Note: Descriptions are shown in the official language in which they were submitted.
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1
MATRIX METALLOPROTEINASE INHIBITORS
Field of the Invention
The present invention relates to certain hydroxy propionic acid derivatives
and the
processes for the synthesis of the same. 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 a 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 and disease
processes that involve remodeling, such as airway diseases, embryonic
development, bone
formation and uterine remodeling 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 TNF-alpha which is implicated in many pathological conditions.
MMP-9, which belongs to the gelatinase family, plays a major role in chronic
inflammatory disorders like COPD, asthma and rheumatoid arthritis. The
concentration of
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MMP-9 has been reported to increase 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 remodeling 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, and osteoclasts, which are easily induced by cytokines and growth
factors,
and plays a role in various physiological and pathological processes.
WIMP-12, also known as macrophage elastase or metalloelastase, 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.
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 2004/014310 discloses processes for the preparation of peripheral opioid
antagonist compounds useful for gastrointestinal motility disorders. WO
02/060888
discloses processes for preparing chromanylbenzoic acids. WO 94/20455
discloses styryl
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derivatives as PDE-IV inhibitors useful in the prophylaxis and treatment of
diseases such
as asthma, where an unwanted inflammatory response or muscular spasm is
present. WO
2004/110974 discloses compounds and their physiologically functional
derivatives
described as inhibitors of matrix metalloproteinase enzymes. WO 2004/113279
discloses
inhibitors of matrix metalloproteinase. WO 2005/026120 discloses compounds
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. WO 2008/023336 discloses P-hydroxy and amino-substituted carboxylic
acids,
which act as matrix metalloproteinase inhibitors.
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
pharmacokinetics 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
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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 hydroxy propionic acid derivatives, which
act
as matrix metalloprotease inhibitors, corresponding processes for the
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 MIYIP-
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 coadministered 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.
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Although the specific enantiomers have been shown by way of examples, the
racemates, diastereomers, pharmaceutically acceptable salts, and
pharmaceutically
acceptable solvates, having the same type of activity, are also provided.
Pharmaceutical
compositions comprising such compounds, with optionally included excipients
are also
provided.
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.
Detailed Description of The Invention
In accordance with one aspect, there are provided compounds having the
structure
of Formula I:
OH OH
Cr. -V-W
0
2-3
Formula I
including racemates, enantiomers and diastereomers thereof, or a
pharmaceutically
acceptable salt thereof wherein,
0 can be selected from phenyl, fluorophenyl, heteroaryl or heterocyclyl;
U can be a selected from bond, -NH-, -C(=0)- , -(CH2)n-, -C(=S)-, -0-, -SO2_
or -S
- wherein n can be zero or an integer between 1 and 2;
V can be a selected from bond, -NH-, -C(=O)-, -C(=S)- or
W can be a selected from bond, -NH-, -C(=0)-,(CH2)n-, -C(=S)-, -0-, -S- or
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11111 can be selected from aryl, cycloalkyl, heteroaryl or heterocyclyl, each
of
which can be further substituted by one or more substituent independently
selected from
R1
R1 can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen,
halogeno-
Cl-C6 alkyl, halogeno-C1-C6 alkoxy, azido, thiol, alkylthiol, -(CH2).-ORf, -
C(=0)-
Rf, -COORf, -NRfRq, -(CE12)n-C(=0)NRfRq, -(CH2)n-NHC(=0)-Rf, -(CH2)õ- 0-
C(=0)-NRfRq, (CH2)õ NHC(=0)NRfRq,, -(CE12)n-o-C(=0)- Rf, -(CH2)n-NH-C(=0)-
Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from
hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl,
alkylaryl,
alkylheteroaryl and alkylheterocyclyl, n is as defined earlier and m is an
integer 0-2};
111 can be selected from heteroaryl or heterocyclyl.
In accordance with another aspect, there are provided compounds having the
structure of Formula Ia:
OH OH
Li 0
023 II
Formula Ia
including racemates, enantiomers and diastereomers thereof, or a
pharmaceutically
acceptable salt thereof wherein,
can be selected from phenyl, fluorophenyl, heteroaryl or heterocyclyl;
L1 can be a selected from bond, -(CH2)n_, -NHCO(CH2)n_, -(CH2)nC(=0)NH-, -
NHC(=0)NH-, -SO2NH-, -NHS02_, -SO2, _NHC(=0)(0)-, -0-(CE12)n-, -(CH2)n-0-, -
(CH2)n0C(=0)NH-, -C(=S)NH-, -NHC(=S)- or -NHC(=S)NH- wherein n can be zero or
an integer between 1 and 2;
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_EID can be selected from aryl, cycloalkyl, heteroaryl or heterocyclyl, each
of
which can be further substituted by one or more substituents independently
selected from
RI.
RI can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen,
halogeno-
CI-C6 alkyl, halogeno-C1-C6 alkoxy, azido, thiol, alkylthiol, -(CH2)õ-ORf, -
C(=0)-R6 -
COORf, -NRfRq, -(CH2)õ-C(-0)NRAI, -(CH2)õ-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NRfRq,
(CH2)n NHC(=0)NRfRq,, -(C112)n-0-q=0)- Rt., -(C112)q-NH-C(=0)-Rf or
-(CH2)qS(---0)m-NRIRI {wherein Rf and Rq are independently selected from
hydrogen, alkyl,
alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl
and
alkylheterocyclyl, n is as defined earlier and m is an integer 0-2};
0 can be selected from heteroaryl or heterocyclyl.
In yet another aspect, the current invention provides a compound of Formula
Ib:
- a OH OH
0 L1 I.
0 2-3 0 I 1
Formula lb
including racemates, enantiomers and diastereomers thereof, or a
pharmaceutically
acceptable salt thereof
wherein,
lican be selected from mono, bi or polycyclic heteroaryl or heterocyclyl
selected from the following
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0 0
0
0
, 1 Nk
/N
I I I (R ), la I
/N--1
N., ..õ....-..)--
.....;,...N /
N
Il
0
(Ri)v
Tvµ
0
0
0 1
1\ 0
\ N
+NAo -Thl 1
-õ,õõ...-------// , 1'1.---0>
(R1)v \\ (R )v
)--*
i
0
0 0
0
j,/. .. .,......,..........,..\,(1- N....
(R1)v i
I / , y )
1 '/..---
)
(R )v ........, (R1 )v (Ri)v
0 N (RN )v N
i 0
H
I
0 0
0
-1-Nj0 INV 1 NV
)._.7/
I / J/
I
,-, N
YN7 1 N 0 R1);------
Th( (
(R, )v (R )v
0
0
0
0
1
)v
HN--1(
L /N-1-
I/ )
I /
(R1)0 (R1);----Y
o'''''..----\ 1 (R1)v
(R )v
wherein R1 is as defined earlier and v can be zero or an integer between 1-4.
Ra can be hydrogen or fluorine;
Li and are as defined earlier.
In yet another aspect, the current invention provides a compound of Formula
Ic:
OH OH
- a
1a 110
4:11 L
0
pill
go 2-3
,
Formula Ic
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including racemates, enantiomers and diastereomers thereof, or a
pharmaceutically
acceptable salt thereof, wherein,
La is selected from S(0)., NHCO(CH2). and NHCO(0);
Ra, 0andli are as defined earlier.
