-Oxo-l,2,3-benzotriazin-3(4/f)-yl)-2-({2-[4-({[4-(trifluoromethyl)
phenyl]carbonyl}amino)phenyl]ethyl}sulfonyl)butanoic acid (Compound no. 72),
4-(4-Oxo-1,2,3-benzotriazin-3 (4H)-yl)-2-( {2- [4-( {[4-(trifluoromethoxy)phenyl]
carbonyl}amino)phenyl]ethyl}sulfonyl)butanoic acid (Compound no. 73),
2- [(4- {[(3,4-Dichlorophenyl)carbonyl]amino} phenyl)sulfonyl] -4-(4-oxo-1,2,3 -benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 74),
2-[(3'-Fiuoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-[4-oxo-7-(trifluoromethyl)-l,2,3-
benzotriazin-3(4//)-yl]butanoic acid (Compound no. 75),
4-(4-Oxo-l,2,3-benzotriazin-3(4/:/)-yl)-2-[(2-{4-[(phenylcarbonyl)amino]
phenyl}ethyl)sulfonyl]butanoic acid (Compound no. 76),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(2-{4-[(thiophen-2-ylcarbonyl)amino]
phenyl }ethyl)sulfonyl]butanoic acid (Compound no. 77),
2-[(2-{4-[(Cyclopentylcarbonyl)amino]phenyl}ethyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 78),
2-[(2-{4-[(CyclopropyIcarbonyl)amino]phenyl}ethyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 79),
2-{[2-(4-{[(3-Methoxyphenyl)carbonyl]amino}phenyl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 80),
2- {[2-(4- {[(3 -Chlorophenyl)carbonyl] amino} phenyl)ethyl] sulfonyl} -4-(4-oxo-1,2,3 -
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 81),
2-{[2-(4-{[(3-Fluorophenyl)carbonyl]amino}phenyl)ethyl]sulfonyl}-4-(4-oxo-l,2,3-
benzotriazin-3(4/f)-yl)butanoic acid (Compound no. 82),
2- {[2-(4- {[(4-Ethylphenyl)carbonyl] amino} phenyl )ethyl] sulfonyl} -4-(4-oxo-1,2,3 -
benzotriazin-3(4/r)-yl)butanoic acid (Compound no. 83),
2- {[2-(4- {[(4-Methoxyphenyl)sulfonyl]amino} phenyl)ethyl] sulfonyl} -4-(4-oxo-1,2,3 -
benzotriazin-3(4/f)-yl)butanoic acid (Compound no. 84),
2-[(4-{[(3-Ethoxyphenyl)carbamoyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 85),
2-{[4-({[2-Fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]sulfonyl}-4-(4-oxol,
2,3-benzotriazin-3(4//)-yl)butanoic acid (Compound no. 86),
2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 87),
2-[(4-{[(4-Fluorophenyl)carbamoyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 88),
2-[(4'-Fluorobiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 89),
74
% 2-[(3'-Ffluoro-4'-methylbiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-
yl)butanoic acid (Compound no. 90),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 91),
2-( {2- [4-(Benzyloxy)phenyl]ethyl} sulfonyl)-4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-yi)butanoic
acid (Compound no. 92),
2- [(3 ',4'-Dimethylbiphenyl-4-yl)sulfonyl] -4-(8-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 93),
2-[(4-{[(3-Methylphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 94),
2-[(4-{[(2-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-
3(4/f)-yl)butanoic acid (Compound no. 95),
2-[(4'-Ethylbiphenyl-4-yi)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yi)butanoic
acid (Compound no. 96),
2-[(4'-Methylbiphenyl-4-yl)sulfonyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 97),
2- {[4-(6-Methoxypyridin-3 -yl)phenyl] suifonyl} -4-(8-methyl-4-oxo-1,2,3 -benzotriazin-3 (4H)-
yl)butanoic acid (Compound no. 98),
2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfonyl)-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 99),
2-[(4- {[(2-Methylphenyl)carbonyl]amino }phenyl)sulfonyl]-4-(4-oxo-1,2,3-benzotriazin-
3(4//)-yI)butanoic acid (Compound no. 100),
2-( {4- [(Cyclopropylcarbonyl)amino]phenyl} sulfonyl)-4-(4-oxo-1,2,3 -benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 101),
4-(4-Oxo-l,2,3-benzotriazin-3(4/f)-yl)-2-({4-[(thiophen-2-ylcarbonyl)
amino]phenyl}sulfonyl)butanoic acid (Compound no. 102),
2-({4-[(Cyclopentylcarbonyl)amino]phenyl}sulfonyl)-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 103),
2- {[4-( {[4-Fluoro-3-(trifluoromethyl)phenyl]carbonyl} amino)phenyl] suifonyl} -4-(4-oxol,
2,3-benzotriazin-3(4//)-yl)butanoic acid (Compound no. 104),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(7-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 105),
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 106),
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 107),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 108),
2- [(3 '-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl] -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 109),
4-(6-Methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethyl)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 110),
