MATRIX METALLOPROTEINASEINHIBITORS
Field of the Invention
The present invention relates to methyl sulfonamides and N-formamides
derivatives and to processes for their syntheses. The invention also relates to
pharmacological compositions containing these derivatives 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 disease,
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 disease processes
that involve remodeling, such as, airway diseases, 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 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
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 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.
MMP-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 have 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 Zn + ion (Whittaker et al. , Chem. Rev. , 99; p. 2735-76 ( 1999),.
WO 95/35276 discloses N-substituted arylsulphonyl amino acid and their
hydroxamic acid derivatives as matrix metallo -proteinase inhibitors. WO 00/06561
discloses tricyclic sulfonamides compounds as matrix metalloproteinases. U.S. Patent No.
6,366,675 discloses N-sulphonyl-diamino: carboxylic acid derivatives used as matrix
metalloprotease inhibitors. WO 2004/1 13279 discloses substituted glycine derivatives,
useful for treating inflammatory conditions or autoimmune disorders 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
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 the 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 the methyl sulfonamide and formamides
derivatives as matrix metalloproteinase 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
MMP9/12 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 and 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, specific enantiomers have been shown by way of examples, racemates,
diastereomers, and pharmaceutically acceptable salts are also provided. Pharmaceutical
compositions comprising the compounds, their enantiomers, racemates, diastereomers and
pharmaceutically acceptable salts are also included.
The therapeutically effective amount 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, antihypertensive agents and immunosuppressive
agents
Other objects will be set forth in accompanying description and in the part will be
apparent from the description or may be by the practice of the invention.
Detailed Description of the Invention
In accordance with one aspect, there is provided compounds having structure of
Formula I :
Formula 1
including racemates, enantiomers, or diastereomers thereof; or a pharmaceutically
acceptable salt thereof, wherein,
L1can be selected from bond, O, S, CH2, NR4, NHCO(CH2)n, (CH2)nCONH,
NHCONH, S0 2NH, NHSO2, NHCO(O), -0-(CH 2)n, -(CH2)n-0-, -OC(0)NH-, C(S)NH,
NHC(S), NHC(S)NH or -COO- wherein n can be zero or an integer between 1 and 2;
R1 can be selected from hydrogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, cyano,
nitro, halogen, halogeno Ci-C6alkyl, C 5-C12 aryl, C -C heteroaryl, C3-C6 cycloalkyl
wherein aryl, heteroaryl, cycloalkyl is optionally substituted by one or more substitutents
independently selected from R5;
R2 can be CHO or S0 2Ci_6 alkyl;
R can be unsubstituted or substituted heteroaryl or -OCONHR' where R' is C -
C12 aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocyclylalkyl each of which is optionally substituted by one or more substitutents
independently selected from R5;
R4 can be H or Ci_6alkyl;
R5 can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-
Ci-C6 alkyl, halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2) -ORf, -C(=0)-R f, -
COORf, -NRfRq,
(CH2) NHC(=0)NRfR -(CH2) -0-C(=0)- Rf, -(CH2) -NH-C(=0)-R f
or -(CH2) S(=0) m-NRfRq {whereinRf and Rq are independently selected from hydrogen, alkyl,
alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and
alkylheterocyclyl, n is as defined earlier andm is an integer 0-2} .
In one aspect the invention encompasses compounds that include, for example,
2-[Formyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 1);
4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[formyl(4'-methylbiphenyl-4-
yl)amino]butanoic acid (Compound no. 2);
2-[(4'-Ethylbiphenyl-4-yl)(formyl)amino]-4-(5-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 3);
0-[(4-Fluorophenyl)carbamoyl ]-N-formyl-N-(4'-methylbiphenyl-4-yl)homoserine
(Compound no. 4);
N-Formyl-N-(4'-methylbiphenyl-4-yl)-0-[(4-methylphenyl)carbamoyl]homoserine
(Compound no. 5);
O-[(3 ,4-Dichlorophenyl)carbamoyl] -N-formyl-N-(4'-methylbiphenyl-4-
yl)homoserine (Compound no. 6);
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-0-{[4-(propan-2-yl)phenyl]carbamoyl}
homoserine (Compound no. 7);
N-(4'-Ethylbiphenyl-4-yl)-0-[(3-fluorophenyl)carbamoyl ]-N-formylhomoserine
(Compound no. 8);
0-[(2,4-Difluorophenyl)carbamoyl ]-N-(4'-ethylbiphenyl-4-yl )-Nformylhomoserine
(Compound no. 9);
N-(4'-Ethylbiphenyl-4-yl)-0-[(2-fluorophenyl)carbamoyl ]-N-formylhomoserine
(Compound no. 10);
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-0-{[4-(trifluoromethyl)phenyl]carbamoyl}
homoserine (Compound no. 11);
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-0-[(2-methylphenyl)carbamoyl]homoserine
(Compound no. 12);
N-(4'-Ethylbiphenyl-4-yl)-0-[(4-ethylphenyl)carbamoyl ]-N-formylhomoserine
(Compound no. 13);
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-0-[(4-methoxyphenyl)carbamoyl]homoserine
(Compound no. 14);
0-[(2,6-Dichlorophenyl)carbamoyl ]-N-(4'-ethylbiphenyl-4-yl )-Nformylhomoserine
(Compound no. 15);
2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-dioxo-l,3-dihydro-2 H-isoindol-2-
yl)butanoic acid (Compound no. 16);
4-(l,3-Dioxo-l,3-dihydro-2 H-isoindol-2-yl)-2-{[4-(6-methoxypyridin-3-
yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 17);
4-(l ,3-Dioxo- 1,3-dihydro-2H-isoindol-2-yl)-2-[(4'-methoxybiphenyl-4-
yl)(methylsulfonyl)amino]butanoic acid (Compound no. 18);
2-{[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 19);
4-(7-Methoxy-4-oxo- 1,2,3-benzotriazin-3(4 H)-yl)-2- {[4-(6-methoxypyridin-3-
yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 20);
2-{[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino}-4-[4-oxo-7-
(trifluoromethyl)-l,2,3-benzotriazin-3(4 H)-yl]butanoic acid (Compound no. 21);
4-(l,3-Dioxo-l,3-dihydro-2 H-isoindol-2-yl)-2-{[4-(6-methoxypyridin-3-
yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 22);
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4-(4-
methylphenoxy)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 23);
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4-(4-methylphenoxy)
phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 24);
2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino} -4-[4-oxo-7-
(trifluoromethyl)-l,2,3-benzotriazin-3(4 H)-yl]butanoic acid (Compound no. 25);
2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino} -4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 26);
2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 27);
2-[(4'-Ethylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 28);
2- {[4-(2-Methoxypyrimidin-5-yl)phenyl] (methylsulfonyl)amino }-4-(4-oxo- 1,2,3 -
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 29);
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 30);
2-[(2',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 31);
2-[(4-Methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 32);
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(4-
methoxyphenyl)(methylsulfonyl)amino]butanoic acid (Compound no. 33);
4-(l ,3-Dioxo- 1,3-dihydro-2H-isoindol-2-yl)-2-[(4-methoxyphenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 34);
2-[(4-Methoxyphenyl)(methylsulfonyl)amino] -4-(5-methyl- 1,3-dioxo- 1,3-dihydro-
2H-isoindo-2-yl)butanoic acid (Compound no. 35);
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-{[4-(4-
methylphenoxy)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 36);
4-(5-Methyl- 1,3-dioxo- 1,3-dihydro-2H-isoindol-2-yl)-2- {[4-(4-methylphenoxy)
phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 37);
2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 38);
2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 39);
2-{(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 40);
2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 41);
2-{[4-(6-Methylpyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 42);
2-{(Methylsulfonyl)[4-(pyrimidin-5-yl)phenyl]amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 43);
2-{(Methylsulfonyl)[4-(pyridin-3-yl)phenyl]amino}-4-(4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 44);
2-{(Methylsulfonyl)[4'-(trifluoromethyl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 45);
2- {(Methylsulfonyl)[4-(pyridin-4-yl)phenyl]amino} -4-(4-oxo- 1,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 46);
2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 47);
2-[(4'-ieri-Butylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 48);
2-[(2',3'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 49);
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 50);
4-(l,3-Dioxo-l,3-dihydro-2 H-isoindol-2-yl)-2-{(methylsulfonyl)[4-(propan-2-
yl)phenyl] aminojbutanoic acid (Compound no. 51);
4-(6-Methoxy-4-oxo- 1,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan-
2-yl)phenyl] aminojbutanoic acid (Compound no. 52);
4-(7-Methyl-4-oxo- 1,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan-2-
yl)phenyl] aminojbutanoic acid (Compound no. 53);
4-(l ,3-Dioxo- 1,3-dihydro-2H-isoindol-2-yl)-2-[(4-ethylphenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 54);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(5-methyl-l,3-dioxo-l,3-dihydro-2 Hisoindol-
2-yl)butanoic acid (Compound no. 55);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 56);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 57);
2-[(Methylsulfonyl)(phenyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic
acid (Compound no. 58);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methyl- 1,3-dioxo- 1,3-
dihydro-2H-isoindol-2-yl)butanoic acid (Compound no. 59);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-chloro-4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 60);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-chloro-4-oxo-l,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 61);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 62);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-(trifluoromethyl)-
l,2,3-benzotriazin-3(4 H)-yl]butanoic acid (Compound no. 63);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methoxy-4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 64);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-fluoro-4-oxo- 1,2,3-
benzotriazin-3(4H)-yl)butanoic acid (Compound no. 65);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(l-methyl-2,4-dioxo-l,4-
dihydroquinazolin-3(2H)-yl)butanoic acid (Compound no. 66);
4- {(Methylsulfonyl) [1-oxo-4-(4-oxo- 1,2,3-benzotriazin-3(4H)-yl)- 1-(prop-2-en- 1-
yloxy)butan-2-yl] amino}benzoic acid (Compound no. 67);
2-[{4-[(4-Methylphenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 68);
2-[ {4-[(4-Chlorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 69);
2- {(Methylsulfonyl)[4-(phenylcarbamoyl)phenyl]amino} -4-(4-oxo- 1,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 70);
2-[ {4-[(3-Fluorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 71);
2-[(Methylsulfonyl)(4- {[4-(propan-2-yl)phenyl]carbamoyl} phenyl)amino]-4-(4-
oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 72);
2-[ {4-[(4-Methoxyphenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 73);
2-[ {4-[(4-Fluorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 74);
2-[(Methylsulfonyl)(4-{[4-(trifluoromethyl)phenyl] carbamoyljphenyl) amino] -4-
(4-oxo- l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 75);
(2R)-2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3 -
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 76);
(2R)-2- {(Methylsulfonyl) [4-(pyrimidin-5-yl)phenyl] amino }-4-(4-oxo- 1,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 77);
(2R)-2-{(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 78);
(2R)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 79);
(2R)-2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 80);
(2R)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 81);
(2R)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 82);
(2R)-2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 83);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 84);
(2R)-2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 85);
(2R)-2-{[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 86);
(2S)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 87);
(2S)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 88);
(2S)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzo triazin-3(4H)-yl)butanoic acid (Compound no. 89);
(2S)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 90);
(2R)-2-[(3',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 91);
(2R)-2-{[4-(2,3-Dihydro-l,4-benzodioxin-6-yl)phenyl](methylsulfonyl)amino}-4-
(4-oxo- l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 92);
(2R)-2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 93);
(2R)-2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 94);
(2R)-2-{(Methylsulfonyl)[4'-(trifluoromethoxy)biphenyl-4-yl]amino}-4-(4-oxol,
2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 95);
(2R)-2-{[4'-Chloro-3'-(trifluoromethyl)biphenyl-4-yl](methylsulfonyl)amino}-4-
(4-oxo- l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 96);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-
(trifluoro methyl)- l,2,3-benzotriazin-3(4 H)-yl]butanoic acid (Compound no. 97);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8-methyl-
4-oxo- l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 98);
(2R)-4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(3'-fluoro-4'-
methoxybiphenyl-4-yl)(methylsulfonyl)amino]butanoic acid (Compound no. 99);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-
methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 100);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-methyl-
4-oxo- l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 101);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8-
methoxy-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 102);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-fluoro-4-
oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 103);
4-(5-Chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[(4-chlorophenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 104);
2-[(4-Bromophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 105);
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4 H)-
yl)butanoic acid (Compound no. 106);
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- 1,2,3-
benzotriazin-3(4 H)-yl)butanoic acid (Compound no. 107);
2-[(4-Chlorophenyl)(methylsulfonyl)amino] -4-(6-methoxy-4-oxo- 1,2,3-
benzotriazin-3(4H )-yl)butanoic acid (Compound no. 108).