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), which
may include, but are not limited to the following, for example
(25)-2- [(S)- {4- [(4-Chlorophenyl)sulfinyl] phenyl (hydroxy)methyl] -4-(4-oxo-
1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 1);
(2S)-2-[(S)- {4- [(4-Chlorophenyl)sulfonyl] phenyl}(hydroxy)methyl] -4-(4-oxo-
1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 2);
(25)-2- [(S)- {4- [(3 ,4-Difluorophenyl)sulfinyl]phenyl (hydroxy)methyl] -4-(4-
oxo-
1,2,3-benzo triazin-3(41])-yl)butanoic acid (Compound No. 3);
(25)-2- [(5)- {4- [(2,3 -Dichlorophenyl)sulfinyl] phenyl}(hydroxy)methyl] -4-
(4-oxo-
1,2,3 -benzo triazin-3(4H)-yl)butanoic acid (Compound No. 4);
(2S)-2-[(S)- {4- [(2,4-Dimethylphenyl)sulfinyl]phenyl (hydroxy)methy1]-4-(4-
oxo-
1,2,3-benzo triazin-3(411)-yebutanoic acid (Compound No. 5);
(25)-2- [(5)- { 4- [(4-Fluorophenyl)sulfonyl]phenyll (hydroxy)methyl] -4-(4-
oxo-
1,2,3-benzotriazin-3(41/)-yl)butanoic acid (Compound No. 6);
(2S)-2-[(S)- {4-[(3 ,4 -D ifluorophenyl)sulfonyl]phenyll(hydroxy)methyl] -4-
(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 7);
2-[{4-[(2,3-Dichlorophenyl)sulfonyl]phenyll(hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(41/)-y1)butanoic acid (Compound No. 8);
(25)-2- [(S)- {4- [(2,4 -Dimethylphenyl)sulfonyl]phenyll(hydroxy)methyl] -4 -
(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 9);
(25)-2- [(5)-(4- [(4-Ethylphenyl)carbonyl]aminolphenyl)(hydroxy)methyl]-4-(4-
oxo-1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 10);
(25)-2- [(5)-(4- [(4-Chlorophenyl)carbonyl]aminolphenyl)(hydroxy)methyl] -4-(4-
oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 11);
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(2S)-2- [(S)-(4- [(3 ,4 -Dichlorophenyl)carbonyl] amino }
phenyl)(hydroxy)methy1]-4-
(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 12);
(2S)-2- [(S)-Hydroxy(4- [(4-methoxyphenyl)carbonyl] amino } phenyl)methyl] -4-
(4-
oxo-1,2,3-benzotriazin-3(4H)-yObutanoic acid (Compound No. 13);
(2S)-2-[(S)-Hydroxy(4- [(3 -methoxyphenyl)c arbonyl] amino phenyl)methy1]-4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 14);
(2S)-2-[(S)-Hydroxy(4- [(4-methylphenyl)carbonyl ] amino } phenyl)methyl] -4-
(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 15);
(2S)-2- [(S)-(4- [(4-Fluorophenyl)carbonyl ] amino } phenyl)(hydroxy)methyl] -
4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 16);
(2S)-2- (S)-Hydroxy[4-({ [4-methoxy-3-(trifluoromethyl)phenyl]carbonyl }
amino)
phenyl] methyl} -4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound
No. 17);
(2S)-2-[(S)-Hydroxy(4- [(5-methyl-1,2-oxazol-3-y1)carbonyl] amino
phenyl)methyl]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound
No. 18);
(2S)-2-[(S)-(4- [(3 -Chloro-4-fluorophenyl)carbonyl] amino phenyl)
(hydroxy)methyl]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound
No. 19);
(2S)-2-[(S)-Hydroxy {4- [(phenylcarbonyl)amino]phenyl } methy1]-4-(4-oxo-1,2,3-
benzotriazin-3 (4H)-yl)butanoic acid (Compound No. 20);
(2S)-2-[(S)-Hydroxy(4- [(4-propylphenyl)carbonyl] amino } phenyl)methyl] -4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 21);
(2S)-2-[(S)-Hydroxy {4- [(phenoxycarbonyl)amino]phenyl } methy1]-4-(4-oxo-
1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound No. 22);
(25)-2-[(S)-Hydroxy{4-[(phenylacetyl)amino]phenyllmethyl]-4-(4-oxo-1,2,3-
benzotriazin-3(4H)-y1)butanoic acid (Compound No. 23);
(2S)-2-[(S)-(4-{ [(2,4-Dichlorophenyl)carbonyl]amino phenyl)(hydroxy)methy1]-4-
(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 24);
(2S)-2-[(S)-Hydroxy(4- [(2-methylphenyl)carbonyl] amino phenyl)methy1]-4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 25);
(2S)-2-[(S)-(4- [(2-Fluorophenyl)carbonyl] amino phenyl)(hydroxy)methyl] -4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 26);
(2S)-2-[(S)-(4-{ [(3-Chlorophenyl)carbonyl]amino phenyl)(hydroxy)methyl] -4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 27);
(2S)-2- [(S)-Hydroxy(4- [(3 -methylphenyl)c arbonyl] amino } phenyl)methyl] -4-
(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 28);
(2S)-2-[(S)-(4- [(3 -F luorophenyl)carb onyl] amino phenyl)(hydroxy)methyl] -
444-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 29);
(2S)-2-[(S)-(4- [(2,6-Dimethoxyphenyl)c arbonyl] amino} phenyl)(hydroxy)
methy1]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 30);
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(25)-2- [(5)- {4- [(Cyc lop entylcarbonyl)amino] phenyll(hydroxy)methyl] -4-(4-
oxo-
1,2,3 -benzo triazin-3(4H)-yl)butanoic acid (Compound No. 31);
(25)-2- [(5)-Hydroxy(4- [(2,4,5-trifluoro-3-methoxyphenyl)carbonyl]amino}
phenyl) methyl] -4-(4-oxo-1,2,3-b enzotriazin-3(4H)-yl)butanoic acid (Compound
No. 32);
(25)-2-[(5)-Hydroxy(4-{ [(2,3,4-trifluorophenyl)carbonyl] amino}
phenyl)methyl] -4-
(4-oxo-1,2,3 -b enzotriazin-3(4H)-yl)butanoic acid (Compound No. 33);
(25)-2- {(S)-Hydroxy[4-({ [2-(trilluoromethyl)phenyl] carbonyllamino)phenyl]
methyl} -4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 34);
(25)-2- [(5)-(4- [(3,5-Dimethoxyphenyl)carbonyl]aminolphenyl)(hydroxy)
methyl] -4-(4-oxo-1,2,3-b enzotriazin-3(4H)-yl)butanoic acid (Compound No.
35);
(2S)-2-[(S)-(4- [(2,3 -Difluorophenyl)c arbony] ] amino
phenyl)(hydroxy)methyl] -4-
(4-oxo-1,2,3 -benzotriazin-3(4H)-yl)butanoic acid (Compound No. 36);
(25)-2-[(5)-(4-{ [(3,5-Dichlorophenyl)carbony] ] amino phenyl)(hydroxy)methyl]
-4-
(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 37);
(2S)-2-[(S)-(4-{ [(2,4-Difluorophenyl)carb onyl] amino}
phenyl)(hydroxy)methyl] -4-
(4-oxo-1,2,3 -benzotriazin-3(4H)-yl)butanoic acid (Compound No. 38);
(25)-2-[(5)-(4-{ [(2,6-Difluorophenyl)c arbonyl ] amino
}phenyl)(hydroxy)methyl] -4-
(4-oxo-1,2,3 -benzotriazin-3(4H)-yl)butanoic acid (Compound No. 39);
(25)-2- [(5)-Hydroxy(4- [(2-methoxyphenyl)carbonyl] amino phenyl)methy1]-4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 40);
(2S)-2-[(S)- {4- [(Cyclohexylcarbonyl)amino]phenyll(hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 41);
(25)-2- [(5)-(4- [(4-Ethoxyphenyl)carbony] ] aminolphenyl)(hydroxy)methyl] -4-
(4-
oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 42);
(25)-2-[(5)-(4-{ [(3,4-Difluorophenyl)carbonyl ] amino 1
phenyl)(hydroxy)methyl] -4-
(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 43);
(25)-2- (5)-Hydroxy[4-({ [4-(trifluoromethoxy)pheny]]carbonyllamino)phenyl]
methyl} -4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 44);
(25)-2-{(5)-Hydroxy[4-({ [3-
(trifluoromethyl)phenyl]carbonyllamino)phenyl ] methyl 1 -4-(4-oxo-1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound No. 45);
(2S)-2-[(S)44-({ [2-Fluoro-4-(trifluoromethyl)phenyl] carbonyl) amino)
phenyl ](hydroxy)methyl] -4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid
(Compound No. 46);
(25)-2- [(5)-(4- [(3-Chloro-2,6-difluorophenyl)carbonyl] amino 1
phenyl)(hydroxy)
methy1]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 47);
(25)-2- (5)-Hydroxy[4-({ [4-(trifluoromethyl)phenyl]carbonyllamino)phenyl]
methyl} -4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 48);
(2S)-2-[(S)-(4- [(2,5-Difluorophenyl)carbony] ] amino }
phenyl)(hydroxy)methyl] -4-
(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 49);
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12
(2S)-2-[(S)-(4-{[(2,3-Difluoro-4-methylphenyl)carbonyl]aminolphenyl)(hydroxy)
methy1]-4-(4-oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 50);
(2S)-2-[(S)- [4-( [4-Fluoro-3-(trifluoromethyl)phenyl] carbonyl} amino)phenyl]
(hydroxy)methy1]-4-(4-oxo-1,2,3-benzotriazin-3(411)-yObutanoic acid (Compound
No. 51);
(2S)-2-[(S)-{4-[(Cyclopropylcarbonyl)amino]phenyll(hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yObutanoic acid (Compound No. 52);
(2S)-2-[(S)-(4-{[(2-Ethylphenyl)carbonyl]aminolphenyl)(hydroxy)methy1]-4-(4-
oxo-1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 53);
(2S)-2-[(S)-Hydroxy(4-{[(4-methoxyphenyl)acetyl]aminolphenyl)methy1]-4-(4-
oxo-1,2,3-benzo triazin-3(41/)-yObutanoic acid (Compound No. 54);
(2S)-2-[(S)-{4-[(Cyclobutylcarbonyl)amino]phenyll(hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 55);
(2S)-2- {(S)-Hydroxy[4-(4-methoxyphenoxy)phenyl]methyll -4-(4-oxo-1,2,3 -
benzotriazin-3(411)-yebutanoic acid (Compound No. 56);
(2S)-2-[(S)-[4-(3-Chloro-4-fluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yebutanoic acid (Compound No. 57);
(2S)-2-[(S)-[4-(4-Chloro-3-methylphenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound no. 58);
(2S)-2-[(S)-[4-(4-Chloro-2-fluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 59);
(2S)-2-[(S)-[4-(4-Fluorophenoxy)pheny]](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(411)-yl)butanoic acid (Compound No. 60);
(2S)-2-[(S)-[4-(3,4-Difluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(41/)-yebutanoic acid (Compound No. 61);
(2S)-2-[(S)-[4-(2-Chlorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(41/)-yl)butanoic acid(Compound No. 62);
(2S)-2-[(S)-[4-(3-Chlorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(411)-yl)butanoic acid (Compound No. 63);
(25)-2-[(5)-[4-(2,6-Difluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(411)-yl)butanoic acid (Compound No. 64);
(2S)-2-[(S)-[4-(2,5-Dichlorophenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-1,2,3-
benzotriazin-3(41/)-yebutanoic acid (Compound No. 65);
(2S)-2-[(S)-[4-(2-Chloro-4-fluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 66);
(2S)-2- { (S)-Hydroxy[4-(3-methoxyphenoxy)phenyl]methy11-4-(4-oxo-1,2,3-
benzotriazin-3(411)-yl)butanoic acid (Compound No. 67);
(2S)-2-[(S)-[4-(2-Chloro-4-methoxyphenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 68);
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(25)-2-[(5)-[4-(2,4-Difluorophenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-1,2,3-
benzotriazin-3(41/)-yl)butanoic acid (Compound No. 69);
(25)-2-[(S)-[3-Fluoro-4-(4-methylphenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 70);
(25)-2-[(5)-[3-Fluoro-4-(3-methylphenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 71);
(25)-2-[(5)-[4-(3,4-Dimethylphenoxy)-3-fluorophenyl](hydroxy)methyl]-4-(4-oxo-
1,2,3-berizo triazin-3(411)-yl)butanoic acid (Compound No. 72);
(25)-2-[(5)-[4-(3,4-Dichlorophenoxy)-3-fluorophenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 73);
(25)-2-[(S)44-(4-tert-Butylphenoxy)-3-fluorophenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 74);
(25)-2-[(5)-[3-Fluoro-4-(4-methoxyphenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(41/)-yl)butanoic acid (Compound No. 75);
including racemates, enantiomers and diastereomers thereof, or a
pharmaceutically
acceptable salt thereof.