2-[(3 ',4'-Dichlorobiphenyl-4-yl)sulfanyl] -4-(6-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. I l l ),
^ 75
9 2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriaziii-3(4//)-
yl)butanoic acid (Compound no. 112),
2- [(3 ',4'-Difluorobiphenyl-4-yl)sulfanyl] -4-(6-methy 1-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 113),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-
yi)butanoic acid (Compound no. 114),
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 115),
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 116),
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 117),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 118),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethyl)biphenyl-4-yI]sulfanyl}butanoic
acid (Compound no. 119),
4-(8-Methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethoxy)biphenyl-4-yl]
sulfanyl}butanoic acid (Compound no. 120),
4-(7-Methyl-4-oxo-1,2,3-benzotriazin-3(4//)-yl)-2- {[4'-(trifluoromethoxy)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 121),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethoxy)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 122),
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethoxy)biphenyl-4-
yl]sulfanyl}butanoic acid (Compound no. 123),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 124),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 125),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 126),
2- [(3 ',4'-Dichlorobiphenyl-4-yl)sulfanyl] -4-(6-methoxy-4-oxo-1,2,3-benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 127),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-
3(4/f)-yl)butanoic acid (Compound no. 128),
2- {[4'-chloro-3 '-(trifluoromethyl)biphenyl-4-yl] sulfanyl} -4-(6-methoxy-4-oxo-1,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 129),
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 130),
2-[(3 ',4'-Dimethylbiphenyl-4-yl)sulfanyl] -4-(6-methoxy-4-oxo-1,2,3 -benzotriazin-3 (4/f)-
yl)butanoic acid (Compound no. 131),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(4'-methylbiphenyl-4-yl)
sulfanyljbutanoic acid (Compound no. 132),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4/f)-yl)-2-{[4'-(trifluoromethyi)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 133),
V 2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 134),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 135),
2-{[4-(6-Methoxypyridin-3-yl)phenyl]sulfanyl}-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 136),
2- [(4'-Methylbiphenyl-4-yl)sulfanyl] -4-(8-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-yl)butanoic
acid (Compound no. 137),
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 138),
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-yl)butanoic
acid (Compound no. 139),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yI)butanoic acid (Compound no. 140),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 141),
2- [(3 ',4'-Dimethoxybiphenyl-4-yl)sulfanyl] -4-(8-methyl-4-oxo-1,2,3 -benzotriazin-3 (4/f)-
yl)butanoic acid (Compound no. 142),
2- [(3 ',4'-Dimethylbiphenyl-4-yl)sulfanyl] -4-(8-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 143),
4-(8-Methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-yl)-2- {[4'-(trifluoromethyl)biphenyl-4-
yl]sulfanyI}butanoic acid (Compound no. 144),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-
yl)butanoic acid (Compound no. 145),
4-(5-Chloro-4-oxo-l,2,3-benzotriazin-3(4/f)-yl)-2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)
sulfanyl]butanoic acid (Compound no. 146),
4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(3'-fluoro-4'-methoxybiphenyl-4-
yl)sulfanyl]butanoic acid (Compound no. 147),
2- {[4-(6-Methoxypyridin-3 -yl)phenyl] sulfanyl} -4-(4-oxo-1,2,3 -benzotriazin-3 (4/f)-
yl)butanoic acid (Compound no. 148),
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl]-4-(4-oxo-1,2,3-benzotriazin-3(4/f)-yl)butanoic acid
(Compound no. 149),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 150),
2-[(3',4'-Difluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoicacid
(Compound no. 151),
2-[(3'-Methoxybiphenyl-4-yl)sulfanyl]-4-(4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 152),
2-[(4'-Fluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo-1,2,3-benzotriazin-3(4/f)-yl)butanoic acid
(Compound no. 153),
2-(Biphenyl-4-ylsulfanyl)-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic acid (Compound no.