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 methods for treating or prophylaxis of an
animal or a human suffering from various inflammatory or allergic diseases, comprising
administering to a mammal in need thereof therapeutically effective amount of one or
more compounds of Formula 1, described herein.
In one embodiment, the diseases or conditions of inflammation and associated
pathologies are selected from 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 disease, tumor metastasis, and other inflammatory disorders
In yet another aspect, the present invention relates to the therapeutically effective
amount of compounds of Formula I in combination with one or more of other therapeutic
agents used in treating various inflammatory and allergic diseases. Examples of such
therapeutic agents includes, 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, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4 -Inhibitors, 5-
lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors,
(iv) MMP inhibitors, and (v) interleukin-I inhibitors;
2) 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.
3) immunosuppressive agents such as cyclosporine, azathioprine and
methotrexate, and anti inflammatory corticosteroids.
The following definitions apply to terms, as used herein.
The term "alkyl", unless otherwise specified, refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1to 20 carbon atoms. This term can
be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term "alkenyl", unless otherwise specified, refers to a monoradical of a
branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms
with cis, trans or geminal geometry.
The term "alkynyl", unless otherwise specified, refers to a monoradical of an
unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
The term "cycloalkyl", unless otherwise specified, refers to cyclic alkyl groups of
from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which
may optionally contain one or more olefinic bonds, unless otherwise constrained by the
definition. Such cycloalkyl groups can include, for example, single ring structures,
including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like or multiple ring
structures, including adamantanyl, and bicyclo [2.2. 1] heptane or cyclic alkyl groups to
which is fused an aryl group, for example, indane, and the like. Spiro and fused ring
structures can also be included.
The term "aryl", unless otherwise specified, refers to aromatic system having 6 to
14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are
carbocyclic aromatic groups. For example, aryl groups include, but are not limited to,
phenyl, biphenyl, anthryl or naphthyl ring, and the like.
The term "aryloxy" denotes the group O-aryl wherein aryl is the same as defined
above.
The term "heteroaryl", unless otherwise specified, refers to an aromatic ring
structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from
8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S
and optionally are benzofused or fused heteroaryl having 5-6 ring members.
The term "heterocyclyl", unless otherwise specified, refers to a non-aromatic
monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1to 4 carbon atoms
in a ring are replaced by heteroatoms selected from O, S or N, and optionally are
benzofused or fused heteroaryl having 5-6 ring members.
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 "halogen" refers to fluorine, chlorine, bromine or iodine;
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.
The compounds of this invention can contain one or more asymmetric carbon atom
and thus may occur as racemic mixtures, enantiomers and diasteromers. These
compounds can also exist as conformers/rotamers. All such isomeric forms of these
compounds are included in the present invention. Each stereogenic carbon atom may be
of the R or S configuration. Although the specific compounds exemplified in this
application may be depicted in a particular sterochemical configuration, compounds
having either the opposite stereochemistry at any given chiral center or mixture thereof are
envisioned as part of the invention.
The term "pharmaceutically acceptable salts" forming part of this invention
includes the salts of carboxylic acids moiety, which can be prepared by reacting the
compound with appropriate base to provide corresponding base addition salts. Examples
of such base 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 with
pharmaceutically acceptable organic and inorganic acids, e.g., hydro halides, 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, tartaratae, maleate, succinate, citrate, etc.
In another aspect, the compounds, disclosed herein, may be prepared by following
reaction sequences as depicted in Schemes I, II, III, IV, V and VI.
Scheme I
Formula 10 Formula 1 Formula 13
{Formula 1when R3 is {Formula 1when R3 is
heteroaryl, L1 is bond} OCONHR, L1 is bond}
The compound of Formula 10 (Path A) and Formula 13 (Path B) can be prepared
according to Scheme I . Thus, reacting 4-bromo-nitrobenzene with a compound of
Formula 2 (wherein is aryl or heteroaryl ring and R6 is hydrogen, alkyl, halogen,
alkoxy or halogeno-Ci-C6 alkyl) gives a compound of Formula 3 which on reduction
forms a compound of Formula 4. The reaction of a compound of Formula 4 with alphabromolactone
gives a compound of Formula 5 which on upon formylation forms a
compound of Formula 6. The compound of Formula 6 on ring opening forms a compound
of Formula 7 (wherein Rp is carboxy protecting group, such as methyl, ethyl, allyl, benzyl,
t-butyl, silyl, BOC-anhydride) which on reaction with a compound of Formula 8 (wherein
is a heteroaryl ring, R5 is same as defined earlier) gives a compound of Formula 9
which finally on deprotection gives a compound of Formula 10. The reaction of a
compound of Formula 7 with a compound of Formula 11 (where R' is same as defined
earlier) gives a compound of Formula 1 which on deprotection give a compound of
Formula 13.
The coupling of 4-bromo-nitrobenzene with a compound of Formula 2 to give a
compound of Formula 3 can be carried out in the presence of inorganic base selected from,
for example, potassium carbonate, sodium carbonate, sodium acetate, potassium acetate in
presence of a solvent selected from, tetrahydrofuran, N,N -dimethylformamide,
dimethylsulfoxide, toluene, or mixture(s) thereof.
The reduction of a compound of Formula 3 to give a compound of Formula 4 can
be carried out using reducing agent selected from, for example, Raney Nickel in hydrazine
hydrate or ammonium formate, zinc, tin or iron in the presence of hydrochloric acid or
lithium aluminum hydride, Pd/C in H 2 in the presence of a solvent, for example,
tetrahydrofuran, methanol, ethanol, diethyl ether, dioxane, or mixture(s) thereof.
The coupling of a compound of Formula 4 with alpha-bromolactone to give a
compound of Formula 5 can be carried out using inorganic base selected from, for
example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate
using solvent selected from, for example, acetonitrile, water, or mixture(s) thereof.
The formylation of a compound of Formula 5 to give a compound of Formula 6
can be carried out using formylating agent selected from, for example, formic acid, acetic
formic anhydride, chloral, activated formic acid using N, N -dicyclohexylcarbodiimide
(DCC) or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), activated formic ester,
ammonium formate in the presence of a solvent selected from, for example, toluene,
dimethoxymethane, xylene, or mixture(s) thereof.
The ring opening of a compound of Formula 6 to give a compound of Formula 7
can be carried out with alkyl/aryl halide in the presence of 18-crown-6 using one or more
inorganic base selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide,
lithium hydroxide in the presence of a solvent, for example, N, N -dimethylformamide,
methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water, or mixture(s)
thereof.
The coupling of a compound of Formula 7 with a compound of Formula 8 to give a
compound of Formula 9 can be carried out in the presence of redox couple. The oxidizing
part of the redox couple is selected from, for example, 1,1' -(azodicarbonyl)piperidine
(ADDP), 4,7-dimethyl-3,5,7-hexahydro-l,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,N,Ntetramethylazodicarboxamide
(TMAD), N,N,N,N-tetraisopropylazodicarboxamide
(TIPA), diethyl azodicarboxylate (DEAD), di-Z-butylazodicarboxylate or
diisopropylazodicarboxylate (DIAD). The reducing part of the redox couple is selected
from, for example, tributylphosphine, triphenylphosphine, />(dimethylaminophenyl) or
triscyclohexylphosphine in the presence of a solvent, for example, tetrahydrofuran,
dimethylsulfoxide, N,7V-dimethylformamide, acetonitrile, or mixture(s) thereof.
The deprotection of a compound of Formula 9 to give a compound of Formula 10
can be carried out can be carried out in the presence of mineral acid, for example,
hydrochloric, hydrobromic, hydroiodic acid in a solvent selected from dichloromethane,
chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile,
tetrahydrofuran, or mixture(s) thereof.
Or alternatively, the deprotection of a compound of Formula 9 to give a compound
of Formula 10 can be carried out in the presence of one or more organic acid(s), for
example, trifluoroacetic acid, />toluenesulphonic acid or camphor sulphonic acid, in a
solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane,
methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
Or alternatively, the deprotection of a compound of Formula 9 to give a compound
of Formula 10 can be carried out in the presence of inorganic base, for example, lithium
hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium
carbonate in a solvent selected from dichloromethane, chloroform, carbon tetrachloride,
dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
Or alternatively, the deprotection of a compound of Formula 9 to give a compound
of Formula 10 can be carried out in the presence of deprotecting agent, for example, Pd/C
in presence of ¾, Pd/C with ammonium formate, Pd/C in presence of triethylsilane, ozone,
boron trichloride dimethylsulfide (BCl3.SMe2), 2,3-dichloro-5,6-dicyano-/>benzoquinone
(DDQ), tetrakis triphenylphosphine in the presence of morpholine using solvent selected
from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol,
ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
The reaction of a compound of Formula 7 with a compound of Formula 11 to give
a compound of Formula 12 can be carried out in the presence of base selected from, for
example, triethylamine, N,N -dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, Nethyldiisoproylamine,
N,N -diisopropylethylamine or N-methylmorpholine in a solvent
selected from, tetrahydrofuran, N, N -dimethylformamide, dimethylsulfoxide, acetonitrile,
or mixture(s) thereof.
The deprotection of a compound of Formula 12 to give a compound of Formula 13
can be carried out under similar conditions as described for the compound of Formula 9 to
give a compound of Formula 10.
Scheme II
Formula 20 Formula 19 Formula 18
[Formula 1when R3 is
heteroaryl and L is bond]
The compound of Formula 20 can be prepared according to Scheme II. Thus, the
t 5
alpha halogenation of a compound of Formula 14 (wherein is a heteroaryl ring, R is
same as defined earlier) to give a compound of Formula 15 (wherein Hal is F, CI, Br, I)
which upon protection gives a compound of Formula 16 (wherein Rp is the same as
defined earlier). The reaction of a compound of Formula 16 with a compound of Formula
17 (wherein Ak is Ci-6alkyl and R is alkyl, halogen, aryl, heteroaryl) can take place in two
ways.
Path C (when ¾ is halogen): The compound of Formula 16 react with a
compound of Formula 17 to form a compound of Formula 18 which upon coupling with a
compound of Formula 2 (wherein ~ is aryl or heteroaryl ring and R6 is the same as
defined earlier) gives a compound of Formula 19. The compound of Formula 19 on
deprotection gives a compound of Formula 20.
Path D (when R is aryl/heteroaryl substituted with R6) : The compound of Formula 16 on
reaction with a compound of Formula 17 gives a compound of Formula 19 which upon
deprotection gives a compound of Formula 20.
The alpha halogenation of a compound of Formula 14 to form a compound of
Formula 15 can be carried out in the presence of red phosphorous/Br 2, in the presence of a
solvent selected from, for example, carbon tetrachloride, chloroform, dichloromethane,
dichloroethane, or mixture(s) thereof.
The O-protection of a compound of Formula 15 to give a compound of Formula 16
can be carried out with carboxy protecting group, for example, methyl, benzyl, allyl, tbutyl,
silyl, BOC anhydride in the presence of organic base selected from, for example,
triethylamine, N,N -dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, Nethyldiisoproylamine,
N,N -diisopropylethylamine or N-methylmorpholine using solvents
selected from, tetrahydrofuran, N, N -dimethylformamide, dimethylsulf oxide, acetonitrile,
or mixture(s) thereof.
Or alternatively, the O-protection of a compound of Formula 15 to give a
compound of Formula 16 can be carried out with carboxy protecting group, for example,
methyl, benzyl, allyl, Z-butyl, silyl, BOC anhydride in the presence of inorganic base
selected from, sodium bicarbonate, lithium bicarbonate, potassium bicarbonate in one or
more solvents selected from, for example, N, N -dimethylformamide, acetonitrile,
dimethylsulfoxide, tetrahydrofuran, methanol, ethanol, water, or mixture(s) thereof.
The reaction of a compound of Formula 16 with a compound of Formula 17 (Path
C) to give a compound of Formula 18 can be carried out in the presence of inorganic base
selected from, for example, lithium carbonate, sodium carbonate, potassium carbonate,
magnesium carbonate, barium carbonate using solvent, for example, acetonitrile,
tetrahydrofuran, dioxane, N,N -dimethylformamide, dimethylsulfoxide, or mixture(s)
thereof.