In another aspect, provided herein are pharmaceutical compositions 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/Ib/Ic
for use in medicine.
In another aspect, provided herein are compounds according to Formula
I/Ia/Ib/Ic
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/Ib/Ic
wherein various inflammatory and allergic diseases are 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 associated with
restenosis and
ischemic heart failure, stroke, renal disease or tumour metastasis.
In yet another aspect, the present invention relates to the therapeutically
effective
dose of a compound of Formula I/Ia/Ib/Ic 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:
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1) Anti-inflammatory agents, experimental or commercial (i) such as
nonsteroidal
anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates,
pyrazolones, salicylates, phosphodiesterase inhibitors including PDE-4
inhibitors, p38 MAP Kinase/Cathepsin inhibitors, CCR-3 antagonists, iNOS
inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists,
cell
adhesion inhibitors (specially 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,
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;
2) Beta-agonists, experimental or commercial (i) suitable 132-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 132- agonists may be chosen
from those in the art or subsequently discovered. (ii) The 132-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 4,011,258;
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)13-
blockers, and (iv) calcium channel blockers;
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4) immunosuppressive agents, for example, cyclosporine, azathioprine and
methotrexate, anti-inflammatory corticosteroids; and
5) anti-infective agents (e.g., antibiotics, antivirals).
Definitions
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 atom, and which has 1 to
20 carbon
atoms unless otherwise specified. This term is exemplified by groups such as
methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-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 form 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, adamantyl, bicyclo [2.2
.1]heptanyl,
bicyclo [2.2.2] octane, tricycle [3.3.1 .]] 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, 0 and S. Examples of heteroaryl
groups
are pyridinyl, quinolinyl, oxazolyl, imidazolyl, pyrrolyl, thiophenyl, 1,2,3-
triazolyl, 1,2,4-
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triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl,
pyridazinyl,
pyrazinyl, thienyl, isoxazolyl, triazinyl, fiiranyl, 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, 0 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[3.1.0]hexyl,
phenoxazine, tetrahydropyran, 1,4-dioxane, and the like.
The terms "cycloalkylalkyl","arylalkyl","heteroarylalkyl","heterocyclylalkyl",
refers respectively, to cycloalkyl, aryl, heteroaryl or heterocyclyl group
linked to the
remainder of the molecule via an alkyl group.
The term "amino" refers to -NH2.
The term "alkoxy" denotes the group 0-alkyl, wherein alkyl is the same as
defined
above.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
The term "halogeno-Ci-C6alkyl" refers to Ci-C6alkyl of which one or more
hydrogen(s) is/are replaced by halogen.
The term "halogeno C1-C6 alkoxy" refers to as halogen atom bonded to C1-C6
alkoxy group. Examples of such groups include trifluoromethoxy,
trichloromethoxy,
difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy etc.
The term "hydroxyl" or "hydroxy" refers to ¨OH.
The term "thior' 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 as CI\T.
The term "azido" refers to as N=N=N.
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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, Cl, 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
moieties/moiety are/is 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 or 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 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
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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 the 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
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ligamentous sprain and regional musculo skeletal 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,
inguinal hernia,
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,
pancrealitis, 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.
The compounds of the said invention can be prepared following any of the below
Schemes.
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20
The compounds of Formulae VII, VIII and IX can be prepared by following Scheme
I.
Scheme I
XH
0
(Rk), = ,.
(IRK)z X + 410
Formula II Formula III Formula IV
Formula V K s.
HO 0 0 HO
(Rk)z
e
Path A (when X is S) Rxõ
HO
LwL(Rk)z
Formula VII Formula VI
Path B (when X is 0)
0 HO 0 (ROz 0 HO =
0
0
HO HO
(Roz
Formula VIII Formula IX
Accordingly, the compound of Formula II (wherein is as
defined earlier, X is
0 or S and Rk is H, halo, alkyl, alkoxy, cyano, halogeno-C1-C6 alkyl or
halogeno-C1-C6
alkoxy and z is 0-4) can react with a compound of Formula III to give a
compound of
Formula IV, which then reacts with a compound of Formula V (wherein
is as
defined earlier, L and W are 0 or S respectively and Rx is alkyl, aryl or
aralkyl ) to give a
compound of Formula VI.
Path A (When X is S): The compound of Formula VI undergoes hydrolysis to give
a
compound of Formula VII, which then further undergoes oxidation to give a
compound of
Formula VIII.
Path B (When X is 0): The compound of Formula VI undergoes hydrolysis to give
a
compound of Formula IX.
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21
The reaction of a compound of Formula II with a compound of Formula III to
give
a compound of Formula IV can be carried out in the presence of a base, for
example,
potassium carbonate, cesium carbonate, sodium acetate or potassium acetate in
a solvent,
for example, dimethylformamide, acetonitrile, toluene, tetrahydrofuran,
acetone, dioxane,
or mixture(s) thereof.
The asymmetric aldol addition of a compound of Formula IV with a compound of
Formula V to give a compound of Formula VI can be carried out by generating
the
enolates with titanium tetrachloride, dibutyl boron triflate, dialkyl boron
chloride or tin(II)
triflate, in the presence of a base, for example, tetramethylethylenediamine,
diisopropylethylamine, tributylamine, N-ethylpiperidine, 1,4-
diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]undec-7-ene, tetramethylpropylenediamine or (-)
sparteine, in a
solvent, for example, dichloromethane or diethyl ether.
Hydrolysis of a compound of Formula VI (Path A, when X is S) to give a
compound of Formula VII can be carried out with hydrogen peroxide and lithium
hydroxide, in the presence of a solvent, for example, tetrahydrofuran, water,
or mixture(s)
thereof.
Oxidation of a compound of Formula VII to give a compound of Formula VIII can
be carried out with an oxidizing agent, for example, meta chloro perbenzoic
acid, oxone or
hydrogen peroxide, in a solvent, for example, chloroform, dichoromethane,
methanol,
water, tetrachloromethane, or mixture(s) thereof.
Hydrolysis of a compound of Formula VI (Path B, when X is 0) to give a
compound of Formula IX can be carried out in a similar way as the hydrolysis
of
compound of Formula VI to give a compound of Formula VII.
The compound of Formula XII can be prepared by following Scheme II.
Scheme II
Lz N G 40 OH 0 G1 OH 0
Rx Formula X
0 Rr..c.zw
Formula V Formula XI Formula XII
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Accordingly, the compound of Formula V (wherein 0, L, W and Rx are as
defined earlier) undergoes aldol addition with a compound of Formula X
(wherein G can
be nitro or C(0)0-benzyl) to give a compound of Formula XI, which then can be
reduced
to give a compound of Formula XII (wherein G1 can be amino or COOH).
Aldol addition of a compound of Formula X to a compound of Formula V to give a
compound of Formula XI can be carried out in a similar way as the aldol
addition of a
compound of Formula IV with a compound of Formula V to give a compound of
Formula
VI.
Reduction of a compound of Formula XI to give a compound of Formula XII can
be carried out with one or more reducing agents, for example, palladium-
carbon/hydrogen,
Raney nickel/hydrogen, platinum/hydrogen or mixture thereof in a solvent, for
example,
tetrahydrofuran, methanol, ethanol, propanol, isopropanol, or mixtures thereof
The compound of Formula XV and XVIII can be prepared by following Scheme
CA 02807097 2013-01-30
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PCT/1B2011/053155
23
Scheme III
= OR
= OH
RN 0
H2N 0
(ROz 0 -i---X /
Formula XVI Ft
L
L
N--- Path D
.-1-3-\ Rxtl""W
0 Rki""'W
(Rk)z4111)
Formula XII (when G1 is NH2)
Formula
XVII
Path C (Fik)z 0 Ni Formula xiii 0
i
. OH
. OH
HN 0
HN
0
/
NH¨
Rj\i,"
L
(7) 0 N--
OH
0Rxc,w
1---\j 111)
(Rk),
(Rk)z
Formula XIV
Formula XVIII
/
aot OH
HN 0
NH¨
C<1 0 OH
(Rk)z II
Formula xv
Accordingly, the compound of Formula XII (when G1 is amino) can react through
two pathways.
Path C: Compound of Formula XII couples with a compound of Formula XIII
(wherein
Rk and z are as defined earlier) to give a compound of Formula XIV, which then
undergoes hydrolysis to give a compound of Formula XV.
Path D: Compound of Formula XII couples with a compound of Formula XVI
(wherein X
is a leaving group for example halogen and R; is -(cH2)0_1-03-, -c(o)o-, -
SO2_, and Rk is
as defined earlier) to give a compound of Formula XVII, which then undergo
hydrolysis to
give a compound of Formula XVIII.
The coupling of a compound of Formula XII with a compound of Formula XIII to
give a compound of Formula XIV (Path C) can be carried out with a suitable
base, for
example, potassium carbonate; sodium carbonate, triethylamine,
diisopropylethyl amine,
CA 02807097 2013-01-30
WO 2012/014114
PCT/1B2011/053155
24
etc. in the presence of solvents like acetonitrile, dimethylformamide,
toluene,
tetrahydrofuran, acetone or dioxane, etc.