154),
2-[(2',3'-Difluorobiphenyl-4-yl)sulfanyl]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoicacid
(Compound no. 155),
W 2-{[(4'-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 156),
2-{[(4'-Chlorobiphenyl-4-yl)niethyl]sulfanyl}-4-(7-methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-
yl)butanoic acid (Compound no. 157),
2-{[(4'-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 158),
2- {[(4'-Chlorobiphenyl-4-yl)methyl] sulfanyl} -4-(6-fluoro-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 159),
2-{[(4'-Chlorobiphenyl-4-yl)methyl]sulfanyl}-4-(8-methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-
yl)butanoic acid (Compound no. 160),
2- {[(4'-Chlorobiphenyl-4-yl)methyl] sulfanyl} -4-[4-oxo-7-(trifluoromethyl)-1,2,3 -benzotriazin-
3(4//)-yl]butanoic acid (Compound no. 161),
2- {[(4'-Chlorobiphenyl-4-yl)methyl] sulfanyl} -4-(5 -chloro-4-oxo-1,2,3-benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 162),
2- {[2-(4'-Chlorobiphenyl-4-yl)ethyl] sulfanyl} -4-(7-chloro-4-oxo-1,2,3 -benzotriazin-3 {4H)-
yl)butanoic acid (Compound no. 163),
2-{[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfanyl}-4-(7-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 164),
2- {[2-(4'-Chlorobiphenyl-4-yl)ethyl] sulfanyl} -4-(8-methyl-4-oxo-1,2,3-benzotriazin-3 (4/f)-
yl)butanoic acid (Compound no. 165),
2-[(4'-/er/-Butylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 166),
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 167),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(propan-2-yl)biphenyl-4-yl]sulfanyl}butanoic
acid (Compound no. 168),
4-(4-Oxo-1,2,3 -benzotriazin-3 (4//)-yl)-2- {[4'-(trifluoromethyl)biphenyl-4-yl] sulfanyl} butanoic
acid (Compound no. 169),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4'-(trifluoromethoxy)biphenyl-4-yl]
sulfanyl}butanoic acid (Compound no. 170),
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-
3(4i/)-yl)butanoic acid (Compound no. 171),
4-(7-Methoxy-4-oxo-1,2,3-benzotriazin-3 (4H)-yl)-2- {[4-(6-methoxypyridin-3 -yl)
phenyl] sulfanyl}butanoic acid (Compound no. 172),
4-(7-Methoxy-4-oxo-1,2,3-benzotriazin-3(4//)-yl)-2- {[4'-(trifluoromethyl)
biphenyl-4-yl]sulfanyl}butanoic acid (Compound no. 173),
2-[(4'-Methoxybiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 174),
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 175),
4-(7-Methoxy-4-oxo-1,2,3 -benzotriazin-3 (4//)-yl)-2- {[4-( 1 -methyl-1 //-pyrazol-4-
yl)phenyl]sulfanyl}butanoic acid (Compound no. 176),
2-[(3',4'-Dimethoxybiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 177),
•
78
2-[(4'-Ethylbiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 178),
2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 179),
2-[(4'-Chlorobiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 180),
2-[(3',4'-Dichlorobiphenyl-4-yl)sulfanyl]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 181),
2- [(4- {[(4-Chlorophenyl)carbonyl]amino} phenyl)sulfanyl] -4-(4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 182),
2-[(4-{[(3-Methoxyphenyl)acetyl]amino}phenyl)sulfonyl]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 183),
2-[(4-{[(2,5-Dimethoxyphenyl)acetyl]amino}phenyl)sulfonyI]-4-(4-oxo-l,2,3-benzotriazin-
3(4/f)-yl)butanoic acid (Compound no. 184),
4-(4-Oxo-l,2,3-benzotriazin-3(4//)-yl)-2-({4-(phenylacetyl)amino]
phenyl}sulfonyl)butanoic acid (Compound no. 185),
2-(4-Fluorobenzyl)-2-[(2-{4-[(4-fluorobenzyl)oxy]phenyl}ethyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 186),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4/f)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 187),
4-(8-Methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 188),
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 189),
4-(8-Methyl-4-oxo-l,2,3-benzotriazin-3(4/f)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 190),
2-(3-Fluorobenzyl)-2- [(2- {4- [(3 -fluorobenzyl)oxy]phenyl} ethyl)sulfonyl] -4-(4-oxo-1,2,3 -