The coupling of a compound of Formula 18 with a compound of Formula 2 to give
a compound of Formula 19 can be carried out in the presence of inorganic catalyst selected
from, for example, te-(diphenylphosphino)ferrocence palladium II dichloride
(Pd(dppf)Cl2), tetrakis(triphenylphosphine) palladium (0) [Pd(Pli3P)4], palladium acetate
or dichlorotriphenylphosphine palladium (II), with suitable base selected from, for
example, potassium carbonate, sodium acetate, potassium acetate in the presence of
solvent selected from, tetrahydrofuran, N,N -dimethylformamide, dimethylsulfoxide,
toluene, or mixture(s) thereof.
The deprotection of a compound of Formula 19 to give a compound of Formula 20
can be carried out under similar conditions as described for the compound of Formula 9 to
give a compound of Formula 10.
The reaction of a compound of Formula 16 with a compound of Formula 17 (Path
D) to give a compound of Formula 19 can be carried out in the presence of inorganic base
selected from, for example, potassium carbonate, sodium carbonate, lithium carbonate,
barium carbonate in a solvent, for example, acetonitrile, tetrahydrofuran, N,N '-
dimethylformamide, dimethylsulfoxide, or mixture(s) thereof.
Scheme III

The compound of Formula 26b (Path E), Formula 29 (Path F), Formula 31 (Path
G), Formula 36 (Path H) can be prepared according to Scheme III. Thus reacting a
compound of Formula 17a (wherein ¾ 'is hydrogen, halogen, alkoxy, aryloxy, aryl,
carboxy) with alpha-hydroxy lactone gives a compound of Formula 2 1 which upon ring
opening gives a compound of Formula 22. The carboxy-protection of compound of
Formula 22 gives a compound of Formula 23 (wherein Rp is same as defined earlier).
Path E (when is halogen): the compound of Formula 23 upon hydroxy
protection gives a compound of Formula 24 (wherein R is hydroxy protecting group).
The coupling of a compound of Formula 24 with a compound of Formula 24a (wherein R6
is alkyl, aryl, heteroaryl) gives a compound of Formula 25 which upon deprotection gives
a compound of Formula 26. The reaction of a compound of Formula 26 with a compound
of Formula 27 gives a compound of Formula 26a. The deprotection of a compound of
Formula 26a gives a compound of Formula 26b.
Path F (when is alkoxy/aryloxy/halogen/hydrogen): the reaction of a compound
of Formula 23 with a compound of Formula 27 gives a compound of Formula 28 which
upon deprotection gives a compound of Formula 29.
Path G: (when is aryl substituted with halogen and Rp is allyl): the reaction of a
compound of Formula 23 with a compound of Formula 27 gives a compound of Formula
30 which upon deprotection gives a compound of Formula 31.
Path H: (when is COORp) : the coupling of a compound of Formula 23 with a
compound of Formula 27 gives a compound of Formula 32 which upon deprotection gives
a compound of Formula 33. The coupling of a compound of Formula 33 with a compound
of Formula 34 gives a compound of Formula 35 which finally upon deprotection forms a
compound of Formula 36.
The reaction of a compound of Formula 17a with oc-hydroxy lactone to give a
compound of Formula 2 1 can be carried out under similar conditions as described for the
reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound
of Formula 9.
The ring-opening of a compound of Formula 2 1 to give a compound of Formula 22
can be carried out as described for the compound of Formula 6 to give a compound of
Formula 7.
The carboxy-protection of a compound of Formula 22 to give a compound of
Formula 23 can be carried out under similar conditions as described for the compound of
Formula 15 to give a compound of Formula 16.
The hydroxy-protection of a compound of Formula 23 to give a compound of
Formula 24 (Path E) can be carried out using protecting group selected from, for example,
tert-butyldimethylsilylchloride (TBDMSC1), trimethylsilylchloride (TMSC1), tertbutyldimethylsilyloxymethylchloride
(TOMC1), triisopropylsilylchloride (TIPSC1),
benzoyl chloride in the presence of base, for example, imidazole, N-methylimidazole,
triethylamine, pyridine, diisopropylethylamine, N,N dimethylaminopyridine in the
presence of solvent, for example, N, N -dimethylformamide, toluene, acetonitrile,
dichloromethane, or mixture thereof.
The coupling of a compound of Formula 24 with a compound of Formula 24a to
give a compound of Formula 25 can be carried out under similar conditions as for the
reaction of a compound of Formula 18 with a compound of Formula 2 to give a compound
of Formula 19.
The deprotection of a compound of Formula 25 to give a compound of Formula 26
can be carried out using deprotecting agent selected from, for example, boron trifluoride
ethearte (BF3.0Et2), HF-pyridine, boron trichloride, boron tribromide, cesium fluoride
(CsF), potassium fluoride (KF), «-tetrabutylammonium fluoride, Pd/C in ¾, potassium
carbonate in presence of solvent, for example, dichloromethane, N, N -dimethylformamide,
acetonitrile, methanol, ethanol, acetone, tetrahydrofuran, or mixture thereof.
The reaction of a compound of Formula 26 with a compound of Formula 27 to give
a compound of Formula 26a can be carried out under similar conditions as described for
the reaction of a compound of Formula 7 with a compound of Formula 8 to give a
compound of Formula 9.
The deprotection of a compound of Formula 26a to give a compound of Formula
26b can be out under similar conditions as described for the deprotection of a compound
of Formula 9 to give a compound of Formula 10.
The reaction of a compound of Formula 23 (Path F) with a compound of Formula
27 to give a compound of Formula 28 can be carried out under similar condition as
described for the reaction of a compound of Formula 7 with a compound of Formula 8 to
give a compound of Formula 9.
The deprotection of a compound of Formula 28 to give a compound of Formula 29
can be out under similar conditions as described for the deprotection of a compound of
Formula 9 to give a compound of Formula 10.
The reaction of a compound of Formula 23 (Path G) with a compound of Formula
27 to give a compound of Formula 30 can be carried out under similar conditions as
described for reaction of a compound of Formula 7 with a compound of Formula 8 to give
a compound of Formula 9.
The deprotection of a compound of Formula 30 to give a compound of Formula 31
can be carried out under similar conditions as described for the deprotection of a
compound of Formula 9 to give a compound of Formula 10.
The reaction of a compound of Formula 23 (Path H) with a compound of Formula
27 to give a compound of Formula 32 can be carried out under similar conditions as
described for the compound of Formula 7 with a compound of Formula 8 to give a
compound of Formula 9.
The deprotection of a compound of Formula 32 to give a compound of Formula 33
can be carried out as described for the compound of Formula 9 to give a compound of
Formula 10.
The coupling of a compound of Formula 33 with a compound of Formula 34 to
give a compound of Formula 35 can be carried out using base selected from triethylamine,
N,N -dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N-ethyldiisoproylamine,
N,N -diisopropylethylamine or N-methylmorpholine, in the presence of a additives for
example hydroxybenzotriazole, 3-hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine, 2-
hydroxypyridine, N-hydroxysuccinimide or 1-hydroxy-7-azabenzotriazole, with a suitable
condensing agent, for example, dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, chlorotripyrrolidinophosphonium hexafluorophosphate
or (benzotriazol-l-yloxy)Zrw-(dimethylamino)phosphonium hexafluorophosphate in the
presence of a solvent selected from, for example, N,N dimethylformamide,
dimethylsulfoxide, acetonitrile, or mixture(s) thereof.
The deprotection of a compound of Formula 35 to give a compound of Formula 36
can be carried out under similar condition as described for the compound of Formula 9 to
give a compound of Formula 10.
Scheme IV
Formula 42 Formula 43
{Formula 1when R is heteroaryl, L is
bond and R is aryl/heteroaryl}
The compound of Formula 43 can be prepared according to Scheme IV. Thus,
protecting a compound of Formula 37 (wherein Rp is same as defined earlier) gives a
compound of Formula 38 (wherein R is same as defined earlier) which on reaction with a
compound of Formula 39 (Wherein R6 is alkyl and Ak is same as defined earlier) gives a
compound of Formula 40. The compound of Formula 40 on deprotection gives a
compound of Formula 4 1 which on reaction with a compound of Formula 27 (wherein R5
is same as defined earlier) forms a compound of Formula 42. The deprotection of a
compound of Formula 42 gives a compound of Formula 43.
The protection of a compound of Formula 37 to give a compound of Formula 38
can be carried out under similar conditions as described for the compound of Formula 23
to give a compound of Formula 24.
The reaction of a compound of Formula 38 with a compound of Formula 39 to give
a compound of Formula 40 can be carried out under similar conditions as described for the
reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound
of Formula 9.
The deprotection of a compound of Formula 40 to give a compound of Formula 41
can be carried out under similar conditions as described for the compound of Formula 25
to give a compound of Formula 26.
The reaction of a compound of Formula 4 1 with a compound of Formula 27 to give
a compound of Formula 42 can be carried out under similar conditions as described for the
reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound
of Formula 9.
The deprotection of a compound of Formula 42 to give a compound of Formula 43
can be carried as described for the compound of Formula 9 to give a compound of
Formula 10.
Scheme V
gen Formula 49
Formula 45 Formula 46 Formula 47
Formula 52 Formula 51 Formula 50
Formula I
[when R3 is heteroaryl,
L1 is bond and R1 is aryl/heteroaryl]
The compound of Formula 52 can be prepared according to Scheme V. Thus
reacting 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane with a compound of Formula 44
gives a compound of Formula 45 which upon ring opening gives a compound of Formula
46. The compound of Formula 46 on O-protection gives a compound of Formula 47
(wherein R is same earlier) which upon reaction with a compound of Formula 48
(wherein Hal and Ak are same as defined earlier) gives a compound of Formula 49. The
coupling of a compound of Formula 49 with a compound of Formula 2 gives a compound
of Formula 50. The compound of Formula 50 on deprotection forms a compound of
Formula 5 1 which finally on oxidation gives a compound of Formula 52.
The reaction of 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane with a compound
of Formula 44 form a compound of Formula 45 can be carried out under similar condition
as for the compound of Formula 7 with a compound of Formula 8 to give a compound of
Formula 9.
The ring opening of a compound of Formula 45 to give a compound of Formula 46
can be carried out in the presence of mineral acids selected from, for example,
hydrochloric acid, hydrobromic acid, hydroiodic acid, or in the presence of catalytic
amount of cerium(IV) ammonium nitrate (CAN), cerium(III) trifluoromethane sulfonate
using solvent, for example, acetone, nitromethane, acetonitrile, water, or described thereof.
The protection of a compound of Formula 46 to give a compound of Formula 47
can be carried out under similar conditions as described for the compound of Formula 23
to give a compound of Formula 24.
The reaction of a compound of Formula 47 with a compound of Formula 48 to give
a compound of Formula 49 can be carried out under similar conditions as described for the
reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound
of Formula 9.
The coupling of a compound of Formula 49 with a compound of Formula 2 to give
a compound of Formula 50 can be carried out under similar conditions as described for
coupling of a compound of Formula 18 with a compound of Formula 2 to give a
compound of Formula 19.
The deprotection of a compound of Formula 50 to give a compound of Formula 5 1
can be carried out under similar condition as described for the deprotection of a compound
of Formula 25 to give a compound of Formula 26.
The oxidation of a compound of Formula 5 1 to give a compound of Formula 52
can be carried using oxidizing agent, for example, sodium chlorite and sodium
hypochlorite in presence of 2,2,6,6-tetramethylpiperidine-N-oxyl) (TEMPO), sodium
periodate in presence of ruthenium trichloride, potassium dichromate, potassium
permanganate, using a solvent selected from, acetonitrile, carbon tetrachloride, water, or
mixture(s) thereof.
Scheme VI
The compound of Formula 6 1 can be prepared according to Scheme VI. Thus,
protecting 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane gives a compound of Formula
53 (wherein Rp is same as defined earlier) which upon ring opening forms a compound of
Formula 54. The compound of Formula 54 upon further protection gives a compound of
Formula 55 (wherein Rp' is same as defined earlier) which on reaction with a compound
of Formula 48 (wherein Hal is same as defined earlier) gives a compound of Formula 56.
The coupling of a compound of Formula 56 with a compound of Formula 2 gives a
compound of Formula 57 which on deprotection forms a compound of Formula 58. The
reaction of a compound of Formula 58 with a compound of Formula 27 (wherein R5 is
same as defined earlier) gives a compound of Formula 59. The compound of Formula 59
on deprotection gives a compound of Formula 60 which on oxidation forms a compound
of Formula 61.