Hydrolysis of compound of Formula XIV to give a compound of Formula XV can
be carried out in a similar way as the hydrolysis of compound of Formula VI to
give a
compound of Formula VII.
The coupling of compound of Formula XII with a compound of Formula XVI to
give a compound of Formula XVII (Path D) can be carried out with a base, for
example,
triethylamine (TEA), N-methyl-morpholine (NMM), N,N-dimethylaminopyridine
(DMAP) or N,N-diisopropylethylamine (DIPEA) in a solvent, for example,
dichloromethane, tetrahydrofuran, dimethylformamide, dioxane, acetonitrile or
acetone.
Hydrolysis of compound of Formula XVII to give a compound of Formula XVIII
can be carried out in a similar way as the hydrolysis of compound of Formula
VI to give a
compound of Formula VII.
The compound of Formula XXI can be synthesized by following Scheme IV.
Scheme IV
HO OH 0 4.0 OH
OH
0 0 L Formula XIXHN 0 HN
0
11 OH
Rr.cw Rx,".
(R,), (R k),
Formula XII (when G1 is COON) Formula XX
Formula XXI
Accordingly, the compound of Formula XII (when G1 is COOH) can couple with a
compound of Formula XIX to give a compound of Formula XX, which then undergoes
hydrolysis to give a compound of Formula XXI.
The coupling of compound of Formula XII with a compound of Formula XIX to
give a compound of Formula XX can be carried out in the presence of a coupling
agent 1-
ethyl-3 -(3 -dimethylaminopropyl) carbodiimide (EDCI) or NAT-
dicyclohexylcarbodiimide
(DCC) and optionally activating catalyst HOBT and an organic base
dimethylaminopyridine, N-methylmorpholine or diisopropylethylamine, in an
organic
solvent, for example, dichloromethane, dichloroethane, chloroform and carbon
tetrachloride. Alternatively, XII can also be activated by converting to the
corresponding
WO 2012/014114 CA 02807097
2013-01-3025
PCT/1B2011/053155
acid chloride (using thionyl chloride, oxalyl chloride, etc.) or the anhydride
(pivaloyl
chloride, etc.) and coupled with the corresponding anilines.
Hydrolysis of compound of Formula XX to give a compound of Formula XXI can
be carried out in a similar way as the hydrolysis of compound of Formula VI to
give a
compound of Formula VII.
In the above schemes, where specific reagents, for example, bases, acids,
solvents,
condensing agents, hydrolyzing agents, catalysts etc., as mentioned, 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.
Table 1 lists the type of compounds synthesized by using the synthetic
procedure
as demonstrated in Schemes I-IV.
CA 02807097 2013-01-30
WO 2012/014114 PCT/1B2011/053155
26
z--z z=z
z...,z
z/
0 1-z/ 1- . I-I
41
o o 0
Z Z Z
0 0 0
C..)
1.4 . I .
\ , >, 0-0
0
1
1111 u. 41
0 c?
N *
0
n
lik
I
0
41) cl ci
5 4
czt
0, o
= cf3 en
411
6,
0
W.,
¨_i
z¨z
i_z/ ¨ = kz=z410 z=z
co
41
0 o 0
I I
1
CA CA CA
I I I
40 404 404
co
5 5
o¨i
0.)
ei
_a
czt 4
ci il el eri
CA 02807097 2013-01-30
WO 2012/014114
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27
z-z
z-z
z=z
z=z
/
/
/41-
-z
/z_z
411
40 . 0 1
_l_z 4.0 4z 4.: 4 40 =
0
0
,
z
z
z
z
z
z
0
0
0
0
0
0
-.;
R
(....)
.
(....)
.
(....)
.
(....)
.
(....)
.
\_,..
,,,--
,,--
=
\õ_
0
u_
>4.,.
-,
O
4
ci
44
ee)
'Tr
kr)
-rp
vo
'Tr
N
'Tr
_
z=z
z¨z
z¨z
,z/z=z
/
/
z¨z
z_z
¨1-z
1-z/ ¨
¨1-z
4./
41 --' . .¨ . .4i¨'-zi = .
0
0
0
0
0
0
,
.
.
........
.
..
.
0
0
6 6 6
7_4
c-?:-D
c/ID
v)
.
c/D
.
v)
.
v)
.
_
õ
>õ. .
-,,..õ/
...,,....
1
5 = 0--
ii
ft II = 5 40
co
_
0
4
ci
-71.
kr;
vo
N
oo
cr,
CA 02807097 2013-01-30
WO 2012/014114
PCT/1B2011/053155
28
z=z
z=z z=z /z_z
. -1-z/ AL\ = _i-z =-1-z/
=
ID. 0 0 0 0 II-.
o 0
Z Z Z Z
Z Z
0 0 0 0
0 0
U U U U
U
-14 L? . . .
.
u_
.,,a,õ. ,
= .,:,''
i'
0
* 40 u_ ''
\
\ .,,,`'.
..././.=Pt
=
LL
.
LL E
6
4
.--1 el m
7r kr) kr) kr)
kr)
s i-z= s z/z=z= _i =-1-z/ =-1-z/ z/ z-z z=z
z-z z-z
o --0 0 o o
== - . o
Z Z Z Z
Z Z
0 0 0 0
0 0
7.4 U U U U U U
. . . .
. .
/
/ /
=sõ,
>,-
. / < .
4411
=
0 0
=
6
4
.--1
CA 02807097 2013-01-30
WO 2012/014114 PCT/1B2011/053155
29
t
z=z
zz=z= 1-z/ z_z z-z
0 _i-z o = 1.7=z
=
0 -z * *
0 0 0 :
_
Z
0
,N Z
0
,-,
. cl? d? d? d?
// /
- -
0
4
k,n vo h oo c::
cA Zin. k,n k,n k,n kin k,n
z-z z=z
z-z -z
--i-z/ -. ii=zAL\ 1.z/z=z= _* 4z/z_* ---1-z/
_i-z/
111 o 0 W- o 0 0 o *
.
Z Z Z Z Z
0 0 0 0 0 0
c...) c...) c...)
;4 CI) I c-i) . . cl)
.Z\ \
= .),...,
0
/ = 5 . 9
d,
s cc
,, el
CA 02807097 2013-01-30
WO 2012/014114
PCT/1B2011/053155
30
z-z i. z/z=z _i_z/ - z-z -z
i z/ z-z -z
-i-z/ -1-
z/z- z-
IC 0 = 0 = o
=o 0 = 0 .
!
. .
0
- d? 4'
_ (4) (:' '::?' .
I
it 4 , = / ,,,,
.õõ. ,
=
m ,
O
4 ,-1 el
en ,er lin
rfj .tz .tz
.tz .tz .tz
_
z=z z=z z=z /z=z
z-z
-1-z/ z --z
0 .4, = 111-z . . .0 0 0
0 0 0
z
z 0
z z z z
!c...) 0 0
0 0
c...) c...)
c...)
¨.4 R . c¨..)
. c¨i)
.
,¨,--- ,¨,---
\
i = 40 411
m
c.)
= 5
(7)
40 104 ,--- _
O
4 en ,er
lin .tz N
.cel el el el
el el
CA 02807097 2013-01-30
WO 2012/014114
PCT/1B2011/053155
31
z¨z
=z z=z z¨z
z¨z-z -
/
_i_zi i 41 41
0 0 0
0 0
0
- - ,
7-4 . l'' d?
d.)1 d?
(2? (2?
1 -
,.,..,./,,
/
/
/
4i
4.
41
11
i o
m ,
\
o o
o o
2 2
2 2
4:3
- 4
- 4;) t=-=
oo cl.. cz
,-1
t=-= t=-=
z-z z-z
z-z z-z _
1-z/ -i-z
/
1-z/ 1-zi -
z-z
o o / =z-z
= =
0
=
0 0
0
=
4 4 4
4 4
4
0 0 0
0 0
0
.= ,-,-
c...) c...)
c...) c...)
c...)
14 I I
. ,
c-i) /
l'
rIL
0
\
0
m A 110 LL
0
0 \
41 10
i
f
IL
O
z.
QC
cz ,-1 el
en
el en en
en en
ci . el -- 1
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WO 2012/014114
PCT/1B2011/053155
32
f
z/z=z z-z
z-z
7-z
. * -1- z/
z
0
0 = 1_ *
. *
,-. 104
C1) d?
C1) C1)
:
=
-,.._ / ,-,.,, ./t,
/ /
-.--. .õ..,
. 2 = 0
0
0
Cop
o f x
HE 2 5 5
0
O
4
el en
7r in
ci N N
N N
z-z
z-z
z-z
z-z
4z/z=z --1-z/
/ --1-z/ -
= -1-z = = *
II 0 = 0
0 0
0
I II
,
Z z
z z
0 C
0 0
0
c...)
c...)
"a ,-.) L?
. Li)
Li.
Li.
., Li.
Li_
6 '=
/ =
. =
c, u_ . ,,
a.
40
m
6
4 It
vo s
oo
w3 79)1. en
en en
en
CA 02807097 2013-01-30
WO 2012/014114 33 PCT/1B2011/053155
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, powder,
granules, lozenges, troches, and cachets. For solid form preparations, active
compounds can
be mixed with one or more inert, pharmaceutically acceptable excipients or
carriers, for
example, sodium citrate, dicalcium phosphate and/or fillers or extenders (for
example,
starches, lactose, sucrose, glucose, mannitol, silicic acid, or mixtures
thereof); binders, for
example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone,
sucrose, acacia
or mixtures thereof; disintegrating agents, for example, agar-agar, calcium
carbonate, potato
starch, alginic acid, certain silicates, sodium carbonate, or mixtures
thereof; absorption
acceletors, for example, quaternary ammonium compounds; wetting agents, for
example,
cetyl alcohol, glycerol mono stearate or mixtures thereof; adsorbants, for
example, Kaolin;
lubricants, for example, talc, calcium stearate, magnesium stearate, solid
polyethyleneglycol,
sodium lauaryl sulfate, or mixtures thereof
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.