benzotriazin-3(4/f)-yl)butanoic acid (Compound no. 191),
4-(6-Methyl-4-oxo-1,2,3 -benzotriazin-3 (4/f)-yl)-2- [(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 192),
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4/7)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 193),
4-(6-Fluoro-4-oxo-l,2,3-benzotriazin-3(4i7)-yl)-2-[(4-{ [(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 194),
2-{[2-(4'-ChIorobiphenyl-4-yl)ethyl]sulfanyl}-4-(6-fluoro-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 195),
2- {[2-(4'-Chlorobiphenyl-4-yl)ethyl] sulfanyl} -4-(6-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 196),
2- {[2-(4'-Chlorobiphenyl-4-yl)ethyl] sulfonyl} -4-(7-methyl-4-oxo-1,2,3 -benzotriazin-3 (4//)-
yl)butanoic acid (Compound no. 197),
2-(2-Chlorobenzyl)-2-[(2-{4-[(2-chlorobenzyl)oxy]phenyl}ethyl)sulfonyl]-4-(4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 198),
2- {[2-(4'-Chlorobiphenyl-4-yl)ethyl]sulfonyl} -4-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 199),
•
79
4-(6-Methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 200),
4-(7-Methyl-4-oxo-1,2,3-benzotriazin-3(4//)-yl)-2-[(4-{ [(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 201),
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 202),
2-[(4-{[(4-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4/f)-yl)butanoic acid (Compound no. 203),
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 204),
2-[(4-{[(4-Ethylphenyl)carbonyl]amino}phenyl)sulfanyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 205),
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4//)-yi)butanoic acid (Compound no. 206),
2- [(4- {[(3,4-Dichlorophenyl)carbonyl]amino} phenyl)sulfonyl] -4-(6-methyl-4-oxo-1,2,3 -
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 207),
2-[(4-{[(4-Ethylphenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 208),
2-[(4-{[(4-Fluorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 209),
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-(6-methyl-4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 210),
2-[(4'-Cchlorobiphenyl-4-yl)oxy]-4-(4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 211),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(6-fluoro-4-oxo-l,2,3-benzotriazin-3(4i/)-yl)butanoic
acid (Compound no. 212),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 213),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-[4-oxo-7-(trifluoromethyl)-l,2,3-benzotriazin-3(4//)-
yljbutanoic acid (Compound no. 214),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 215),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 216),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 217),
2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4/f)-yl)butanoic acid
(Compound no. 218),
(2i?)-2-[(4'-chlorobiphenyl-4-yl)oxy]-4-(6-fluoro-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 219),
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(7-chloro-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 220),
(2i?)-2- [(4'-Chlorobiphenyl-4-yl)oxy] -4-(6-methoxy-4-oxo-1,2,3 -benzotriazin-3 (4/^-
yl)butanoic acid (Compound no. 221),
^ 80
™ (2/?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 222),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(7-chloro-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 223),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(7-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 224),
(2i?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-(2,4-dioxo-2//-l,3-benzoxazin-3(4//)-yl)butanoicacid
(Compound no. 225),
(2/?)-2-[(4'-Chlorobiphenyl-4-yl)oxy]-4-( 1 -oxophthalazin-2( 1 //)-yl)butanoic acid (Compound
no. 226),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 227),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-( 1 -oxophthalazin-2( 1 //)-yl)butanoic acid (Compound
no. 228),
2-[(4'-Chlorobiphenyl-4-yl)methoxy]-4-(2,4-dioxo-2//-l,3-benzoxazin-3(4//)-yl)butanoicacid
(Compound no. 229).