The protection of 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane to give a
compound of Formula 53 can be carried out using alkyl/aryl halides using inorganic base
selected from lithium hydride, sodium hydride or organic base selected from pyridine,
triethylamine, trimethylamine, tributylamine, N-ethyldiisopropylamine, 4-N,Ndimethylaminopyridine,
N-methylmorpholine or 2,6-lutidine in the presence of a solvent,
for example, N,N -dimethylformamide, dimethylsulfoxide, acetonitrile, or mixture(s)
thereof.
The ring opening of a compound of Formula 53 to give a compound of Formula 55
can be carried out under similar conditions as described for compound of Formula 45 to
give a compound of Formula 46.
The protection of a compound 54 to give a compound of Formula 55 can be carried
out under similar conditions as described for the protection of compound of Formula 23 to
give a compound of Formula 24.
The reaction of a compound of Formula 55 with a compound of Formula 48 to give
a compound of Formula 56 can be carried out under similar conditions as described for the
compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
The coupling of a compound of Formula 56 with a compound of Formula 2 to give
a compound of Formula 57 can be carried out under similar conditions as described for
coupling of a compound of Formula 18 with a compound of Formula 2 to give a
compound of Formula 19.
The deprotection of a compound of Formula 57 to give a compound of Formula 58
can be carried out as described for the deprotection of a compound of Formula 9 to give a
compound of Formula 10.
The coupling of a compound of Formula 58 with a compound of Formula 27 to
gives a compound 59 can be carried out under similar conditions as described for the
compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
The deprotection of a compound of Formula 59 to give a compound of Formula 60
can be carried out under similar conditions as described fro the compound of Formula 25
to give a compound of Formula 26.
The oxidation of a compound of Formula 60 to give a compound of Formula 6 1
can be carried out under similar condition as described for the compound of Formula 51 to
give a compound of Formula 52.
In the above schemes, where specific reagents, for example, bases, acids, solvents,
condensing agents, reducing agent, deprotecting agent, hydrolyzing agents, catalysts, etc.,
as mentioned, is to be understood that other reagents, e.g., other acids, bases, solvents,
condensing agents, reducing agent, deprotecting agent, 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, powder,
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; antiadherents, for example,
magnesium stearate or sodium luaryl 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 mg of active
compound while tablet fill weight may range from 50 mg to 1000 mg. An example is
illustrated below:
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 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 packaged preparations containing discrete
capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams
or any combination and number of such packaged forms.
Table I
R
Formula 1
c R1 L1 R2 R3
No.
1 bond -CHO

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 particular aspect of the disclosure and do not limit the scope of
the present invention.
Experimental
Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc.,
were dried using various drying reagents according to procedure as described in the
literature.
Synthesis of intermediate
Synthesis of 6-methyl-l,2,3-benzotriazin-4(3 H )-one
The title compound was prepared following the procedure outlined in J . Med.
Chem., 35(14), p. 2626-2630 (1992).
The following analogues of benzotriazin-4(3 H)-one were prepared analogously:
7-Methoxy- 1,2,3-benzotriazin-4(3 H)-one
7-(Trifluoromethyl)- 1,2,3-benzotriazin-4(3 H)-one;
7-Methyl- 1,2,3-benzotriazin-4(3 H)-one;
6-Methoxy- 1,2,3-benzotriazin-4(3 H)-one;
5-Chloro- 1,2,3-benzotriazin-4(3 H)-one;
7-Chloro- 1,2,3-benzotriazin-4(3 H)-one;
5-Methoxy- 1,2,3-benzotriazin-4(3 H)-one;
5-Fluoro- 1,2,3-benzotriazin-4(3 H)-one;
8-Methoxy- 1,2,3-benzotriazin-4(3 H)-one;
6-Fluoro- 1,2,3-benzotriazin-4(3 H)-one.
Synthesis of 5-methyl-l H-isoindole-1.3(2 H)-dione
The title compound was prepared following the procedure outline in Chem. Ber.
1877, 10, 1163.
Synthesis of 4-(1.3-dioxo-1.3-dihvdro-2 H-isoindol-2-yl)butanoic acid
To a solution of g-aminobutyric acid (20.68 g, 0. 199 moles) and phthalic anhydride
(29.6 g, 0. 199 moles) in toluene (300 mL) was added triethylamine (3 mL, 0.0215 moles)
and heated at 110°C for aboutl8 hours. After completion, the reaction mixture was
allowed to cool to room temperature. The reaction mixture was washed with IN HC1
solution (20 mL) at 40°C and solid was crystallized out from organic layer. The residues
was filtered, washed with water and dried under vacuum overnight to get desired product.
Yield: 31.64 g
LCMS: 234.2 (M+l)
Synthesis of N-(4-bromophenyl)methane sulfonamide
To a solution of 4-bromoaniline (100 g, 581 mmoles) in dichloromethane (75 mL)
and pyridine (75 mL) was slowly added methanesulphonyl chloride (99 g, 872 mmoles).
The reaction mixture was allowed to stir for about one hour at the same temperature.
After one hour, dilute hydrochloric acid was added to the reaction mixture to remove
pyridine. The organic layer was collected, dried over anhydrous sodium sulphate and
evaporated under reduced pressure to obtain a crude product. The crude product was
purified on a silica gel column using 60% ethyl acetate: hexane as eluent to afford a
desired compound.
Yield: 110 g
LCMS: 267.03, 268.97 (M+Na)
Synthesis of N-r4-(4-methylphenoxy)phenyl1methane sulfonamide
To a solution of 4-(4-methylphenoxy)aniline (3.5 g, 17.6 mmoles) in pyridine (20
mL) and dichloromethane (20 mL) at 0°C was added methanesulfonyl chloride (2.2 mL,
26.4 mmoles). The reaction mixture was allowed to stir at room temperature for about 2
hours. After completion of reaction, pyridine was evaporated and the reaction mixture
was extracted with ethyl acetate. The organic layer was collected, washed with water,
dried over anhydrous sodium sulphate and evaporated to get a crude product. The crude
product obtained was purified on silica gel column using 25% ethyl acetate: hexane as
eluent to get desired compound.
Yield: 3.1 g
The following compound can be prepared accordingly: N-(4-Methoxyphenyl)
methanesulfonamide.
Synthesis of benzyl 2.4-dihydroxybutanoate
To a solution of oc-hydroxylactone (10 g, 0.098 moles) in methanol (50 mL) was
added sodium hydroxide (5.88 g, 0.147 moles) in water (10 mL) and allowed to stir at
room temperature for about one hour. The reaction mixture was concentrated and taken in
N, N '-dimethylformamide (40 mL) and benzyl bromide (14 mL, 0. 117 moles) was added
drop wise. The reaction mixture was again allowed to stir for overnight at room
temperature. After completion of reaction, solvent was evaporated under vacuum and the
reaction mixture was extracted with ethyl acetate. The organic layer was washed with
water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum to
obtain a crude product. The crude product was purified on silica gel column using 80%
ethyl acetate: hexane as eluent to afford the title compound.
Yield: 10.4 g
LCMS: 2 11.47 (M+l), 233.5 (M+Na)
Synthesis of N-(biphenyl-4-yl)methanesulfonamide
To the solution of 4-biphenyl amine ( 1 g, 0.0059 moles) in dimethylformamide (10
mL) was added potassium carbonate (1.63 g, 0.01 18 moles) and stirred for about 10
minutes and then methanesulfonyl chloride (3.64 mL, 0.0472 moles) was added slowly.
The reaction mixture was allowed to stir at room temperature for about 30 minutes. After
completion, the reaction mixture was extracted with ethyl acetate while washing with
water. The organic layer was dried over anhydrous sodium sulphate and evaporated under
reduced pressure to get a crude product which was purified on silica gel column to get
desired product.
Yield: 0.75 g
Synthesis of tert-butyl 4- (r4-hvdroxy-l-oxo-l-rprop-2-en-l-yloxy)butan-2-yl1 (methyl
sulfonyDamino }benzoate
Step a : Preparation of tert-b \ 4-nitrobenzoate
To a solution of />nitrophenol (10 g, 59.88 mmoles) in r -butanol (100 mL) and
tetrahydrofuran ( 100 mL) were added N,N -dimethylaminopyridine ( 1.4 g, 11.97 mmoles)
and Boc anhydride (38.4 mL, 179.64 mmoles) at room temperature. The reaction mixture
was allowed to stir for about 10 hours at room temperature. The temperature was
increased slowly to 35°C and reaction mixture was stirred for about 6 hours. After
completion, solvent was evaporated under reduced pressure and reaction mixture was
extracted with ethyl acetate. The organic layer was washed with water, brine and
evaporated under vacuum to get a crude product. The crude product was purified on silica
gel column using 20% ethyl acetate: hexane as eluent to get desired compound.
Yield 12 g
Step b: Preparation of tert-b \ 4-aminobenzoate
To a solution of compound obtained from Step a ( 11 g) in tetrahydrofuran (50 mL)
and methanol (50 mL) was added 10% Pd/C (3 g) and ¾ was supplied at 60 psi in Panapparatus
for about 2 hours. After completion, reaction mixture was filtered through celite
pad and residue was washed with ethyl acetate. The filtrate obtained was concentrated
under vacuum to get the desired compound.
Yield: 10 g.
LCMS: 194.47 (M+l)
Step c : Preparation of tert-b \ 4-[(methylsulfonyl)amino]benzoate
To an ice cooled solution of compound obtained from Step b (10 g, 51.81 mmoles)
in pyridine (50 mL) and dichloromethane (50 mL) was added methanesulphonyl chloride
(8.86 g, 77.72 mmoles). The reaction mixture was allowed to stir for about one hour at
same temperature. After one hour, HC1 ( 11N) solution was added to bring the pH of the
reaction mixture to neutral and then extracted with ethyl acetate. The organic layer was
washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum
to get crude product. The crude product obtained was purified on silica gel column using
50% ethyl acetate: hexane as eluent to get desired product.
Yield: 10 g
LCMS: 293.76 (M+Na)
Step d: Preparation of tert-b \ 4-[(methylsulfonyl)(2-oxotetrahydrofuran-3-
yl)amino] benzoate
To an ice cooled solution alpha-hydroxy lactone ( 1 g, 9.80 mmoles) in
tetrahydrofuran (30 mL) were added compound obtained from Step c (2.6 g, 9.80 mmoles)
and triphenylphosphine (13.6 g, 14.70 mmoles). The reaction mixture was stirred for
about 15 minutes and diisopropylazodicarboxylate (DIAD) (2.9 g, 14.70 mmoles) was
added at same temperature. The reaction mixture was allowed to stir for about 2 hours at
room temperature. After complete conversion of starting material, solvent was evaporated
under vacuum to obtain a crude compound. The crude compound was purified on silica
gel column using 30% ethyl acetate: hexane as elutent to get the desired product.
Yield: 6 g
LCMS: 354.82 (M).
Step e : Preparation of ,-[4-(teri-butoxycarbonyl)phenyl]-A'-(methylsulfonyl)
homoserine
To an ice-cooled solution of compound obtained from Step d (4 g, 11.26 mmoles)
in ethanol (30 mL) and methanol (10 mL) was added sodium hydroxide (0.495 g, 12.39
mmoles) in water (5 mL). The reaction mixture was allowed to stir at same temperature
for about 30 minutes. After 30 minutes, solvent was evaporated and reaction mixture was
extracted with ethyl acetate while washing with water. The aqueous layer was acidified
with aqueous solution of sodium bisulfate and extracted with ethyl acetate. The combined
organic layer was dried over anhydrous sodium sulphate and evaporated to get desired
compound.
Yield: 3g
Step f : Preparation of tert-buty\ 4-{[4-hydroxy-l-oxo-l-(prop-2-en-l-yloxy)butan-2-
yl](methylsulfonyl)amino}benzoate
To a solution of compound obtained from step e (3 g, 8.04 mmoles) in N,N -
dimethylformamide (25 mL) were added sodium bicarbonate ( 1 g, 12.06 mmoles) and
allyl bromide ( 1.07 g, 8.84 mmoles) at room temperature. The reaction mixture was
allowed to stir at room temperature for about 12 hours. After completion of reaction,
solvent was evaporated and reaction mixture was extracted with ethyl acetate. The
organic layer was washed with water, dried over anhydrous sodium sulphate and
evaporated to get crude product. The crude product was purified on silica gel column
using 40% ethyl acetate: hexane to get the desired compound.
Yield: 1.4 g.
LCMS: 413.87 (M+l).