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
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WO 2012/014114 34 PCT/1B2011/053155
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
condition
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 packed preparations containing discrete
capsules,
powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels,
creams or any
combination and number of such packed forms.
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:
Synthesis of 3-[4-((45)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1)-4-oxobuty1]-3H-
benzo[d][1,2,3] triazin-4-one
Synthesis of the title compound was carried out according to reference
procedure
described in WO 2008/023336, p. 54-55.
CA 02807097 2013-01-30
WO 2012/014114 35 PCT/1B2011/053155
Synthetic procedures for Scheme I (Path A)
Example I: Synthesis ofi2S)-2-I(8)-{4-114-ChlorophenyljsulfonylJphenylt
(hydroxy)methy11-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound
No. 2)
Step 1: Synthesis of 4-[(4-chlorophenyl)sulfanyl]benzaldehyde
To a solution of 4-chlorothiophenol (1.0 g, 0.0069 mol) in dimethylformamide
(5m1), potassium carbonate (2.8 g, 0.0207 mol) and 4-fluorobenzaldehyde (0.904
g,
0.0072 mol) were added and the reaction mixture was heated to about 100 C for
about 4
hours. After completion of reaction, water was added and extracted in ethyl
acetate.
Organic layer was concentrated, purified by column using 7% ethyl
acetate/hexane as
eluent to obtain the title compound. (Yield: 0.6g)
Mass-248
LCMS-M+1 (248.97)
Step 2: Synthesis of 3-{(3S)-4-[(4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1]-3-
1(S)-{4-[(4-
chlorophenyl)sulfanyllphenyl}(hydroxy)methyll-4-oxobuty1}-1,2,3-benzotriazin-
4(31/)-one
To a solution of the 3- {4-[(45)-4-benzy1-2-oxo-1,3-thiazolidin-3-y]]-4-
oxobuty11-1,2,3-benzotriazin-4(31/)-one (0.2 g, 0.00049 mol) in
dichloromethane (5m1) under argon
atmosphere cooled to about 0 C, titanium tetrachloride (0.12 g, 0.00063 mol)
was added
slowly. After about 30 minutes, tetramethylethylenediamine (0.068 g, 0.00058
mol) was
added at about 0 C. The reaction mixture was stirred for about 45 minutes at
the same
temperature and then a solution of 4-[(4-chlorophenypsulfanyl]benzaldehyde
(0.206 g,
0.00083 mol) in dichloromethane (5 ml) was added very slowly. This reaction
mixture
was again stirred for about 5 hours at room temperature. On completion, the
reaction was
quenched with ammonium chloride solution and subsequently by dilute
hydrochloric acid
and then extracted with dichloromethane and water, purified by column using 8%
ethyl
acetate/hexane as eluent to obtain the title compound. (Yield: 0.150 g)
Mass-657
LCMS-M+1 (658.02)
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WO 2012/014114 36 PCT/1B2011/053155
Step 3: Synthesis of (2S)-2-[(5)-{4-[(4-chlorophenyl)sulfinyllphenyl}(hydroxy)
methyl]-4-(4-oxo-1,2,3-benzotriazin-3(41i)-yl)butanoic acid (Compound No. 1)
To a solution of the 3-{(35)-4-[(45)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1]-3-
[(5)-
{ 4- [(4-chlorophenyl)sulfanyl]phenyll (hydroxy)methy1]-4-oxobutyll -1,2,3 -
benzotriazin-
4(311)-one (0.1 g, 0.0001mol) in tetrahydrofuran (5m1) under argon atmosphere
at 0 C,
hydrogen peroxide solution (0.0102 g, 0.0003 mol) and then lithium hydroxide
(0.006 g,
0.00015 mol) were added. The reaction mixture was stirred for about 2 hours at
room
temperature. The reaction was quenched by acidifying the reaction mixture with
sodium
bisulfate and extracting in ethyl acetate and water. Organic layer thus
obtained was
concentrated and purified by preparative TLC using 10%
methanol/dichloromethane as
eluent to obtain the title compound. (Yield: 0.090 g)
MS-497.95
LCMS-M-1 (496.04)
NMR (DMSO-d6, 400 MHz) 8: 8.04-8.06 (2H, d, J= 8.0 Hz), 7.92-7.93 (1H, d, J =
4.0Hz), 7.81-7.83 (1H, d, J= 8.0 Hz), 7.67-7.69 (2H, d, J = 8.0 Hz), 7.57-7.59
(4H, d, J =
8 Hz), 7.42-7.44 (2H, d, J = 8 Hz), 4.84 (1H, m), 4.38-4.29 (2H, m), 2.54-2.57
(1H, m),
2.07 (1H, m), 1.89 (1H, m).
The following compounds were prepared by following above route of synthesis:
(25)-2- [(5)- { 4-[(3,4-difluorophenyOsulfinyl]phenyll(hydroxy)methy1]-4-(4-
oxo-
1,2,3-benzo triazin-3(411)-yDbutanoic acid (Compound No. 3);
Mass: 499.48
(2S)-2-[(5)- {4- [(2,3 -dichlorophenypsulfinyl]phenyll (hydroxy)methy1]-4-(4-
oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 4);
Mass: 532.39
(2S)-2-[(5)- {4- [(2,4-dimethylphenypsulfinyl]phenyll(hydroxy)methyl] -4-(4-
oxo-
1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 5);
Mass: 491.55
Step 4: Synthesis of (2S)-2- [(S)- (4-[(4-
chlorophenyl)sulfonyllphenyl)(hydroxy)
methyl]-4-(4-oxo-1,2,3-benzotriazin-3(41i)-yl)butanoic acid (Compound No. 2)
To a solution of (25)-2-[(5)-{4-[(4-
chlorophenypsulfinyl]phenyll(hydroxy)methyl]
-4-(4-oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (0.09 g, 0.00018 mol) in
chloroform
(5m1) at about 0 C, metachloroperbenzoic acid (0.124 g, 0.00072 mol) was added
and the
reaction mixture was stirred for about 1 hour at room temperature. On
completion, the
CA 02807097 2013-01-30
WO 2012/014114 37 PCT/1B2011/053155
reaction was quenched by sodium metabisulphite solution and then extracted in
dichloromethane. The organic layer was dried with sodium sulphate and
concentrated,
purified by preparative TLC and eluted in 10% methanol/dichloromethane to
obtain the
title compound. (Yield: 0.04 g)
MS-513.95
LCMS-M-1 (512.00)
NMR(DMS0d6, 400 MHz) 6: 8.16 (2H, m), 8.08 (1H, m), 7.93-7.95 (4H, d, J = 8.0
Hz),
7.82-7.84 (1H, d, J= 8.0 Hz), 7.68-7.70 (2H, d, J = 8 Hz), 7.53-7.55 (2H, d, J
= 8 Hz),
4.90 (1H, m), 4.30-4.40 (2H, m), 2.50 (1H, m),1.90-2.10 (2H, m).
The following compounds can be prepared by following above route of synthesis:
(25)-2-[(5)-{4-[(4-Fluorophenypsulfonyl]phenyll(hydroxy)methy1]-4-(4-oxo-
1,2,3-benzotriazin-3(41])-yl)butanoic acid (Compound No. 6)
Mass: 497.49
(25)-2-[(5)-{4-[(3,4-Difluorophenyl)sulfonyl]phenyll(hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(41])-yl)butanoic acid (Compound No. 7)
Mass: 515.48
2- [ {4- [(2,3 -Dichlorophenyl)sulfonyl]phenyll (hydroxy)methy1]-4-(4-oxo-
1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound No. 8)
Mass: 548.39
(25)-2-[(5)-{4-[(2,4-Dimethylphenyl)sulfonyl]phenyll(hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 9)
Mass: 507.55
Synthetic procedure for Scheme I (Path B)
Exam ele II: S nthesis of 2S -2- S -H drox 4- 4-methox ohenox .hen meth 1 -4-
(4-oxo-1,2,3-benzotriazin-441D-yl)butanoic acid (Compound No. 56)
Step 1: Synthesis of 4-(4-methoxyphenoxy)benzaldehyde
To a solution of 4-methoxy phenol (1.0 g, 0.0080 mol) in dimethylformamide
(5m1), potassium carbonate (3.3 g, 0.024 mol) and 4-fluorobenzaldehyde (1.1 g,
0.0088
mol) were added and the reaction mixture was heated to about 100 C for about 4
hours.