including racemates, enantiomers and diastereomers thereof, or a pharmaceutically acceptable salt.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound
according to any one of claims 1 to 3, together with a pharmaceutically acceptable carrier, excipient or
diluents.
5. A compound according to any one of claims 1 to 3, for use in the treatment or prophylaxis of
an animal or a human suffering from an inflammatory or allergic disease.
6. A compound according to claim 5, wherein the inflammatory disease or allergic disease is
asthma, rheumatoid arthritis, COPD, dry eye, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis,
pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis,
multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal proliferation associated with
restenosis and ischemic heart failure, stroke, renal disease or tumor metastasis.
7. A pharmaceutical composition according to claim 4, further comprising one or more additional
active ingredients selected from:
a) Anti-inflammatory agents selected from (i) nonsteroidal anti-inflammatory agents
piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4/p38
MAP Kinase/Cathepsin inhibitors, CCR-3 antagonists, iNOS inhibitors, tryptase and
elastase inhibitors, beta-2 integrin antagonists, cell adhesion inhibitors (especially
ICAM), adenosine 2a agonists; (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5-
lipoxygenase inhibitors and PAF-receptor antagonists; (iii) Cox-2 inhibitors; (iv) other
MMP inhibitors; (v) interleukin-I inhibitors; and (vi) corticosteroids, such as
alclometasone, amcinonide, amelometasone, beclometasone, betamethasone, budesonide,
ciclesonide, clobetasol, cloticasone, cyclomethasone, deflazacort, deprodone.
81
9 dexbudesonide, diflorasone, difluprednate, fluticasone, flunisolide, halometasone,
haloperedone, hydrocortisone, methylprednisolone, mometasone, prednicarbate,
prednisolone, rimexolone, tixocortol, triamcinolone, ulobetasol, rofleponide, GW
215864, KSR 592, ST-126, dexamethasone and pharmaceutically acceptable salts,
solvates thereof. Preferred corticosteroids include, for example, flunisolide,
beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and
dexamethasone;
b) beta-agonists, selected from one or more p2-agonists - albuterol, salbutamol, biltolterol,
pirbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol,
fenoterol, salmeterol, carmoterol, arformoterol, formoterol, and their pharmaceutically
acceptable salts, or solvates thereof;
c) antihypertensive agents, selected from (i) the ACE inhibitors, enalapril, lisinopril,
valsartan, telmisartan and quinapril; (ii) angiotensin II receptor antagonists and agonists,
e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan; (iii) (3-blockers; and (iv)
calcium channel blockers;
d) immunosuppressive agents, selected from cyclosporine, azathioprine and methotrexate,
anti-inflammatory corticosteroids; and
e) anti-infective agents.