Synthesis of prop-2-en-l-yl N-(4'-chlorobiphenyl-4-yl )-N-(methylsulfonyl)homoserinate
Step a : Preparation of A'-(4,-chlorobiphenyl-4-yl)methanesulfonamide
To a solution of N-(4-bromophenyl)methanesulfonamide (2 g, 0.008 moles) in N,
N -dimethylformamide (15 mL) and water (15 mL) were added 4-chlorophenylboronic
acid (2.49 g, 0.016 moles), potassium carbonate (3.3 g, 0.024 moles) and tetrakis
triphenylphosphine (277 mg, 0.002 moles). The reaction mixture was heated upto 100°C
for about 14 hours. After completion, the reaction mixture was quenched with water and
extracted with ethyl acetate. The combined organic layer was washed with water, brine,
dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a
crude product. The crude product was purified on silica gel column using 25% ethyl
acetate: hexane as eluent to get title compound.
Yield: 1.8 g
Step b: Preparation of A'-(4,-chlorobiphenyl-4-yl)-A'-(2-oxotetrahydrofuran-3-
yl)methane sulfonamide
To a compound obtained from step a (10 g, 0.035 moles) in tetrahydrofuran (70
mL) were added oc-hydroxy lactone (8.8 g, 0.05 moles) and triphenylphosphine (13.9 g,
0.05 moles) at 0°C. The reaction mixture was allowed to stir for about 10 minutes and
diisopropylazodicarboxylate DIAD (10.7 mL, 0.05 moles) was added to it at 0°C. The
reaction mixture was again stirred for about 2 hours at room temperature. After
completion, solvent was evaporated to obtain a crude product which was purified on silica
gel column using 20% ethyl acetate: hexane as eluent to get the desired product.
Yield: 10 g
LCMS: 365.71 (M+l)
Step c : Preparation of A'-(4,-chlorobiphenyl-4-yl)-A'-(methylsulfonyl)homoserine
To a solution of compound obtained from step b (10 g, 0.0273 moles) in ethanol:
water mixture (10:1) (100ml: lOmL) at 0°C was added sodium hydroxide (1.2g, 0.037
moles) in water (2 mL). The reaction mixture was allowed to stir for about 2 hours at 0°C.
After 2 hours, solvent was evaporated under reduced pressure and residues obtained were
taken in water and extracted with ethyl acetate. The aqueous layer obtained was acidified
by aqueous solution of sodium bisulphite and then extracted with ethyl acetate. The
combined organic layer was washed with water, brine, dried over anhydrous sodium
sulphate and evaporated under reduced pressure to get title compound.
Yield: lOg
Step d: Preparation of prop-2-en-l-ylA'-(4 ,-chlorobiphenyl-4-yl)-A'-(methylsulfonyl)
homoserinate
To a compound obtained from step c (10 g, 0.026 moles) in ethanol: water: DMF
mixture (60 mL: 6 mL: 60 mL) at room temperature was added sodium bicarbonate (2. 1 g,
0.026 moles). The reaction mixture was allowed to stir at room temperature for about 30
minutes. After 30 minutes, the reaction mixture was concentrated under reduced pressure
and treated with toluene. The toluene was evaporated and residue so obtained was taken
in dry N, N -dimethylformamide (20 mL) at room temperature. To this reaction mixture
was slowly added allyl bromide (3.4 g, 0.028 moles) and stirred for overnight at room
temperature. After completion, water was added to the reaction mixture and extracted
with ethyl acetate. The organic layer was collected, washed with water, brine, dried over
anhydrous sodium sulphate solution and evaporated under reduced pressure to obtain a
crude product. The crude product was purified on silica gel column using 30% ethyl
acetate: hexane as eluent to get title compound.
Yield: 5.2 g
Example 1: Synthesis of 2-[formyir4'-methylbiphenyl-4-yl)aminol-4-r6-methyl-4-oxo-
1.2.3-benzo triazin-3(4H )-yl)butanoic acid (Compound no. 1) (Scheme I. Path A)
Step a : Preparation of 4-methyl-4'-nitrobiphenyl
To a solution of 4-bromo-nitrobenzene (5 g, 0.0247 moles) in N,Ndimethylformamide
(25 mL) were added potassium carbonate (10.2 g, 0.0741 moles) and
4-methylboronic acid (4 g, 0.0297 moles) under argon atmosphere and heated at 100°C for
about 3 hours. After completion, reaction mixture was quenched by addition of water and
extracted with ethyl acetate. The organic layer was separated, dried over anhydrous
sodium sulphate and concentrated under vacuum to get a crude product which was purified
on silica gel column using 15% ethyl acetate: hexane as eluent to obtain desired compound.
Yield: 5.3 g
LCMS: 236.07 (M+23)
Step b: Preparation of 4'-methylbiphenyl-4-amine
To a solution of compound obtained from Step a (5.2 g, 0.0244 moles) in
tetrahydrofuran (25 mL) and methanol (25 mL) was added 10% Pd/C (5.2 g) under
vacuum and then hydrogen gas was supplied by balloon. The reaction mixture was
allowed to stir for about 2 hours at room temperature. After completion, reaction mixture
was filtered through celite pad and filtrate was concentrated under vacuum to obtained title
compound. Yield: 5 g
LCMS: 184.01 (M+l)
Step c : Preparation of 3-[(4'-methylbiphenyl-4-yl)amino]dihydrofuran-2(3//)-one
To alpha-bromo lactone (3 g, 0.018 moles) was added compound obtained from
Step b (4.9 g, 0.027 moles) and heated to 100°C to 110°C for about 3 hours. After
completion consumption of starting material, reaction mixture was evaporated under
reduced pressure and purified on silica gel column using 20% ethyl acetate: hexane as
eluent to get desired compound.
Yield: 4 g
LCMS: 268.1 1 (M+l)
Step d: Preparation of A'-(4,-methylbiphenyl-4-yl )-A'-(2-oxotetrahydrofuran-3-
yl)formamide
To a solution of compound obtained from Step c (2 g, 0.00749 moles) in toluene
(30 mL) was added formic acid (0.4 g, 0.0089 moles) and reflux for about 9 hours. After
complete, reaction mixture was evaporated under reduced pressure to get a crude product
which was purified over silica gel column using 15% ethyl acetate: hexane as eluent to
obtain title compound.
Yield: 1.9 g
LCMS: 295.94 (M+l)
Step e : Preparation of methyl A'-formyl-7V-(4,-methylbiphenyl-4-yl)homoserinate
To a solution of compound obtained from Step d (1.9 g, 0.0064 moles) in N,Ndimethylformamide
(4 mL) and water ( 1 mL) was added sodium hydroxide (0.309 g,
0.0077 moles) and stirred for about 30 minutes at room temperature. After 30 minutes
sodium bicarbonate (0.624 g, 0.0074 moles), 18-crown-6 (0.168 g, 0.00064 moles) amd
methyl iodide (1.3 g, 0.0914 moles) was added to the reaction mixture and again stirred
for overnight at room temperature. After completion, reaction mixture was quenched by
addition of water and extracted with ethyl acetate. The organic layer was separated, dried
over anhydrous sodium sulphate and concentrated under reduced pressure to get crude
product which was purified on silica gel column using 8% ethyl acetate: hexane as eluent.
Yield: 2.1 g
Step f : Preparation of methyl 2-[formyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl-
4-oxo-l,2,3-benzotriazin-3(4 H)-yl)butanoate
To a compound obtained from step e (0.3 g, 0.0009 moles) in tetrahydrofuran (5
mL) were added 6-methylbenzotriazinone (0. 177 g, 0.001 1 moles) and triphenyl
phosphine (0.353 g, 0.0013 moles) under argon atmosphere. The reaction mixture was
allowed to cool to 0°C and to it was added diisopropylazodicarboxylate (0.272 g, 0.0013
moles) and stirred for about 30 minutes at room temperature. After completion, reaction
mixture was quenched by addition of water and extracted with ethyl acetate. The organic
layer was separated, dried over anhydrous sodium sulphate and evaporated under reduced
pressure to get crude compound which was purified on silica gel column using 7% ethyl
acetate: hexane as eluent to get desired product.
Yield: 0. 15 g
LCMS: 470 (M+l)
Step g : Preparation of 2-[formyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl-4-oxol,
2,3-benzotriazin-3(4 H )-yl)butanoic acid
To a compound obtained from Step f (0.15 g, 0.0003 moles) in tetrahydrofuran (5
mL) and methanol (5 mL) was added solution of lithium hydroxide (0.018 g, 0.0004
moles) in water ( 1 mL). The reaction mixture was allowed to stir for about one hour at
room temperature. After completion, the reaction mixture was acidified with sodium
bisulphate solution (pH~2) and extracted with ethyl acetate. The organic layer was dried
over anhydrous sodium sulphate and concentrated under vacuum to get crude compound
which was purified by preparative TLC using 10% methanol: dichloromethane as mobile
phase. Yield: 0.030 g
LCMS-455.35 (M-l)
¾ M (400 MHz) d 8.40 (1H, s), 8.03-8.05 (1H, m), 7.87 (2H, m), 7.61-7.63 (2H, m),
7.52-7.54 (2H, m), 7.40-7.42 (2H, m), 7.24-7.26 (2H, m), 4.84 (1H, m), 4.39 (2H, m), 2.51
(2H, m), 2.28-2.33 (6H, m).
The following compounds can be prepared by following the above synthetic route.
4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4 H)-yl)-2-[formyl(4'-methylbiphenyl-4-
yl)amino]butanoic acid (Compound no. 2);
LCMS-447.23 (M-28)
2-[(4'-Ethylbiphenyl-4-yl)(formyl)amino]-4-(5-methyl-4-oxo-l,2,3-benzotriazin-
3(4H)-yl)butanoic acid (Compound no. 3).
LCMS-469.34 (M-1)
Example 2 : Synthesis of 0-[(4-fluorophenyl)carbamoyll -N-formyl-N-(4'-methylbiphenyl-
4-yl)homoserine (Compound no. 4) (Scheme L Path B)
Step a : Preparation of methyl 0-[(4-fluorophenyl)carbamoyl]-A'-formyl-A'-(4,-methyl
biphenyl-4-yl)homoserinate
To a solution of methyl N-formyl-N-(4'-methylbiphenyl-4-yl)homoserinate (0.3 g,
0.0009 moles) in tetrahydrofuran (5 mL) was added triethylamine (0.272 g, 0.0027 moles)
and 1-fluoro-4-isocyanatobenzene (0.147 g, 0.0010 moles) under argon atmosphere at
room temperature. The reaction mixture was allowed to stir for about 2 hours at room
temperature. After completion, the reaction mixture was quenched by addition of water
and extracted with ethyl acetate. The organic layer obtained was dried over anhydrous
sodium sulphate and concentrated under reduced pressure to get crude compound. The
crude compound was purified on silica gel column using 15% ethyl acetate: hexane as
eluent to obtain desired product.
Yield: 0.15 g
LCMS: 464.93 (M+l)
Step b: Preparation of ^-fluorophenylJcarbamoyll-A^-formyWV-^'-
methylbiphenyl-4-yl)homoserine
To a compound obtained from Step a (0. 15 g, 0.0003 moles) in tetrahydrofuran (5
mL) and methanol (5 mL) was added solution of lithium hydroxide (0.018 g, 0.0004
moles) in water and stirred for about one hour at room temperature. After completion, the
reaction mixture was acidified with sodium bisulfite (pH~2) and extracted with ethyl
acetate. The organic layer was separated and dried over anhydrous sodium sulphate and
concentrated under vacuum to get crude compound which was purified by preparative
TLC using 10% methanol: dichloromethane as mobile phase to obtain a desired product.
Yield: 0.03 g
LCMS-449.28 (M-l)
¾ M (400 MHz)-d 9.63 (1H, s), 8.45(1H, s), 7.67-7.69 (2H, m), 7.53-7.55 (4H, m),
7.26-7.28 (2H, m), 7.12-7.14 (4H, m), 4.89-4.93 (1H, m), 4.06-4.10 (2H, s), 2.45 (2H, m),
2.41-2.43 (3H, m).
The following compounds can be prepared by following the above synthetic route.