On completion of reaction, water was added to it and extracted in ethyl
acetate. The
organic layer was concentrated, and purified by column using 7% ethyl
acetate/hexane as
eluent to obtain the title compound. (Yield: 0.9 g)
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38
Step 2: Synthesis of 3-[(3S)-4-[(4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1]-3-
{(S)-
hydroxy14-(4-methoxyphenoxy)phenyl]methy1}-4-oxobuty11-1,2,3-benzotriazin-
4(3H)-
one
To a solution of 3-[4-((4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1)-4-oxobuty1]-
3H-
benzo[d][1,2,3]triazin-4-one (5.5 g, 0.013 mol) in dichloromethane (50 ml)
under argon
atmosphere at 0 C, titanium tetrachloride (3.19 g, 0.0169 mol) was added
slowly. The
reaction mixture was stirred for about 30 minutes and then
tetramethylethylenediamine
(3.77 g, 0.0325 mol) at 0 C was added slowly and the reaction mixture
continued to stir
for about 45 minutes at the same temperature. Subsequently, a solution of 4-(4-
methoxyphenoxy)benzaldehyde (5.2 g, 0.022 mol) in dichloromethane (20 ml) was
added
slowly and allowed to stir for about 5 hours. On completion, the reaction was
quenched
with ammonium chloride solution and subsequently by dilute hydrochloric acid,
extracted
with dichloromethane and water, and purified by column using 8% ethyl
acetate/hexane to
obtain the title compound. (Yield: 2.6 g)
Step 3: Synthesis of (2S)-2-{(5)-hydroxy[4-(4-methoxyphenoxy)phenyllmethy1}-4-
(4-
oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 56)
To a solution of the 3-[(35)-4-[(45)-4-benzyl-2-oxo-1,3-thiazolidin-3-y1]-3-
{(5)-
hydroxy[4-(4-methoxyphenoxy)phenyl]methy11-4-oxobutyl]-1,2,3-benzotriazin-
4(3H)-
one (2.6 g, 0.0040 mol) in tetrahydrofuran (30 ml) under argon atmosphere at
about 0 C,
hydrogen peroxide solution (0.408 g, 0.012 mol) and then lithium hydroxide
(0.256 g,
0.0061 mol) were added and this reaction mixture was stirred for about 2
hours. The
reaction was quenched by acidifying the reaction mixture with sodium bisulfate
and
extracting with ethyl acetate and water. The organic layer was concentrated,
and purified
by column using 8% methanol/dichloromethane as eluent to obtain the title
compound.
(Yield: 0.9g)
MS-461.46
LCMS-M-1 (460.08)
NMR(DMSO-d6, 400 MHz) 6: 8.19-8.21 (1H, d, J= 8.0 Hz), 8.15-8.17 (1H, d, J=
8.0
Hz), 8.04-8.08 (1H, d, J= 16.0 Hz), 7.89-7.92 (1H, d, J= 12.0 Hz), 7.18-7.20
(2H, d, J=
8 Hz), 6.93 (4H, d), 6.72-6.74 (2H, d, J= 8 Hz), 4.77-4.78 (1H, m, J= 4 Hz),
4.30-4.40
(2H, m), 3.73 (3H, s), 2.59 (1H, m), 2.03-2.07 (2H, m).
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The following compounds were prepared by following above route of synthesis:
(25)-2-[(5)-[4-(3-Chloro-4-fluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(41/)-yl)butanoic acid (Compound No. 57)
Mass: 482.28
(25)-2-[(5)-[4-(4-Chloro-3-methylphenoxy)pheny]](hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yebutanoic acid (Compound No. 58)
Mass: 478.25
(2S)-2-[(8)-[4-(4-Chloro-2-fluorophenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yObutanoic acid (Compound No. 59)
Mass: 482.28
(25)-2-[(5)-[4-(4-Fluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(414)-yebutanoic acid (Compound No. 60)
Mass: 448.29
(25)-2- [(5)- [4-(3 ,4-Difluorophenoxy)phenyl ] (hydroxy)methyl] -4-(4-oxo-
1,2,3 -
benzotriazin-3(414)-yebutanoic acid (Compound No. 61)
Mass: 466.31
(25)-2-[(5)-[4-(2-Chlorophenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-1,2,3-
benzotriazin-3(414)-yebutanoic acid(Compound No. 62)
Mass: 464.26
(25)-2-[(5)-[4-(3-Chlorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(411)-yl)butanoic acid (Compound No. 63)
Mass: 464.26
(25)-2-[(5)-[4-(2,6-Difluorophenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-1,2,3-
benzotriazin-3(411)-yl)butanoic acid (Compound No. 64)
Mass: 466.31
(25)-2-[(5)-[4-(2,5-Dichlorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(414)-yObutanoic acid (Compound No. 65)
Mass: 498.25 and 500.16
(25)-2-[(5)-[4-(2-Chloro-4-fluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(41/)-yObutanoic acid (Compound No. 66)
Mass: 482.28
(25)-2-1(5)-Hydroxy[4-(3-methoxyphenoxy)phenyl]methyll-4-(4-oxo-1,2,3-
benzotriazin-3(414)-yebutanoic acid (Compound No. 67)
Mass: 460.30
(25)-2-[(5)-[4-(2-Ch1oro-4-methoxyphenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yObutanoic acid (Compound No. 68)
Mass: 494.29
(2S)-2-[(S)-[4-(2,4-Difluorophenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-1,2,3-
benzotriazin-3(411)-yl)butanoic acid (Compound No. 69)
Mass: 466.31
(25)-2-[(5)-[3-Fluoro-4-(4-methylphenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(411)-yebutanoic acid (Compound No. 70)
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PCT/1B2011/053155
Mass: 462.36
(25)-2-[(5)-[3-Fluoro-4-(3-methylphenoxy)phenyl](hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 71)
Mass: 462.34
(2S)-2-[(5)-[4-(3,4-Dimethylphenoxy)-3-fluorophenyl](hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 72)
Mass: 476.46
(25)-2-[(5)-[4-(3,4-Dichlorophenoxy)-3-fluorophenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 73)
Mass: 516.33 and 518.29
(25)-2-[(5)-[4-(4-tert-Butylphenoxy)-3-fluorophenyl](hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 74)
Mass: 504.44
(25)-2-[(5)-[3-Fluoro-4-(4-methoxyphenoxy)phenyl](hydroxy)methy1]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 75)
Mass: 478.38
Synthetic Procedure For Scheme II
Example III: Synthesis of 3-[(3S,4S)-4-(4-Aminopheny1)-3-{ [(4S)-4-benzy1-2-
oxo-1,3-
thiazo lidin-3 carbony11-4-hydroxybutyll -1,2,3 -benzotriazin-4131])-one
Step 1: Synthesis of 34(3S)-41(4S)-4-benzy1-2-oxo-1, 3-thiazolidin-3-y1]-31(S)-
hydroxy(4-nitrophenyl)methy1]-4-oxobuty1}-1,2,3-benzotriazin-4(311)-one
To a solution of 3-{4-[(45)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1]-4-oxobutyll-
1,2,3-benzotriazin-4(3H)-one (20 g, 0.049 mol) in dichloromethane (350 ml) at
about 0 C,
titanium tetrachloride (58.8 ml, 0.311 mol) was added and the reaction mixture
was stirred
for about 20 minutes at room temperature (-25 C). To this,
tetramethylethylenediamine
(18.5 ml, 0.122 mol) was added at 0 C and the reaction mixture was allowed to
stir for
about 20 minutes. At the same temperature, 4-nitrobenzaldehyde (12.6 g, 0.083
mol) in
dichloromethane (50 ml) was added and allowed to stir for about 2 hours at
room
temperature (-25 C). On completion, saturated solution of ammonium chloride
and
subsequently dilute hydrochloric acid were added to the reaction mixture.
Organic layer
was extracted in dichloromethane, concentrated, purified on silica gel (60-120
mesh) using
25% ethyl acetate:hexane as eluent to get the desired product. (Yield: 18.2g)
MS: 560.15 (M+1)
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Step 2: Synthesis of 3-[(3S,4S)-4-(4-aminopheny1)-3-{[(4S)-4-benzy1-2-oxo-1,3-
thiazolidin-3-yl]carbonyll-4-hydroxybutyll-1,2,3-benzotriazin-4(31/)-one
To a solution of 3-1(35)-4-[(45)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1]-3-[(5)-
hydroxy(4-nitrophenyl)methyl]-4-oxobutyll-1,2,3-benzotriazin-4(3H)-one (18 g,
0.032
mol) in tetrahydrofuran (100 ml) and methanol (100 ml), 10% Pd/C (6.0 g) was
added at
room temperature (-25 C) and H2 was supplied in Parr apparatus at 50 psi for
about one
hour. The reaction mixture was filtered through celite and the residue was
washed with
10% methanol/dichloromethane. The filtrate was concentrated, purified on
silica gel (60-
120 mesh) column using 60% ethyl acetate:hexane as eluent to get desired
product. (Yield:
14.57 g)
MS: 512.02 (M-18)
Synthetic procedure for Scheme III
Example IV: Synthesis of (2S)-2-1(S)-14-(1[2-fluoro-44trifluoromethyl)
phenyl]carbonyl}aminolphenyl](Ilydroxy)methyll-4-(4-oxo-1,2,3-benzotriazin-
3(4H)-
yl)butanoic acid (Compound No. 46)
Step 1: Synthesis of N-14- [(1S,2S)-2-11(4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-
yl]carbonyl}-1-hydroxy-4-(4-oxo-1,2,3-benzotriazin-3(41/)-Abutyliphenyll-2-
fluoro-
4-(trifluoromethyl)benzamide
To a solution of 3-[(3S,45)-4-(4-aminopheny1)-3-1[(45)-4-benzy1-2-oxo-1,3-
thiazolidin-3-yl]carbony1}-4-hydroxybuty1]-1,2,3-benzotriazin-4(3H)-one (0.3
g, 0.00057
mol) in dichloromethane (40 ml), triethylamine (0.24 ml, 0.0017 mol) was added
at about
0 C. To this reaction mixture, 2-fluoro-4-trifluoromethyl benzoylchloride
(0.19 g,
0.00086 mol) was added under nitrogen atmosphere and the reaction mixture was
allowed
to stir for about 2 hours at room temperature. On completion, water was added
and the
organic layer was extracted and concentrated to get crude product. (Yield: 153
mg)
Step 2: Synthesis of (2S)-2-[(S)-[4-(112-fluoro-4-
(trifluoromethyl)phenylicarbonyll
amino)phenyll(hydroxy)methyll-4-(4-oxo-1,2,3-benzotriazin-3(41/)-Abutanoic
acid
(Compound No. 46)
To the solution of N-14-[(1S,25)-2- {[(4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-
yl] carbonyl} -1-hydroxy-4-(4-oxo-1,2,3-benzotriazin-3(411)-yl)butyl]phenyll -
2-fluoro-4-
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(trifluoromethyl) benzamide (0.153 g, 0.000213 mol) in tetrahydrofuran (20
ml), hydrogen
peroxide (0.022 g, 0.00064 mol), lithium hydroxide (0.0134 g, 0.000032 mol)
and water
(2.0 ml) were added and the reaction mixture was stirred for about one hour at
room
temperature. The organic layer was extracted with ethyl acetate, dried over
anhydrous
sodium sulphate, and concentrated to get crude product. Purification was done
on
preperative TLC using 10% methanol:dichloromethane as eluent to get the title
product.
(Yield: 61.0 mg)
MS: 545.16 (M+1)
NMR (DMSO-d6, 400 MHz), 6: 10.56 (1H, s), 8.22-8.17 (2H, m), 8.07 (1H, t, J =
7.44
Hz), 7.92-7.87 (3H, m), 7.73 (1H, d, J= 8.04Hz ), 7.56 (2H, d, J= 8.4 Hz),
7.25 (2H, d, J
= 8.4 Hz), 4.82 (1H, d, J= 6.04Hz), 4.40-4.32 (2H, m), 2.75-2.60 (1H, m), 2.30-
2.0 (2H,
m)
Example V: Synthesis of (2S)-2-1(S)-(4-{ [(4-
ethylphenyl)carbonyliaminolphenyl)
(hydroxy)methy1J-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound
No. 10)
Step 1: Synthesis of 3-{(3S)-4-1(4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-y11-3-
[(S)-
hydroxy(4-nitrophenyl)methy11-4-oxobuty1}-1,2,3-benzotriazin-4(31/)-one
To a solution of 3- {4-[(4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1]-4-oxobutyll-
1,2,3-benzotriazin-4(3H)-one (1 g, 0.0025 mol) in dichloromethane (20 ml) at 0
C,
titanium tetrachloride (2.94 ml, 0.0029 mol) was added drop wise and the
reaction mixture
was stirred for about 40 minutes at room temperature (-25 C). To this,
tetramethylethylenediamine (0.712 g, 0.0061 mol) was added at about 0 C and
the reaction
mixture was allowed to stir for another 30 minutes. At same temperature, a
solution of 4-
nitrobenzaldehyde (0.64 g, 0.0042 mol) in dichloromethane (50 ml) was added to
the
reaction mixture and allowed to stir for about 2 hours at room temperature (-
25 C). On
completion, saturated solution of ammonium chloride was added and the reaction
mixture
was worked up by dichloromethane and water. Purification was done on silica
gel (60-120
mesh) using 30% ethyl acetate:hexane as eluent to get the title product.
(Yield: 0.62g)
MS: 559.91 (M+1)
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Step 2: Synthesis of 3-1(3S,4S)-4-(4-aminopheny1)-3-11(4S)-4-benzy1-2-oxo-1,3-
thiazolidin-3-yllcarbonyll-4-hydroxybutyll-1,2,3-benzotriazin-4(31/)-one
To a solution of 3-1(3S)-4-[(4S)-4-benzy1-2-oxo-1,3-thiazolidin-3-y1]-3-[(S)-
hydroxy(4-nitrophenypmethyl]-4-oxobuty1}-1,2,3-benzotriazin-4(311)-one (0.61
g, 0.0011
mol) in tetrahydrofuran (20 ml), 10% Pd/C (0.5 g) at room temperature (-25 C)
was added
and H2 was supplied using balloon for about 2 hours. The reaction mixture was
filtered
through celite and the residue was washed with 10% methanol:dichloromethane.
The
filtrate was concentrated to get the desired compound. (Yield: 0.6g)
MS: 511.94 (M-18)
Step 3: Synthesis of N-14-[(1S,2S)-2-{[(45)-4-benzy1-2-oxo-1,3-thiazolidin-3-
yl]carbony1}-1-hydroxy-4-(4-oxo-1,2,3-benzotriazin-3(41/)-y1)butyllpheny11-4-
ethylbenzamide
To a solution of 3-[(3S,4S)-4-(4-aminopheny1)-3-1[(4S)-4-benzy1-2-oxo-1,3-
thiazolidin-3-yl]carbonyl} -4-hydroxybuty1]-1,2,3-benzotriazin-4(311)-one (0.6
g, 0.0011
mol) in dichloromethane (20 ml), triethylamine (0.47 ml, 0.0034 mol) was added
at about
0 C. Afterwards, 4-ethyl benzoylchloride (0.29 g, 0.0017 mol) was added and
the reaction
mixture was stirred for about 30 minutes at 0 C. The reaction was worked up
with
dichloromethane and water to get crude product. (Yield: 680 mg)
MS: 662.04 (M+1)
Step 4: Synthesis of (2S)-2-[(S)-(4-{[(4-
ethylphenyl)carbonyl]aminolphenyl)(hydroxy)
methyl]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 10)
To the solution of N-14-[(1S,29-2-1[(45)-4-benzyl-2-oxo-1,3-thiazolidin-3-
yl]carbonyl} -1-hydroxy-4-(4-oxo-1,2,3-benzotriazin-3(411)-yl)butyllphenyl} -4-
ethylbenzamide (0.35 g, 0.00053 mol) in tetrahydrofuran (10 ml), hydrogen
peroxide
(0.3m1, 2.65 moles) was added and reaction mixture was stirred for about 15
minutes at
0 C. Subsequently, lithium hydroxide (0.033 g, 0.00079 mol) and water (5 ml)
were
added to it and again stirred for about 2 hours at room temperature. On
completion, the
reaction was quenched by adding water and extracted with ethyl acetate. The
organic
layer was dried over anhydrous sodium sulfate, concentrated and purified by
preparative
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44
TLC using 10% methanol:dichloromethane as eluent to get the title product.
(Yield: 84.0
mg)
MS: 485.17 (M-1)
NMR (DMSO-d6,400 MHz), 8: 10.06 (1H, s), 8.20-8.15 (2H, m), 8.06-8.02 (1H, m),
7.89-7.85 (3H, m), 7.61 (2H, d, J= 8.4 Hz), 7.35 (2H, d, J= 8.4 Hz), 7.21 (2H,
d, J= 8.4
Hz), 4.80-4.78 (1H, m), 4.40-4.32 (2H, m), 2.70-2.65 (3H, m), 2.20-2.00 (2H,
m).
The following compounds were prepared by following above route of synthesis:
(2S)-2-[(S)-(4-{ [(4-Chlorophenyl)carbonyl] amino phenyl)(hydroxy)methyl] -4-
(4-
oxo-1,2,3-benzotriazin-3(41/)-yl)butanoic acid (Compound No. 11)
Mass: 492.91
(2S)-2-[(S)-(4-{ [(3,4-Dichlorophenyl)carbonyl] amino phenyl)(hydroxy)methyl] -
4-
(4-oxo-1,2,3-benzotriazin-3(41/)-yl)butanoic acid (Compound No. 12)
Mass: 528.84
(2S)-2-[(S)-Hydroxy(4-{ [(4-methoxyphenyl)carbonyl] amino phenyl)methyl] -4-(4-
oxo-1,2,3-benzotriazin-3(41/)-yObutanoic acid (Compound No. 13)
Mass: 489.97
(2S)-2-[(S)-Hydroxy(4- [(3 -methoxyphenyl)carbonyl] amino } phenyl)methyl] -4-
(4-
oxo-1,2,3-benzotriazin-3(41/)-yl)butanoic acid (Compound No. 14)
Mass: 489.97
(2S)-2-[(S)-Hydroxy(4-{ [(4-methylphenyl)carbonyl]amino } phenyl)methy1]-4-(4-
oxo-1,2,3-benzotriazin-3(41-/)-yObutanoic acid (Compound No. 15)
Mass: 473.01
(2S)-2-[(S)-(4- [(4-F luorophenyl)carbonyl] amino } phenyl)(hydroxy)methyl -4-
(4-
oxo-1,2,3-benzotriazin-3(41/)-yObutanoic acid (Compound No. 16)
Mass: 477.96
(25)-2- {(S)-Hydroxy[4-({ [4-methoxy-3-(trifluoromethyl)phenyl ]carbonyl}
amino)phenyl] methy11-4-(4-oxo-1,2,3-benzotriazin-3(41/)-y1)butanoic acid
(Compound No. 17)
Mass: 557.94
(25)-2- [(S)-Hydroxy(4- [(5-methyl-1,2-oxazol-3 -yl)carbonyl] amino phenyl)
methyl]-4-(4-oxo-1,2,3-benzotriazin-3(41/)-yl)butanoic acid (Compound No. 18)
Mass: 464.96
(25)-2- [(S)-(4- [(3 -Chloro-4-fluorophenyl)carbonyl] amino } phenyl)(hydroxy)
methy1]-4-(4-oxo-1,2,3-benzotriazin-3(41/)-y1)butanoic acid (Compound no. 19)
Mass: 510.80
(25)-2-[(S)-Hydroxy{4-[(phenylcarbonypamino]phenyllmethyl]-4-(4-oxo-1,2,3-
benzotriazin-3(41/)-y1)butanoic acid (Compound No. 20)
Mass: 459.95
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45
(25)-2- [(S)-Hydroxy(4- [(4-propylphenyl)carbonyl] amino phenyl)methy1]-4-(4-
oxo-1,2,3-benzotriazin-3(41/)-yl)butanoic acid (Compound No. 21)
Mass: 501.92
(25)-2-[(S)-Hydroxy{4-[(phenoxycarbonyl)amino]phenyllmethyl]-4-(4-oxo-1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound No. 22)
Mass: 475.92
(2S)-2-[(S)-Hydroxy {4-[(phenylacetypamino]phenyllmethyl]-4-(4-oxo-1,2,3-
benzotriazin-3(4H)-y1)butanoic acid (Compound No. 23)
Mass: 473.94
(25)-2- [(S)-(4- { [(2,4-D ichlorophenyl)carbonyl] amino
phenyl)(hydroxy)methy1]-4-
(4-oxo-1,2,3-benzotriazin-3(4H)-y1)butanoic acid (Compound No. 24)
Mass: 526.84
(25)-2- [(S)-Hydroxy(4- [(2-methylphenyl)carbonyl]aminolphenypmethyl]-4-(4-
oxo-1,2,3-benzotriazin-3(411)-y1)butanoic acid (Compound No. 25)
Mass: 472.92
(25)-2- [(S)-(4- [(2-Fluorophenyl)carbonyl]aminolphenyl)(hydroxy)methyl]-4-(4-
oxo-1,2,3-benzotriazin-3(411)-yDbutanoic acid (Compound No. 26)
Mass: 476.88
(25)-2- [(S)-(4- [(3 -Chlorophenyl)carbonyl] aminolphenyl)(hydroxy)methyl] -4-
(4-
oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 27)
Mass: 492.85
(25)-2- [(S)-Hydroxy(4- [(3-methylphenyl)carbonyl]aminolphenyl)methyl]-4-(4-
oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 28)
Mass: 472.92
(25)-2- [(S)-(4- [(3-Fluorophenyl)carbonyl]aminolphenyl)(hydroxy)methyl]-4-(4-
oxo-1,2,3-benzotriazin-3(411)-y1)butanoic acid (Compound No. 29)
Mass: 476.88
(25)-2-[(S)-(4- [(2,6-Dimethoxyphenyl)carbonyl]aminolphenyl)(hydroxy)
methyl]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 30)
Mass: 518.92
(25)-2- [(5)- {4-[(Cyclopentylcarbonyl)amino]phenyll(hydroxy)methyl]-4-(4-oxo-
1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 31)
Mass: 450.94
(25)-2- [(5)-Hydroxy(4- [(2,4,5 -trifluoro-3 -methoxyphenyecarbonyl] amino}
phenyl)methy1]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound
No. 32)
Mass: 543.09
(25)-2-[(5)-Hydroxy(4-{ [(2,3 ,4-trifluorophenyl)carbonyl] aminolphenyemethyl
] -4-
(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 33)
Mass: 513.06
(25)-2- {(5)-Hydroxy[4-({ [2-(trifluoromethyl)pheny] ]carbonyl } amino)phenyl]
methyl} -4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 34)
Mass: 527.11
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(25)-2- [(5)-(4- [(3,5 -D imethoxyphenyl)carbonyl] amino } phenyl)(hydroxy)
methy1]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yebutanoic acid (Compound No. 35)
Mass: 519.13
(2S)-2-[(S)-(4- [(2,3 -Difluorophenypc arbonyl] amino }phenyl)(hydroxy)methyl
] -4-
(4-oxo-1,2,3-benzotriazin-3(411)-yebutanoic acid (Compound No. 36)
Mass: 495.04
(28)-2-[(S)-(4-{[(3,5-Dichlorophenyl)carbonyl]amino}phenyl)(hydroxy)methyl]-4-
(4-oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 37)
Mass: 526.99
(25)-2- [(5)-(4- [(2,4-Difluorophenyl)carbonyl] amino } phenyl)(hydroxy)methyl
] -4-
(4-oxo-1,2,3-benzotriazin-3(411)-yebutanoic acid (Compound No. 38)
Mass: 495.04
(25)-2- [(5)-(4- [(2,6-D ifluorophenyl)carbonyl] amino }
phenyl)(hydroxy)methyl ] -4-
(4-oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 39)
Mass: 495.10
(25)-2-[(5)-Hydroxy(4- [(2-methoxyphenyl)carbonyl ] amino} phenyl)methy1]-4-(4-
oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 40)
Mass: 489.16
(25)-2- [(S)- {4- [(Cyclohexylc arbonyl)amino] phenyl } (hydroxy)methy1]-4-(4-
oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 41)
Mass: 465.20
(2S)-2-[(S)-(4- [(4-Ethoxyphenyl)carbonyl] amino }phenye(hydroxy)methy1]-4-(4-
oxo-1,2,3-benzotriazin-3(4H)-yObutanoic acid (Compound No. 42)
Mass: 503.20
(2S)-2-[(S)-(4- [(3,4-Difluorophenyl)carbonyl ] amino } phenyl)(hydroxy)m
ethyl] -4-
(4-oxo-1,2,3-benzotriazin-3(411)-yebutanoic acid (Compound No. 43)
Mass: 495.16
(25)-2- (5)-Hydroxy [4-( [4-(trifluoromethoxy)phenyl]carbonyllamino)phenyl]
methyl} -4-(4-oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 44)
Mass: 545.15
(25)-2- (5)-Hydroxy[4-({ [3-(trifluoromethyl)pheny] ] carbonyl} amino)phenyl]
methyl} -4-(4-oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 45)
Mass: 527.15
(2S)-2-[(S)-(4- [(3-Chloro-2,6-difluorophenyl)carbonyl ]aminolphenyl)(hydroxy)
methy1]-4-(4-oxo-1,2,3-benzotriazin-3(411)-yObutanoic acid (Compound No. 47)
Mass: 529.13
(25)-2- (5)-Hydroxy[4-({ [4-(trifluoromethyl)phenyl ] carbonyl} amino)phenyl]
methyl} -4-(4-oxo-1,2,3-benzotriazin-3(411)-yebutanoic acid (Compound No. 48)
Mass: 527.16
(25)-2- [(5)-(4- [(2,5-Difluorophenyl)c arbonyl] amino }
phenyl)(hydroxy)methyl] -4-
(4-oxo-1,2,3-benzotriazin-3(411)-yl)butanoic acid (Compound No. 49)
Mass: 495.15
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(25)-2- [(5)-(4- [(2,3-Difluoro-4-methylphenyl)carbonyl] amino)
phenyl)(hydroxy)
methy1]-4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 50)
Mass: 509.18
(2S)-2-[(5)-[4-({ [4-Fluoro-3 -(trifluoromethyl)phenyl] carbonyl amino)phenyl]
(hydroxy)methyl]-4-(4-oxo-1,2,3-benzotriazin-3(41/)-y1)butanoic acid (Compound
No. 51)
Mass: 545.15
(2S)-2- [(S)- {4-[(Cyclopropylcarbonyl)amino]phenyll(hydroxy)methyl]-4-(4-oxo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 52)
Mass: 423.19
(2S)-2-[(5)-(4- [(2-Ethylphenyl)carbonyllamino)phenyl)(hydroxy)methyl]-4-(4-
oxo-1,2,3-benzo triazin-3(411)-yl)butanoic acid (Compound No. 53)
Mass: 485.19
(25)-2-[(5) -Hydro xy(4- [(4-metho xyphenyl)acetyl] aminolphenyl)methyl] -4-(4-
oxo-1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 54)
Mass: 503.20
(25)-2- [(5)- {4- [(Cyclobutylc arbonyl)amino]phenyll(hydroxy)methyl]-4-(4-o
xo-
1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound No. 55)
Mass: 437.21
Assay for Matrix Metalloproteinases (MMPs)
New chemical entities of the present invention and corresponding standards
used in
the present invention were prepared (stock 10 mM) in 100% DMSO and subsequent
dilutions were made in MMP assay buffer [50 mM HEPES, 10 mM CaC12, 150 nM
NaCl,
1 uM Zinc Acetate, 600 iM CHAPS (pH 7.4)]. Assays used human MMPs expressed
either as full length or catalytic domain. The Collagenase (MMP-1), Gelatinase
(MMP-9),
Elastase (MMP-12) and membrane type-1 (MMP-14) were cleaved and activated
using
reagent APMA (4-amino phenyl mercuric acetate) to obtain active catalytic
domains. In a
typical 100 ul reaction assay mixture, 1.0 ul of desired MMP enzyme was
incubated in
buffered solution in absence or presence of 1.0 of NCEsistandards for 30
minutes.
Reaction was started with desired flurogenic substrate ¨ FAM-TAMRA (FAM-Thr-
Pro-
G1y-Pro-Leu-G1y-Leu-Dpa-A1a-Arg-Arg-Lys-TAMRA-NH2) at a final concentration of
10 uM per well and reaction was allowed to proceed for 45 minutes and rate of
velocity
was monitored (increase in RFUs) at excitation wavelength of 495 rim and
emission 525
nm. Blank reaction rate (without enzyme) was subtracted from each value. The
percent
control was calculated using the following formula:
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Percent activity = (inhibited rate/control rate) x 100.
IC50 values were calculated using least square regression analysis method by
Graph-Pad prism version 4.2 software; using a 5-6 point dose response curve in
presence
of inhibitor. IC50 values were averaged for duplicate assay data and values
tabulated.
The present invention relates to compounds that act as dual MMP-9/12
inhibitors,
which have desirable activity profiles.
MMP-9 activities of the compounds disclosed in the invention, provided IC50
values from about 10 micromolar to about 1 nM, or from about 1 micromolar to
about 1
nM, or from about 650 nM to about 1 nM, or from about 300 nM to about 1 nM, or
from
about 100 nM to about 1 nM, or from about 50 nM to about 1 nM, or from about
30 nM to
about 1 nM, or from about 20 nM to about 1 nM, or from about 12 nM to about 1
nM, as
compared to about 1.4 nM to 3.2 nM for marimastat.
MMP-12 activities of the compounds disclosed in the invention, provided IC50
values from about 10 micromolar to about 1 nM, or from about 1 micromolar to
about 1
nM, or from about 300 nM to about 1 nM, or from about 100 nM to about 1 nM, or
from
about 50 nM to about 1 nM, or from about 30 nM to about 1 nM, or from about 20
nM to
about 1 nM, or from about 15 nM to about 1 nM, or from about 7 nM to about 1
nM as
compared to 0.2 nM to 0.9 nM for marimastat.