8. A process for preparing a compound of Formula X [Formula I when R is H, X' is G (O and S)
U-V-W - is a bond and A is phenyl]
O ^ O H
Formula X
comprising:
a) converting a compound of Formula II
\ = / o
^ 82
W Formula II
to give a compound of Formula III;
O RV—
O
OH
Formula III
b) reacting a compound of Formula III with a compound of Formula IV to give a compound
of Formula V;
Formula IV Formula V
coupling a compound of Formula V with a compound of Formula VI to give a compound
of Formula VII
O R„
^ / "
V—O
Formula VI Formula VII;
c) deprotecting a compound of Formula VII to give a compound of Formula X;
or
d) coupling a compound of Formula II with a compound of Formula VI
^ ^ O ^-^Rk)z
Formula II Formula VI
83
W to give a compound of Formula VIII;
Formula VIII
e) converting a compound of Formula VIII to give a compound of Formula IX;
Formula IX
f) reacting a compound of Formula IX with a compound of Formula IV to give a compound
of Formula VII;
/—°
H—N E (
Formula IV Formula VII
g) deprotecting a compound of Formula VII to give a compound of Formula X
wherein,
G is O or S;
Rp is a carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl and silyl;
v_y represents mono-, bi- or polycyclic heteroaryl or heterocyclyl selected from the
following
84
w ° ^ 0
(R^v^^ \\ (R ) v ^ ^ " O^ / \ J_
O '
,9 o o
I U I H
!J^ .9^' S^ .^
o
„i^<>kA, ,,'A^£ A< A-^^'
I (R )v
^-^-V represents Ce-Cn aryl, C3-C12 cycloalkyl, C6-C12heteroaryl or C6-C12 heterocyclyl,
each of which is optionally further substituted by one or more substituents independently
selected from R ' ;
R' represents alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl,
halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfR<„
-(CH2)„-C(=0)NR^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NR,Rq, (CH2)n
NHC(=0)NRfRq,, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0)m-NR,R<,
{whereinRf and Rq each independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl,
heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl};
n is zero or an integer between 1 and 2;
m is an integer from 0-2;
z is an integer from 0-2; and
Rk is H, halo, alkyl, alkoxy, cyano, halogeno-Ci-Cs alkyl, halogeno-Ci-Ce alkoxy.
9. A process for preparing a compound of Formula XI [Formula I wherein R is H, X' is SO2, UV-
W - is a bond and A is phenyl]
^ 85
o = s = o
('-""^^^V'^ 0-2
JL B I
Formula XI
comprising:
a) oxidizing a compound of Formula X (when G is S)
O OH
Formula X
to give a compound of Formula XI;
wherein,
v_^ represents C6-Ci2aryl, Cs-Cncycloalkyl, Ce-Ciiheteroaryl or Ce-Ciiheterocyclyl,
each of which is optionally further substituted by one or more substituents independently
selected from R ' ;
R' represents alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl,
halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfRq,
-(CH2)„-C(-0)NRfR<„ -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NRfR<„ (CH2)n
NHC(=0)NRiR<,,, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0)n,-NRfR<,
{wherein Rf and Rq each independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl,
heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl};
n is zero or an integer between 1 and 2;
m is an integer 0-2;
_ 86
• (^
V ^ represents mono, bi or polycyclic heteroaryl or heterocyclyl selected from the
following
- " " (R )v " O^ * '
(R ) v ^ ^ ^ (R)v^^ " 0^ / \ J„
0 '
I O H
•5^ .p6->- ...e6t. ...ec^*-
0
o o 0
I (R )v
z is an integer 0-2; and
Rk is H, halo, alkyl, alkoxy, cyano, halogeno-Ci-Ce alkyl, halogeno-Ci-Ce alkoxy.