N-Formyl-N-(4'-methylbiphenyl-4-yl)-0-[(4-methylphenyl)carbamoyl]homoserine
(Compound no. 5);
LCMS-417.27 (M-28)
O-[(3 ,4-Dichlorophenyl)carbamoyl] -N-formyl-N-(4'-methylbiphenyl-4-
yl)homoserine (Compound no. 6);
LCMS-501.15 (M)
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-0- {[4-(propan-2-
yl)phenyl]carbamoyl}homoserine (Compound no. 7);
LCMS-487.35 (M-l)
N-(4'-Ethylbiphenyl-4-yl)-0-[(3-fluorophenyl)carbamoyl ]-N-formylhomoserine
(Compound no. 8);
LCMS-463.33 (M-l)
0-[(2,4-Difluorophenyl)carbamoyl ]-N-(4'-ethylbiphenyl-4-yl )-Nformylhomoserine
(Compound no. 9);
LCMS-48 1.32 (M-l)
N-(4'-Ethylbiphenyl-4-yl)-0-[(2-fluorophenyl)carbamoyl ]-N-formylhomoserine
Compound no. 10);
LCMS-463.33 (M-l)
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-<9- {[4-
(trifluoromethyl)phenyl]carbamoyl}homoserine (Compound no. 11);
LCMS-513.32 (M-1)
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-0-[(2-methylphenyl)carbamoyl]homoserine
(Compound no. 12);
LCMS-459.33 (M-l)
N-(4'-Ethylbiphenyl-4-yl)-0-[(4-ethylphenyl)carbamoyl ]-N-formylhomoserine
(Compound no. 13);
LCMS-473.30 (M-1)
N-(4'-Ethylbiphenyl-4-yl )-N -formyl-0-[(4-methoxyphenyl)carbamoyl]homoserine
(Compound no. 14);
LCMS-475.35 (M-l)
0-[(2,6-Dichlorophenyl)carbamoyl ]-N-(4'-ethylbiphenyl-4-yl )-Nformylhomoserine
(Compound no. 15);
LCMS-515.29 (M-1)
Example 3 : Synthesis of 4-(l,3-Dioxo-l,3-dihydro-2 H-isoindol-2-yl)-2 - (4'-
methoxybiphenyl-4-yl) (methyl) amino Ibutanoic acid (Compound no. 18); (Scheme II,
Path C)
Step a : Preparation of 2-bromo-4-(l,3-dioxo-l,3-dihydro-2 H-isoindol-2-yl)butanoic
acid
To a solution of 4-(l,3-dioxo-l,3-dihydro-2 H-isoindol-2-yl)butanoic acid ( 11.7 g,
0.050 moles) in carbon tetrachloride (60 mL) was added red phosphorous (5.2 g, 0.167
mole) and heated at about 60°C. To this reaction mixture, bromine (40 mL, 0.792 mole)
was added slowly over a period of about one hour and again heated up to 60°C for about 8
hours then cooled to 0°C. After that, water (50 mL) was added to the reaction mixture.
The reaction mixture was solidified and extracted with ethyl acetate. The organic layer
was washed with aqueous solution of sodium bicarbonate. The obtained aqueous layer
was acidified (pH~2) using aqueous solution of hydrochloric acid and extracted with ethyl
acetate. The combined organic layer was washed with brine, dried over anhydrous sodium
sulphate and evaporated to get desired product.
Yield: 10.8 g
LCMS: 313.4 (M+l)
Step b: Preparation of tert-b \ 2-bromo-4-(l,3-dioxo-l,3-dihydro-2 H-isoindol-2-yl)
butanoate
To a solution of compound obtained from Step a (180 mg, 0.576 mmoles) in
tetrahydrofuran (5 mL) was added Boc anhydride ( 1 mL, 0.461 mmoles) and N,Ndimethylaminopyridine
(7 mg, 0.057 mmoles). The reaction mixture was allowed to stir at
room temperature for about 18 hours. After completion of reaction, solvent was
azeotropically distilled using toluene and ethyl acetate to obtain a crude product. The
crude product was purified on silica gel column using 20% ethyl acetate: hexane as eluent
to get the desired product.
Yield: 180 mg
Step c : Preparation of tert-buty\ 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-(l,3-
dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoate
To a solution of N-(4-bromophenyl)methanesulfonamide ( 1 g, 0.04 moles) in
acetonitrile (20 mL) was added potassium carbonate (0.276 g, 0.002 moles) at room
temperature. The reaction mixture was allowed to stir for about 15 minutes and then
compound obtained from Step b (1.472 g, 0.004 moles) was added. The reaction mixture
was heated at about 80°C for about 56 hours. After completion, the reaction mixture was
concentrated and residue obtained was taken in ethyl acetate. The organic layer was
washed with water, brine, dried over anhydrous sodium sulphate and evaporated under
reduced pressure to get a crude product. The crude product was purified by preparative
TLC using 30% ethyl acetate: hexane as mobile phase to get the desired product.
Yield: 1.7 g
LCMS: 555.9 (M+NH4
+)
Step d: Preparation of tert-b \ 4-(l,3-dioxo-l,3-dihydro-2 H-isoindol-2-yl)-2-[(4 -
methoxy biphenyl-4-yl)(methylsulfonyl)amino]butanoate
To a solution of a compound obtained from Step c (0.205 g, 0.381 moles) in dry
NN -dimethylformamide (5 mL) were added tetrakistriphenylphosphine (8 mg, 0.007
moles), potassium carbonate (0.21g, 1.527 moles) and 4-methoxyphenylboronic acid
(0.191 g, 1.259 moles) at room temperature. The reaction mixture was heated to 105°C
for about 4.5 hours. After 4.5 hours, it was allowed to cool to room temperature and N,
N -dimethylformamide was evaporated and residues obtained were taken in ethyl acetate.
The organic layer was washed with water, brine and evaporated under vacuum to get crude
product which was purifiedby preparative TLC using 30% ethyl acetate: hexane as mobile
phase to get desired product.
Yield: 0.161 g
LCMS: 587.1 (M+Na)
Step e : Preparation of 4-(l,3-dioxo-l,3-dihydro-2 H-isoindol-2-yl)-2-[(4 -
methoxybiphenyl-4-yl)(methylsulfonyl)amino]butanoic acid
To a solution of compound obtained from step d (0.144 g, 0.00025 moles) in
dichloromethane (5 mL) was added trifluoroacetic acid (1.2 mL) at 0°C. The reaction
mixture was allowed to stir for about 3 hours at 0°C and then at room temperature for
about 4 hours. After completion, the reaction mixture was extracted with dichloromethane,
washed with water and brine. The organic layer was evaporated under reduced pressure to
get a crude product which was purified on silica gel column using 50% ethyl acetate:
hexane as eluent to get desired product.
Yield: 0.1 13 g
LCMS: 509.1 (M+l)
H NMR (CDCI3, 400 MHz) d: 7.84 (2H, m), 7.71 (2H, m), 7.62 (4H, m), 7.51 (2H, d, J =
8 Hz), 6.97 (2H, d, J =8 Hz), 5.04 (1H, m), 4.12 (2H, m), 3.85 (3H, s), 3.13 (3H, s), 2.36
(lH, m), 1.95 (lH, m).
Example 4 : Synthesis of 2-rbiphenyl-4-yl(methylsulfonyl)amino1-4-(l,3-dioxo-l,3-
dihydro-2H-isoindol-2-yl)butanoic acid (Compound no. 16) (Scheme II. Path D)
Step a : Preparation of tert-b \ 2-[biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-
dioxo-l,3-dihydro-2 H-isoindol-2-yl)butanoate
To a solution of tert-butyl 2-bromo-4-(l,3-dioxo-l,3-dihydro-2 H-isoindol-2-yl)
butanoate (300 mg, 0.815 mmoles) in N, N -dimethylformamide (5 mL) were added N-
(biphenyl-4-yl)methanesulfonamide (161 mg, 0.652 mmoles) and potassium carbonate
( 112 mg, 0.815 mmoles). The reaction mixture was heated at 80°C for about 7.5 hours.
After completion, reaction mixture was allowed to cool to room temperature and water
was added to it. The reaction mixture was extracted with ethyl acetate. The combined
organic layer was washed with brine, dried over anhydrous sodium sulphate and
evaporated under reduced pressure to obtain a crude product. The crude product was
purified on silica gel column using 40% ethyl acetate: hexane as eluent to get desired
product.
Yield: 152 mg
LCMS: 552.1 (M+NH4
+)
Step b : Preparation of 2-[biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-dioxo-l,3-
dihydro-2H-isoindol-2-yl)butanoic acid
To an ice-cooled solution of compound obtained from Step a (152 mg, 0.0002
moles) in dichloromethane (10 mL) was added trifluoroacetic acid (0.7 mL) and stirred for
about 2.5 hrs at room temperature. After completion of reaction, the solvent was
evaporated and the reaction mixture was taken in dichloromethane and washed with water.
The organic layer was separated, dried over anhydrous sodium sulphate and concentrated
to get crude product. The crude product was purified on silica gel column using 40% ethyl
acetate: hexane as eluent to get desired product.

0 69
WE CLAIM:
1. A compound of Formula I:
I
R2
»
Formula 1
including racemates, enantiomers or diastereomers thereof; or a pharmaceutically acceptable salt
thereof, wherein,
L' is selected from bond, O, S, CH2, NR\ NHC0(CH2)n, (CH2)nC0NH, NHCONH, SO2NH,
NHSO2, NHCO(O), -0-(CH2)n, -(CH2)n-0-, -OC(0)NH-, C(S)NH, NHC(S), NHC(S)NH or -
COO- wherein n is zero or an integer between 1 and 2;
R* is selected from hydrogen, Ci-Cealkyl, hydroxyl, Ci-Cealkoxy, cyano, nitro, halogen,
halogeno Ci-Cealkyl, C5-Ci2aryl, C6-Ci2heteroaryl, Ca-Cecycloalkyl wherein aryl, heteroaryl,
cycloalkyl is optionally substituted by one or more substitutents independently selected from
R^isCHOorS02Ci^alkyl;
R^ is unsubstituted or substituted heteroaryl or -OCONHR' where R' is C6-C12 aryl, heteroaryl,
cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl each of
which is optionally substituted by one or more substitutents independently selected from R^;
R'* is H or Ci-6alkyl;
R^ is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-CpCe alkyl,
halogeno-Ci-C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfRq, -
(CH2)n-C(=0)NR,R<„ -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NR,R<„ (CH2)n NHC(=0)NRfRq,,
-(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {whereinRf and R^are
independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl,
alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2}.
2. A compound of Formula I, which is:
2-[Fomiyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 1);
4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[formyl(4'-niethylbiphenyl-4-yl)amino]butanoicacid
(Compound no. 2);
0 70
2-[(4'-Ethylbiphenyl-4-yl)(formyl)amino]-4-(5-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoicacid
(Compound no. 3);
0-[(4-Fluorophenyl)carbamoyl]-A^-formyl-A^-(4'-methylbiphenyl-4-yl)homoserine (Compound no. 4);
A'^-Formyl-A'^-(4'-methylbiphenyl-4-yl)-0-[(4-methylphenyl)carbamoyl]homoserine (Compound no. 5);
0-[(3,4-Dich!orophenyl)carbamoyl]-A^-formyl-A'^-(4'-methylbiphenyl-4-yl)homoserine (Compound no.
6);
A^-(4'-Ethylbiphenyl-4-yl)-7V-formyl-0-{[4-(propan-2-yl)phenyl]carbamoyl}
homoserine (Compound no. 7);
A^-(4'-Ethylbiphenyl-4-yl)-0-[(3-fluorophenyl)carbamoyl]-A^-formylhomoserine (Compound no. 8);
0-[(2,4-Difluorophenyl)carbamoyl]-A'-(4'-ethyIbiphenyl-4-yl)-A^-formylhomoserine (Compound no. 9);
A'-(4'-Ethylbiphenyl-4-yl)-0-[(2-fluorophenyl)carbamoyl]-A^-formylhomoserine (Compound no. 10);
#-(4'-Ethylbiphenyl-4-yl)-A'-formyl-6>-{[4-trifluoromethyl)phenyl]carbamoyl}
homoserine (Compound no. 11);
7V-(4'-Ethylbiphenyl-4-yl)-A'-formyl-0-[(2-methylphenyl)carbamoyl]homoserine (Compound no. 12);
A'^-(4'-Ethylbiphenyl-4-yl)-0-[(4-ethyIphenyi)carbamoyl]-A^-formylhomoserine (Compound no. 13);
A'-(4'-Ethylbiphenyl-4-yl)-A'^-formyl-(9-[(4-methoxyphenyl)carbamoyl]homoserine (Compound no. 14);
0-[(2,6-Dichlorophenyl)carbamoyl]-7V-(4'-ethylbiphenyI-4-yl)-A'-formylhomoserine (Compound no.
15);
2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-dioxo-l,3-dihydro-2//-isoindol-2-yl)butanoic acid
(Compound no. 16);
4-(l,3-Dioxo-l,3-dihydro-2//-isoindol-2-yl)-2-{[4-(6-methoxypyridin-3-yl)phenyl]
(methyl sulfonyl)amino}butanoic acid (Compound no. 17);
4-( 1,3-Dioxo-1,3-dihydro-2//-isoindol-2-yl)-2-[(4'-methoxybiphenyl-4yl)
(methylsulfonyl) aminojbutanoic acid (Compound no. 18);
2-{[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 19);
4-(7-Methoxy-4-oxo-1,2,3 -benzotriazin-3(4/0-yl)-2- {[4-(6-methoxypyridin-3 -
yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 20);
2-{[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino}-4-[4-oxo-7-(trifluoromethyl)-l,2,3-
benzotriazin-3(4/f)-yl]butanoic acid (Compound no. 21);
4-( 1,3 -Dioxo-1,3 -dihydro-2//-isoindol-2-y l)-2- {[4-(6-methoxypyridin-3 -yl)phenyl](methy 1
sulfonyl)amino}butanoic acid (Compound no. 22);
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4-(4-methylphenoxy)phenyl](methyl
sulfonyl)amino}butanoic acid (Compound no. 23);
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{[4-(4-methylphenoxy)phenyl](methyl sulfonyl)
amino}butanoic acid (Compound no. 24);
2-{[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino}-4-[4-oxo-7-(trifluoromethyl)-l,2,3-
benzotriazin-3(4//)-yl]butanoic acid (Compound no. 25);
2-{[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 26);
2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 27);
2-[(4'-Ethylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 28);
2-{[4-(2-Methoxypyrimidin-5-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-benzotriazin -3(4//)-
yl)butanoic acid (Compound no. 29);
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(niethylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 30);
2-[(2',4'-Dimethoxybiplienyl-4-yl)(methylsulfonyi)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 31);
2-[(4-Methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yi)butanoicacid
(Compound no. 32);
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(4-methoxyphenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 33);
4-(l,3-Dioxo-l,3-dihydro-2//-isoindol-2-yi)-2-[(4-methoxyphenyl)methylsulfonyl)amino]butanoicacid
(Compound no. 34);
2-[(4-Methoxypiienyl)(methylsulfonyl)amino]-4-(5-methyl-l,3-dioxo-l,3-dihydro-2//-isoindo-2-
yl)butanoic acid (Compound no. 35);
4-(7-Methoxy-4-oxo-1,2,3 -benzotriazin-3 (4//)-y l)-2- {[4-(4-methylphenoxy )pheny l](methy I
sulfonyl)amino}butanoic acid (Compound no. 36);
4-(5-Methyl-l,3-dioxo-l,3-dihydro-2//-isoindol-2-yl)-2-{[4-(4-methylphenoxy)
phenyl](methylsuifonyl)amino}butanoic acid (Compound no. 37);
2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 38);
2-[(4'-Fluorobiphenyi-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 39);
2-{(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 40);
2-[Biphenyl-4-yl(methyIsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 41);
2-{[4-(6-Methylpyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 42);
2-{(Methylsulfonyl)[4-(pyrimidin-5-yl)phenyl]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 43);
2-{(Methylsulfonyl)[4-(pyridin-3-yI)phenyl]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 44);
2-{(Methylsulfonyl)[4'-(trifluoromethyl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 45);
2-{(Methylsulfonyl)[4-(pyridin-4-yl)phenyl]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 46);
2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 47);
2-[(4'-?er/-Butylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 48);
2-[(2',3'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 49);
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 50);
4-( 1,3-Dioxo-1,3-dihydro-2//-isoindol-2-yI)-2- {(methylsulfonyl)[4-(propan-2-
yl)phenyl]amino}butanoic acid (Compound no. 51);
0 72
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{(methylsuIfonyl)[4-(propan-2-
yl)phenyl]amino}butanoic acid (Compound no. 52);
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-{(methylsulfonyl)[4-(propan-2-
yl)phenyl]amino}butanoic acid (Compound no. 53);
4-(l,3-Dioxo-l,3-dihydro-2//-isoindol-2-yl)-2-[(4-ethylphenyl)(methylsuifonyl)amino]butanoic acid
(Compound no. 54);
2-[(4-Ethylphenyl)(methyisuifonyl)amino]-4-(5-methyl-l,3-dioxo-l,3-dihydro-2//-isoindol-2-
yl)butanoic acid (Compound no. 55);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 56);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 57);
2-[(Methylsulfonyl)(phenyl)amino]-4-(4-oxo-l ,2,3-benzotriazin-3(4/f)-yl)butanoic acid (Compound no.
58);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methyl-l,3-dioxo-l,3-dihydro-2//-isoindol-2-
yl)butanoic acid (Compound no. 59);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-chloro-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 60);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-chloro-4-oxo-l,2,3-benzotriazin-3(4//)-
yi)butanoic acid (Compound no. 61);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-
yi)butanoic acid (Compound no. 62);
2-[(4'-Ciilorobiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-(trifluoromethyl)-l,2,3-benzotriazin-
3(4//)-yl]butanoic acid (Compound no. 63);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 64);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-fluoro-4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 65);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-( 1 -methyl-2,4-dioxo-1,4-dihydroquinazolin-
3(2//)-yl)butanoic acid (Compound no. 66);
4-{(Methylsulfonyl)[l-oxo-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)-l-(prop-2-en-l-yloxy)butan-2-yl]
amino}benzoic acid (Compound no. 67);
2-[{4-[(4-Methylphenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 68);
2-[{4-[(4-Chlorophenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 69);
2-{(Metiiylsulfonyl)[4-(phenylcarbamoyl)phenyl]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 70);
2-[{4-[(3-Fluorophenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 71);
2-[(Methylsulfonyl)(4-{[4-(propan-2-yl)phenyl]carbamoyl}phenyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 72);
2-[{4-[(4-Methoxyphenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 73);
2-[{4-[(4-Fluorophenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4/f)-
yl)butanoic acid (Compound no. 74);
0 73
2-[(Methylsulfonyl)(4-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl)amino]-4-(4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 75);
(2/?)-2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 76);
(2/?)-2-{(Methylsulfonyi)[4-(pyrimidin-5-yl)phenyl]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 77);
(2/?)-2-{(Methylsulfonyl)[4'-(propan-2-yi)biphenyl-4-yI]amino}-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yi)butanoic acid (Compound no. 78);
(2/?)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 79);
(2/?)-2-[(3',4'-Difluorobipiienyl-4-yl)(methyIsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 80);
(2/?)-2-[(3'-Fiuoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 81);
(2/?)-2-[(4'-Chlorobiphenyl-4-yl)(methylsuifonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 82);
(2/?)-2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 83);
(2/?)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yI)butanoic acid (Compound no. 84);
(2/?)-2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoicacid
(Compound no. 85);
(2/?)-2-{[4-(6-Methoxypyridin-3-yi)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yi)butanoic acid (Compound no. 86);
(25)-2-[(4'-Chlorobipiienyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 87);
(25)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 88);
(25)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4i:0-
yI)butanoic acid (Compound no. 89);
(25)-2-[(3'-Fluoro-4'-methoxybiphenyI-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 90);
(2i?)-2-[(3',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4/0-
yl)butanoic acid (Compound no. 91);
(2/?)-2-{[4-(2,3-Dihydro-l,4-benzodioxin-6-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 92);
(2/?)-2-[(4'-Methoxy-3'-methyibiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yI)butanoic acid (Compound no. 93);
(2/?)-2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4//)-
yl)butanoic acid (Compound no. 94);
(2/?)-2-{(Methylsulfonyl)[4'-(trifluoromethoxy)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-benzotriazin-
3(4//)-yl)butanoic acid (Compound no. 95);
(2/?)-2-{[4'-Chloro-3'-(trifluoromethyl)biphenyl-4-yl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 96);
(2/?)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-(trifluoro methyl)-
l,2,3-benzotriazin-3(4//)-yl]butanoic acid (Compound no. 97);
• 74
(2/?)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8-methyl-4-oxo-1,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 98);
(2/?)-4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(3'-fluoro-4'-methoxybiphenyI-4-
yl)(methylsulfonyl)amino]butanoic acid (Compound no. 99);
(2/?)-2-[(3'-Fluoro-4'-methoxybiphenyI-4-yl)(methylsulfonyi)amino]-4-(7-methoxy-4-oxo-1,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 100);
(2/?)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-y!)(methylsulfonyl)amino]-4-(6-methyl-4-oxo-1,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 101);
(2/?)-2-[(3'-Fluoro-4'-methoxybiphenyI-4-yl)(methylsulfonyl)amino]-4-(8-methoxy-4-oxo-1,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 102);
(2^)-2-[(3'-Fluoro-4'-methoxybipheny!-4-yl)(methylsulfonyl)amino]-4-(6-fluoro-4-oxo-1,2,3-
benzotriazin-3(4//)-yl)butanoic acid (Compound no. 103);
4-(5-Chloro-4-oxo-l,2,3-benzotriazin-3(4//)-yl)-2-[(4-chlorophenyl)(methyIsulfonyl)amino]butanoic
acid (Compound no. 104);
2-[(4-Bromophenyl)(methylsulfonyl)amino]-4-(4-oxo-1,2,3-benzotriazin-3(4//)-yl)butanoic acid
(Compound no. 105);
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(47/)-yI)butanoic acid
(Compound no. 106);
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 107);
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo-l,2,3-benzotriazin-3(4//)-yl)butanoic
acid (Compound no. 108)
including racemates or diastereomers thereof; or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound
according to claims 1 and 2, together with one or more pharmaceutically acceptable carriers,
excipients or diluents.
4. A compound according to claims 1 and 2, for use in the treatment or prophylaxis of an animal
or a human suffering from an inflammatory or allergic disease.
5. A compound according to claim 4, wherein the inflammatory or allergic disease is 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, tumor metastasis.
6. A pharmaceutical composition according to claim 3, further comprising one or more of
additional active ingredients selected from:
a) Anti-inflammatory agents, selected from (i) the nonsteroidal anti-inflammatory agents
piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4
inhibitors, p38 MAP Kinase/Cathepsin inhibitors, (ii) leukotrienes
LTC4/LTD4/LTE4/LTB4-Inhibitors, 5-lipoxygenase inhibitor and PAF-receptor
antagonists, (iii) Cox-2 inhibitors, (iv) other MMP inhibitors, and (v) interleukin-I
inhibitors;
b) antihypertensive agents, selected from (i) the ACE inhibitors, Hke enalapril, lisinopril,
valsartan, telmisartan and quinapril (ii) the angiotensin II receptor antagonists and
agonists-. losartan, candesartan, irbesartan, valsartan, and eprosartan, (iii) P-blockers, and
(iv) calcium channel blockers.
c) immunosuppressive agents selected from cyclosporine, azathioprine and methotrexate,
and anti inflammatory corticosteroids.
7. A process for preparing a compound of Formula 10 (Formula 1 when R^ is heteroaryl, L' is
9 1 ^
bond, R is CHO and R is substituted aryl or heteroaryl) and Formula 13 (Formula 1 when R is -
OCONHR', L is bond R is CHO and R is substituted aryl or heteroaryl) comprising:
a) reacting 4-bromo-4-nitrobenzene with a compound of Formula 2
HO /OH
B o
Formula 2
to give a compound of Formula 3;
Formula 3
b) reducing a compound of Formula 3 to give a compound of Formula 4
Formula 4
c) reacting a compound of Formula 4 with alpha-bromolactone, to give a compound of
Formula 5
Formula 5
d) formylating a compound of Formula 5 to give a compound of Formula 6
H ^ O Q
Formula 6
e) ring opening of a compound of Formula 6 to give a compound of Formula 7
^r--^ OH
Formula 7
f) reacting a compound of Formula 7 with a compound of Formula 8
H
0
Formula 8
to give a compound of Formula 9
Formula 9
g) deprotecting a compound of Formula 9 to give a compound of Formula 10
( ^
R5
Formula 10
or
h) reacting a compound of Formula 7 with a compound of Formula 11
0 77
^ / -
R ' . ^ - ^ OH R'NCO
Formula 7 Formula 11
to give a compound of Formula 12
R'i^^ ^ O h
NHR'
Formula 12
i) deprotecting a compound of Formula 12 to give a compound of Formula 13
R^-X / O
NHR'
Formula 13
wherein,
^ - ^ is aryl or heteroaryl ring;
R* is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-Cg alkyl;
Rp is carboxy protecting group, such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC
anhydride;
(HetN
^-^ is a heteroaryl ring;
R' is C6-Ci2aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocyclylalkyl each of which is optionally substituted by one or more
substitutents independently selected from R^;
R^ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl, halogeno-Ci-
C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfR,, -(CH2)n0
78
C(=0)NR,Rq, -(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(=0V-NRfRq {wherein Rf and R^
are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer
• between 1 and 2 and m is an integer 0-2}.
8. A process for preparing a compound of Formula 20 (Formula 1 when R^ is heteroaryl, L' is
bond, R^ is S02-Ci.6-alkyl and R' is substituted aryl or heteroaryl) comprising:
a) halogenating a compound of Formula 14 at alpha position
Formula 14
to give a compound of Formula 15
Hal
Formula 15
b) protecting a compound of Formula 15 to give a compound of Formula 16
R5-(HetNv.'-Y^ORp
^ - ^ Hal
Formula 16
c) reacting a compound of Formula 16 with a compound of Formula 17 (where Rk is
halogen) to give a compound of Formula 18
Ak
I
SO2
KC^^ R'
Formula 17 Formula 18
d) coupling of a compound of Formula 18 with a compound of Formula 2 to give a
compound of Formula 19
0 79
Ak
SO,Q
HO OH nc^ 0 V
R^ R5
Formula 2 Formula 19
e) deprotecting a compound of Formula 19 to give a compound of Formula 20
Ak
so,o
( ^
R5
Formula 20
or
f) reacting a compound of Formula 16, with a compound of Formula 17 (where Rk is
aryl/heteroaryl substituted with R )
Rs/Het Ns^^ORp A J ^'''''^'
^ - ^ Hal RK ^ ^
Formula 16 Formula 17
to give a compound of Formula 19
Ak
I
SO2
^ '
R5
Formula 19
g) deprotecting a compound of Formula 19 to give a compound of Formula 20
0 80
Ak
I
Formula 20
wherein,
^—' IS a heteroaryl ring;
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC
anhydride;
R^ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl, halogeno-Ci-
Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NR,Rq, -(CH2)n-
C(=0)NRfR<„ -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NRfR<„ (CH2)n NHC(=0)NRfRq,, -
(CH2)n-0-C(=0)-Rf,-(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0VNRfR<, {wherein Rf and Rq
are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer
between 1 and 2 and m is an integer 0-2};
Hal is F, CI, Br, I;
Ak is Ci-ealkyl;
o
is aryl or heteroaryl ring;
R^ is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-Ce alkyl.
9. A process for preparing a compound of Formula 26b (Formula 1 when R^ is heteroaryl, L ' is
bond, R^ is S02-Ci.6-alkyl and R' is aryl/heteroaryl substituted with OR^) and Formula 29 (Formula 1
when R^ is heteroaryl, L ' is bond, R^ is S02-Ci.6-alkyl and R' is halogen/hydrogen, alkoxy/aryloxy)
comprising:
a) reacting a compound of Formula 17a with alpha hydroxy lactone, to give a compound of
Formula 21
Ak
I
Formula 17a Formula 21
b) ring opening of a compound of Formula 21 to give a compound of Formula 22
«
Ak
SO, o
OH
Formula 22
c) protecting a compound of Formula 22 at carboxyl group to give a compound of Formula
23
Ak
so,o
OH
Formula 23
d) protecting a compound of Formula 23 (when Rk- is halogen) at hydroxyl group to give a
compound of Formula 24
Ak
I
SO2 o
ORp'
Formula 24
e) coupling of a compound of Formula 24 with a compound of Formula 24a, to give a
compound of Formula 25
^ 82
Ak
HO OH I
^ B ^^2 O
Formula 24a Formula 25
f) deprotecting a compound of Formula 25 to give a compound of Formula 26
Ak
SO, o
Formula 26
g) reacting a compound of Formula 26 with a compound of Formula 27, to give a compound
of Formula 26a
Ak
SO, o
[HetJ
R5-(Het NH ^
Formula 27 Formula 26a
h) deprotecting a compound of Formula 26a to give a compound of Formula 26b
Ak
SO,
Formula 26b
or
H 83
i) reacting a compound of Formula 23 (when R^ is alkoxy/aryloxy/halogen/hydrogen)
with a compound of Formula 27
Ak
*
Formula 23 Formula 27
to give a compound of Formula 28
Ak
I
SO2 .of-'
(Z)
R5
Formula 28
j) deprotecting a compound of Formula 28 to give a compound of Formula 29;
Ak
SO2O
(J)
R5
Formula 29
wherein,
Ak is Ci.6alkyl:
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC
anhydride;
Rp' is hydroxyl protecting group such as benzoyl, silyl groups /er/-butyldimethylsilyl,
trimethylsilyl, rer^butyldimethylsilyloxymethyl, triisopropylsilyl;
^ 84
(net N
^-^ is a heteroaryl ring;
Rk' is hydrogen, halogen, alkoxy, aryloxy, aryl, carboxy;
R^ is alkyl, alkenyl, alkynyl, cyano, nitre, halogen, halogeno-Ci-Ce alkyl, halogeno-Ci-
C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NR,Rq, -(CH2)n-
C(=0)NR,Rq, -(CH2)„-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NR^, (CH2)n NHC(=0)NR,Rq,, -
(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0)ni-NR,Rq {wherein Rf and R<,
are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer
between 1 and 2 and m is an integer 0-2}.
o is aryl or heteroaryl ring;
O R ' wherein R is hydrogen, alkyl, halogen, alkoxy or halogeno-CpCe alkyl.
10. A process for preparing a compound of Formula 31 (Formula 1 when R is heteroaryl, L is
bond, R^ is S02-Ci-6-alkyl and R ' is aryl/heteroaryl substituted with halogen) and Formula 36
(Formula 1 when R is heteroaryl, L is -CONH-, R is S02-Ak and R is aryl/heteroaryl) comprising:
a) reacting a compound of Formula 23 (when Rk' is aryl/heteroaryl substituted with halogen
and Rp is allyl) with a compound of Formula 27
Ak
so,o
Rk' I R5 4; Het NH
" OH \0
Formula 23 Formula 27
to give a compound of Formula 30
Ak
I
SOj o
N
Formula 30
9 85
b) deprotecting a compound of Formula 30 to give a compound of Formula 31;
Ak
SO, o
Hal ^ ' ^N V
Formula 31
or
c) reacting a compound of Formula 23 (when Rk' is -COORp) with a compound of Formula
27
Ak
"'I
•^ OH V_^
Formula 23 Formula 27
to give a compound of Formula 32;
Ak
SO2 o
R p O O C ^ ^ ^ 6
R5
Formula 32
d) deprotecting a compound of Formula 32 to give a compound of Formula 33;
0 86
Ak
I
SO, Q
H O O C - ^ ^ ^
; ©
Formula 33
e) coupling of a compound of Formula 33 with a compound of Formula 34
0
Formula 34
to give a compound of Formula 35
Ak
I
SO, o
^R5
Formula 35
f) deprotecting a compound of Formula 35 to give a compound of Formula 36;
Ak
I
SO, O
" 9
R5
Formula 36
0 87
wherein,
Ak is Ci.6alkyl;
Hal is F, CI, Br, I;
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC
anhydride;
« ^—^ is aryl or heteroaryl ring;
^—' is a heteroaryl ring;
R^ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl, halogeno-Ci-
C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfRq, -(CH2)n-
C(=0)NR,Rq, -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NRfR<„ (CH2)n NHC(=0)NR,Rq,, -
(CH2)n-0-C(=0)-Rf,-(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0VNR,R, {wherein Rf and R<,
are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer
between 1 and 2 and m is an integer 0-2};
R* is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-Ce alkyl.
11. A process for preparing a compound of Formula 43 (Formula 1 when R is heteroaryl, L is
bond, R^ is S02-Ci.6-alkyl and R ' is aryl/heteroaryl) comprising:
a) protecting a compound of Formula 37, to give compound of Formula 38
OH ORp.
Formula 37 Formula 38
b) reacting a compound of Formula 38 with a compound of Formula 39 to give a compound
of Formula 40
Ak
SO20
RejO-^y^ORp
^ " ^ ^ OR,
Formula 39 Formula 40
c) deprotecting a compound of Formula 40 to give a compound of Formula 41
0 88
Ak
OH
Formula 41
• d) reacting a compound of Formula 41 with a compound of Formula 27 to give a
compound of Formula 42
Ak
I
SOj
e fnetj
^H ^^3
Formula 27 Formula 42
e) deprotecting a compound of Formula 42 to give a compound of Formula 43
Ak
so,o
R5
Formula 43
wherein,
Akis Ci-ealkyl:
o
is aryl or heteroaryl ring;
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC
anhydride;
Rp' is hydroxyl protecting group such as benzoyl, silyl groups ?er/-butyldimethylsilyl,
trimethylsilyl, ^er/-butyldimethylsilyloxymethyl, triisopropylsilyl;
(net N
^-^ is a heteroaryl ring;
• 89
R" is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl, halogeno-Ci-
C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NRfRq, -(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)m-NR,R^ {wherein Rf and R^
' are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer
between 1 and 2 and m is an integer 0-2};
R^is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-Ce alkyl.
12. A process for preparing a compound of Formula 52 (Formula 1 when R is heteroaryl, L is
bond, R^ is S02-Ci.6-alkyl and R' is substituted aryl/heteroaryl) comprising:
a) reacting a compound of Formula 44 with 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane
to give a compound of Formula 45
e e
Formula 44 Formula 45
b) ring opening of a compound of Formula 45 to give a compound of Formula 46
HO OH
0
Formula 46
c) protecting a compound of Formula 46 to give a compound of Formula 47
Rp'O OH
0
Formula 47
d) reacting a compound of Formula 47 with a compound of Formula 48 to give a compound
of Formula 49
0 90
S02.Ak
NHSO,-Ak '
V "'' /-NX
Hal Q!!9
Formula 48 Formula 49
e) coupling of a compound of Formula 49 with a compound of Formula 2 to give a
«
compound of Formula 50
SOj-Ak
"X" r-P"^"'
Formula 2 Formula 50
f) deprotecting a compound of Formula 50 to give a compound of Formula 51
SOj-Ak
Formula 51
g) oxidizing a compound of Formula 51 to give a compound of Formula 52
S02-Ak
N P
Formula 52
wherein,
AkisCi-ealkyl:
^—^ is aryl or heteroaryl ring;
Rp' is hydroxyl protecting group such as benzoyl, silyl including rer^butyldimethylsilyl,
trimethylsilyl, /er/-butyldimethylsilyloxymethyl, triisopropylsilyl;
^ 91
f Het N
—' is a heteroaryl ring;
Hal is F, CI, Br, I; and
R* is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-Ce alkyl.
13. A process for preparing a compound of Formula 61 (Formula 1 when R^ is heteroaryl, L' is
^' bond, R^ is S02-Ci.6-alkyl and R' is substituted aryl/heteroaryl) comprising:
a) protecting 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane to give a compound of
Formula 53;
ORp'
Formula 53
b) ring opening of a compound of Formula 53 to give a compound of Formula 54;
HO OH
ORp"
Formula 54
c) protecting a compound of Formula 54 to give a compound of Formula 55;
Rp"0 OH
ORp'
Formula 55
d) reacting a compound of Formula 55 with a compound of Formula 48 to give a compound
of Formula 56;
Ak
SO2
SOjAk ^)
XT'" <
Formula 48 Formula 56
9 92
e) coupling of a compound of Formula 56 with a compound of Formula 2 to give a
compound of Formula 57
* Ak
SO,
HO OH I "
m
Formula 2 Formula 57
f) deprotecting a compound of Formula 57 to give a compound of Formula 58
Ak
SO2
^AJ OH
Formula 58
g) reacting a compound of Formula 58 with a compound of Formula 27 to give a compound
of Formula 59
Ak
i
SO2
Formula 27 Formula 59
h) deprotecting a compound of Formula 59 to give a compound of Formula 60
Ak
SO2
(J)
R5
Formula 60
i) oxidizing a compound of Formula 60 to give a compound of Formula 61
9 93
Ak
I
SO,
R>
* Formula 61
wherein,
Akis Ci.6alkyl:
o
is aryl or heteroaryl ring;
Rp' and Rp" is hydroxyl protecting group such as benzoyl, silyl groups tertbutyldimethylsilyl,
trimethylsilyl, /er^butyldimethylsilyloxynlethyl, triisopropylsilyl;
(HetN
^^— is a heteroaryl ring;
R^ is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-CpCe alkyl, halogeno-Ci-
C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-0Rf, -C(=0)-Rf, -COORf, -NR,R<„ -(CH2)n-
C(-0)NR,R^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- 0-C(=0)-NR,R<„ (CH2)n NHC(=0)NRfR<,,, -
(CH2)n-0-C(=0)-Rf,-(CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0VNRfR