10. A process for preparing a compound of Formula XXVI [Formula I wherein R is H, X' is SO2,
U-V-W - is a bond and A is phenyl]
O./P II
Formula XXVI
comprising:
a) oxidizing a compound of Formula XIV (Rm is Br or NO2) to give a compound of Formula
XV;
87
W Formula XIV Formula XV
b) reacting a compound of Formula XV with a compound of Formula XVI to give a
compound of Formula XVII;
Formula XVI Formula XVII
c) coupling a compound of Formula XVII (wherein Rm is Br) with a compound of Formula
VI to give a compound of Formula XXV;
O O
Formula VI Formula XXV
d) hydrolyzing a compound of Formula XXV to give a compound of Formula XXVI;
wherein,
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl and silyl;
X is a leaving group such as halogen, mesylate, triflate;
v_y represents Ce-Ciiaryl, Cs-Ciicycloalkyl, Ce-C^heteroaryl or C6-Ci2heterocyclyl,
each of which is optionally further substituted by one or more substituents independently
selected from R' '
R' represents salkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl,
halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfR<„
-(CH2)n-C(=0)NR^, -(CH2)n-NHC(=0)-Rf, -(CH2)„-0-C(=0)-NRfR^, (CH2)n
NHC(=0)NRfRq,, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=OV-NRfRq
{whereinRf and Rq each independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl,
heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl};
n is zero or an integer between 1 and 2;
88 • n
^—y represents mono-, bi- or polycyclic heteroaryl or heterocyclyl selected from the
following:
(R )v W (R )v ° / -viw-
0 '
0 0 o
// II
-'A s^ y^ .-0^"'
o
I (R )v
m is an integer 0-2;
z is an integer 0-2; and
Rk is H, halo, alkyl, alkoxy, cyano, halogeno-Ci-Ce alkyl, halogeno-Ci-Ce alkoxy.
11. A process for preparing a compound of Formula XXIX [Formula I wherein R is H, X is SO2,
U is -NH-,V is -CO-,W is -NH- and A is phenyl] and Formula XXXII [Formula I wherein R is H, X'
is SO2, W is -NH-,V-U is -Rj- (-(CH2)o-i-CO-, -C(0)0-, -SO2.) and A is phenyl] comprising:
a) 0-protecting a compound of Formula XIX to give a compound of Formula XX;
H,N—(/ \—S O J , J—^
\ = / W H^N^fV^ °-«P
OH \=y
Formula XIX Formula XX
b) N-protecting a compound of Formula XX to give a compound of Formula XXI;
NH-•
o
0 O °
I (R )v
14. A process for preparing a compound of Formula XLV [Formula I wherein R is H, X is SO2, U
is -CH2-, V is -bond, W is -0-, A and B are phenyl]
"-^0-20 ^
Formula XLV
comprising:
a) oxidizing a compound of Formula XLII to give a compound of Formula XLIII;
O R. O—R„
Formula XLII Formula XLIII
•
98
b) reacting a compound of Formula XLIII with a compound of Formula XVI to give a
compound of Formula XLIV;
Formula XVI Formula XLIV
c) hydrolyzing a compound of Formula XLIV to give a compound of Formula XLV;
wherein,
Rp is a carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl and silyl;
X is a leaving group such as halogen, mesylate, triflate; and
V—/ is selected from mono, bi or polycyclic heteroaryl or heterocyclyl selected from the
following:
° ij 0
O '
I U I H
:A £^ .f^:i .><'
o
9 o °
I (R )v
99
^ 15. A process for preparing a compound of Formula XLVlll [Formula 1 wherein R is arylalkyl
(benzyl), X' is SO2, U is -CH2-, V is -bond, W is -O- and A and B are phenyl] comprising:
0-20 /
HO
Formula XLVIIl
a) deprotecting a compound of Formula XLIV to give a compound of Formula XLVI;
Formula XLIV Formula XLVI
b) reacting a compound of Formula XLVI to give a compound of Formula XLVII;
Formula XLVII
c) hydrolyzing a compound of Formula XLVII to give a compound of Formula XLVIIl;
wherein,
Rp is a carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl and silyl; and
v_y represents mono-, bi- or polycyclic heteroaryl or heterocyclyl selected from the
following: