FIELD OF THE INVENTION:
The present invention relates to novel fused imidazobenzothiazole derivatives their
pharmaceutically acceptable salts, and their isomers, steroisomers, atropisomers, conformers,
tautomers, polymorphs, hydrates, solvates and N-oxide. The present invention also
encompasses pharmaceutically acceptable compositions of said compounds and process for
preparing novel compounds. The invention further relates to the use of the above mentioned
compounds for the preparation of medicament for use as pharmaceuticals.
BACKGROUND OF THE INVENTION:
The prevalence of airway diseases has increased in recent decades despite therapeutic
advances. Among the airway diseases, asthma exacerbations and chronic obstructive
pulmonary disease (COPD) are major causes of hospitalization. Both asthma and COPD
involve chronic inflammation of the respiratory tract. Despite the presentation of similar
symptoms, such as dyspnea, coughing, wheezing and expectoration, these airway diseases
have different underlying pathophysiological processes. COPD is a term which refers to a
large group of lung diseases characterized by obstruction of air flow that interferes with
normal breathing. Emphysema and chronic bronchitis are the most important conditions that
compose COPD (COPD-Chronic Bronchitis & Emphysema; Australian lung foundation,
2006). COPD involves chronic inflammation of the peripheral airways and lung parenchyma,
which leads to progressive narrowing of the airways and shortness of breath. On the other
hand Asthma is characterized by episodic airway obstruction and symptoms and usually
starts early in life. The inflammation differs markedly between asthma and COPD, with
different cells, mediators, consequences and, there is a difference in response to
corticosteroids (Clinics (Sao Paulo). 2012; 67(11): 1335-43). However, more recently it has
become clear that severe asthma is much more similar to COPD, with similarities in the
inflammation and sharing a poor response to corticosteroids (J Allergy Clin Immunol.
2013;131(3):636-45). Interestingly, studies of molecular genetics are now showing that
severe asthma and COPD share several gene polymorphisms (Comp Funct Genomics. 2012;
2012: 968267).
Chronic obstructive pulmonary disease (COPD) is a major global health problem that
is becoming prevalent, particularly in developing countries. It is one of the most common
diseases in the world, with a lifetime risk estimated to be as high as 25%, and now equally
affects both men and women (Nature Reviews 2013 ; 12: 543-559)
Current forms of therapy for COPD are relatively ineffective, as there are no drugs
available that considerably reduce disease progression or mortality or have a substantial
effect on exacerbations, which are one of the most common causes of hospital admissions.
Long acting bronchodilators are the mainstay of current COPD therapy. There have
been several advances in the development of 2 - adrenergic receptor agonists and muscarinic
receptor antagonists that only need to be administered once a day. Moreover, long acting 2-
adrenergic receptor agonists (LABAs) and long -acting muscarinic acetylcholine receptor
antagonists (LAMAs) have additive effects on bronchodilation and in the improvement of
symptoms, which has led to the development of LABA-LAMA combination inhalers.
However, although these drugs produce effective bronchodilation, they fail to treat the
underlying inflammatory disease in patients with COPD.
Alternatively or additional to bronchodilators, oral or inhaled corticosteroids could
also be used as COPD therapy. But corticosteroids have limitations as long term oral
corticosteroid therapy is not recommended and inhaled corticosteroids are known to be
associated with increased risk of pneumonia in patients (www.bcguidelines.ca) Moreover,
Inhaled corticosteroids are found largely ineffective in significant number of COPD patients
as an anti- inflammatory therapy in COPD (Ann Fam Med. 2006; 4(3):253-62).
Phosphodiesterase inhibitors (PDE-4 inhibitors ) have recently been shown to document
clinical efficacy in COPD, although their utility is hampered by class related side effects..
(International Journal of COPD 2007; 2(2) : 121 129)
With better understanding of the pathophysiology of COPD disease process and
recognition of inflammation as an important feature, it is anticipated that disease modifying
therapy for COPD targeting underlying inflammation will prove effective the way it has been
successful in the treatment of other chronic inflammatory conditions like RA.
Many kinases are involved in the regulation of proinflammatory transcription factors
and inflammatory genes. The mitogen-activated protein kinase (MAPK) family includes the
p38 kinases, which consists of highly conserved proline-directed serine-threonine protein
kinases that are activated in response to inflammatory signals. The p38 MAPK pathway,
which is activated by cellular stress, regulates the expression of many inflammatory genes
that are involved in COPD (Nature Reviews 2013; 12: 543-559). Proinflammatory
cytokines/chemokines and environmental stress activates p38 mitogen activated protein
kinase (MAPK) by phosphorylation, which in turn activates p38 MAPK signaling pathway.
p38 is involved in the inflammatory responses induced by different stimuli through activation
and release of proinflammatory cytokines/chemokines, posttranslational regulation of these
genes, and activation of inflammatory cell migration. Therefore, p38 inhibitors present a
potentially attractive treatment target for the chronic inflammatory conditions including
COPD. Of the four isoforms known so far, p38 alpha is the most abundant in inflammatory
cells and has been the most studied.
Over the past two decades, p38 MAPK (mitogen-activated protein kinase) has been
the subject of intense multidisciplinary research. p38 MAPK inhibitors have been shown to
be efficacious in several disease models, including rheumatoid arthritis, psoriasis, Crohn's
disease, and stroke. Recent studies support a role for p38 MAPK in the development,
maintenance, and/or exacerbation of a number of pulmonary diseases, such as asthma, cystic
fibrosis, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. There is
now an abundant literature which demonstrates that p38 MAPK is activated in chronic
inflammatory conditions and that its activation results in the elaboration and release of
further pro-inflammatory cytokines (Expert Opin. Investig. Drugs 2008; 17(10): 141 1-1425).
Though orally administered small molecule inhibitors targeted to P38 MAPK have
proved to be effective in reducing various parameters of inflammation in cells and tissues
obtained from patients with COPD in initial clinical studies, the major obstacle hindering the
definition and exploitation of the potential utilities of p38 MAPK inhibitors in the treatment
of human chronic inflammatory diseases has been the toxicity observed in patients. This has
been sufficiently severe to result in the withdrawal from clinical development of many of the
compounds progressed. Presently, none of them is yet approved anywhere in the world
because one or the other problems associated with selected molecules such as toxicity or
selectivity (Expert Opin. Investig. Drugs 2008; 17(10): 141 1-1425 & Chest
2011;139(6): 1470 1479).
For example, pyridinyl imidazole based p38 MAPK inhibitors into clinical trials were
found to be associated with unacceptable safety profile. The side effects reported both
preclinically and clinically for other similar p38 MAPK inhibitors include hepatotoxicity,
cardiotoxicity, light headedness and other CNS toxicities, skin rash, gastrointestinal tract
symptoms, and infections. Some question of selectivity has also arisen for these molecules.
Similarly, BIRB-796, a noncompetitive p38 MAPK inhibitor for ATP was evaluated for its
activity but it has been withdrawn from Phase II clinical trials for rheumatoid arthritis,
possibly because of liver enzyme elevations. (Expert Opin. Investig. Drugs 2008;
17(10):1411-1425 & Chest 2011; 139(6): 1470 1479).
A Phase II study with another p38 MAPK inhibitor Vx-745, in rheumatoid arthritis
patients displayed significant clinical benefit compared to placebo at the single low dose
tested. However, it was also discontinued because of undisclosed CNS toxicity in dogs
during a 6-month safety study. (Expert Opin. Investig. Drugs 2008; 17(10): 1411-1425)
To overcome these problems of toxicity and selectivity of the target associated with
known p38 MAPK inhibitors, some alternative strategies were designed. One of them was to
design the treatment approaches wherein p38 kinase inhibitor is dosed directly to the
inflamed organ.
Other strategies include developing newer generation p38 MAPK inhibitors with
improved selectivity and lesser side effect profile. For example, PH-797804 and
Losmapimod have been shown to be well tolerated in clinical studies when treated up to 12-
24 weeks. (Thorax. 2013 Aug; 68(8): 738-45 & J Clin Pharmacol. 2012 Mar; 52(3): 416-24)
There remains a need to identify and develop new p38 MAPK inhibitors which
provides desired therapeutic potential along with improved pharmacokinetic profile and/or
lesser side effects.
WO2002 14321 discloses polycyclic imidazole derivatives as STAT-6 inhibitors for
the treatment of cancer or to sensitize cancer cells to other anti-cancer treatment.
GB2232666 and GB221 1186 disclose imidazobenzothiazoles as benzodiazepine
inverse agonist for the treatment of memory problem, obesity or can be used as minor
tranquillizers.
Present invention provides novel fused imidazobenzothiazole derivatives as p38
MAPK inhibitors, which have demonstrated desired efficacy and safety profile.
SUMMARY OF THE INVENTION:
In one embodiment, the present invention provides novel compounds of formula (I),
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers,
conformers, tautomers, polymorphs, hydrates, solvates and N-oxide;
wherein,
X is selected from O, S(0) , NH and N(Ci-C3)alkyl;
Ri and R2 is independently selected from hydrogen, A, CHO, C=N-OH, C=N-0-(Ci-
C6)alkyl, CH2OH, CH2R3, N(R5)C0 2R4, CH2-halogen, NR5R6, N(R5)C(0)-A, N(R5)S(0) m-A,
N(R5)C(0)N(R 5)-A, N(R5)C(S)N(R5)-A, C(0)NR 5R6, C0 2R , C(0)-A, CH(OH)-A
C(CH3)=N-OH, C(CH3)=N-0-(Ci-C 6)alkyl, C(0)CH 2-halogen and C(0)CH 2R3;
R is independently selected from hydrogen, (Ci-C )alkyl, (C3-Cio)carbocycle, CN, CHO,
C(0)-A, C(CH3)=N-OH, C(CH3)=N-0-(Ci-C 6)alkyl, C(0)CH 2-halogen, C(0)CH 2R3,NR5R6,
N(R5)C(0)-A, N(R5)S(0) -A, N(R5)C(0)0-A, N(R5)C(0)N(R 5)-A, N(R5)C(S)N(R5)-A,
C0 2R , C(0)N(R 5)-A, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (Ci-C6)alkyl-N3, ( -
C6)alkyl-NR5R6, (Ci-C6)alkyl-N(R5)C(0)-A, (Ci-C6)alkyl-N(R5)S(0) m-A, (Ci-C6)alkyl-
N(R5)C(0)0-A, (Ci-C6)alkyl-N(R5)C(0)N(R 5)-A, (Ci-C6)alkyl-N(R5)C(S)N(R5)-A and (QC
6)alkyl-OC(0)N(R 5)-A;
A is independently selected from (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl
and heterocyclic, the said (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl or heterocyclic
may be optionally substituted with 1-3 substituents independently selected from halogen,
(Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl, heterocyclic, hydroxyl, CF3, OCF3, 0(Ci-
C6)alkyl, O-(C3-Ci0)carbocycle, N0 2, C(0)-(Ci-C 6)alkyl, C(0)CH 2-halogen, C(0)CH 2R3,
NR5R6, C0 2R , C(0)N(R 5)-A, N(R5)S(0) m-A, SH, S(0) (Ci-C6)alkyl, S(0) mN(R5)-A, CN,
CHO, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen and (Ci-C6)alkyl-NR5R 6 wherein each aryl or
heteroaryl may be further optionally substituted with 1-3 substituents independently selected
from halogen, (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl, heterocyclic, hydroxyl, CF3,
OCF3, 0(Ci-C 6)alkyl, O-(C3-Ci0)carbocycle, N0 2, C(0)-(Ci-C 6)alkyl, C(0)CH 2-halogen,
C(0)CH 2R3, NR5R6, C0 2R , C(0)N(R 5)-A, N(R5)S(0) m-A, SH, S(0) (Ci-C6)alkyl,
S(0) mN(R5)-A, CN, OS0 3H, CHO, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (Ci-C6)alkyl-
' °
NR5R and ;
R3 is independently selected from O-A, NR5R6, S(0) -A, S(0) -(Ci-C6)alkyl-C0 2(Ci-
C6)alkyl, S(0) -(Ci-C6)alkyl-OH, S(0) -(Ci-C6)alkyl-C0 2H, N(R5)C(0)-A, N(R5)C(0)0-A,
N(R5)C(0)N(R 5)-A, N(R5)S(0) m-A, N(R5)C(0)-heterocyclic and N(R5)C(S)N(R5)-A;
R4 is hydrogen or A;
R 5 and R 5 is independently selected from hydrogen, (Ci-C )alkyl, (Ci-C )alkyl-(C3-
Cio)carbocycle and (C3-Cio)carbocycle;
R and R is independently selected from hydrogen, A, (Ci-C )alkyl-OH, (Ci-C )alkyl-
NR5
'R6
'
, CH(CH2OH)-aryl, CH(CH2OH)2, (Ci-C6)alkyl-aryl, (Ci-C6)alkyl-heterocyclic and
(Ci-C )alkyl-heteroaryl;
R and R or R and R together with the nitrogen to which they are attached may form a 3 to
8 membered monocyclic or 8 to 12 membered bicyclic heterocycle ring, which ring
optionally contains an additional heteroatom selected from O, S or N and the said ring is
optionally substituted by one or more R 9 or Rio substituent. The nitrogen of said ring may
also form N-oxide. In bicyclic heterocyclic system, the rings can be attached to each other in
a spiro or fused manner;
R is hydrogen or A;
Each R is independently 1-2 substituents and each selected from hydrogen, halogen, A, CN,
CHO, C(0)-A, C(0)CH 2-halogen, C(0)CH 2R3, hydroxyl, CF3, OCF3, NR5R6, N(R5)C(0)-A,
N(R5)S(0) m-A, C(0)N(R 5)-A, 0-(Ci-C 6)alkyl, O-(C3-Ci0)carbocycle, S(0) -A and
S(0) mN(R5)-A, wherein R and are simultaneously not hydrogen;
R 9 is independently selected from hydrogen, halogen, A, hydroxyl, CF3, OCF3, 0(Ci-
C6)alkyl, O-(C3-Ci0)carbocycle, N0 2, C(0)-A, C(0)CH 2-halogen, C(0)CH 2R3, NR5R6,
N(R5)C(0)0-A, N(R5)C(0)N(R 5)-A, N(R5)C(S)N(R5)-A, C0 2R , C(0)N(R 5)-A, CN, CHO,
(Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (Ci-C6)alkyl-aryl, (Ci-C6)alkyl-NR5R6, ( -
C6)alkyl-N(R5)C(0)0-A, (Ci-C6)alkyl-N(R5)C(0)N(R 5)-A, (Ci-C6)alkyl-N(R5)C(S)N(R5)-A,
(Ci-C6)alkyl-OC(0)N(R 5)-A and N(R5)S(0) m-A;
Rio is selected from hydrogen, halogen, A, hydroxyl, (Ci-C )alkyl-(C3-Cio)carbocycle, (Ci-
C6)alkyl-aryl, C(0)-A, C0 2R , C(0)N(R 5)-A, C(0)(Ci-C 6)alkyl-A, oxo, thio, =N-OH, =N-
0-(Ci-C 6)alkyl, 0-(Ci-C 6)alkyl, O-(C3-Ci0)carbocycle, O-aryl, O-heteroaryl, S(0) -A,
NR5R6, N(R5)C(0)-A, N(R5)C(0)0-A, N(R5)C(0)N(R 5)-A, N(R5)S(0) m-A, N(R5)C(0)-
heterocyclic and N(R5)C(S)N(R5)-A;
m is 1 or 2;
n is 0, 1 or 2;
In another embodiment, the present invention pertains to a compound as above,
however only including pharmaceutically acceptable salts thereof.
In another embodiment, the present invention pertains to a compound as above,
however only including N-oxide.
In another embodiment, the present invention includes synthetic intermediates that
are useful in preparing the compounds of formula (I) and process for preparing such
intermediates.
Another embodiment of the present invention is a method for preparation of a
compound of formula (I) as herein described in Schemes 1 to 6.
Another embodiment of the present invention is a pharmaceutical composition
comprising a compound of formula (I), optionally in admixture with a pharmaceutically
acceptable adjuvant or carrier.
Another embodiment of the present invention is a method for treating allergic and
non-allergic airway diseases by administering a therapeutically effective amount of a
compound of formula (I) to a mammal, including human being, in need thereof.
Another embodiment of the present invention is a method for treating chronic
obstructive pulmonary disease and asthma by administering a therapeutically effective
amount of a compound of formula (I) to a mammal, including human being, in need thereof.
Another embodiment of the present invention is the use of a compound of formula (I)
for the preparation of a medicament for treating allergic and non-allergic airway diseases.
Another embodiment of the present invention is the use of a compound of formula (I)
for the preparation of a medicament for treating chronic obstructive pulmonary disease and
asthma.
FIGURES
Fig 1: Effect of treatment of compound no 31, on lung function parameters;
1. Functional residual capacity (Fig la), 2. Residual volume of lungs (Fig lb).
Fig 2 : Effect of treatment of compound no 31, on lung function parameters;
1. Inspiratory capacity to total lung capacity ratio (Fig 2a) and 2. Total lung resistance (Fig
2b).
DETAILED DESCRIPTION OF THE INVENTION:
In one embodiment, the present invention provides novel compounds of formula (I),
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers,
conformers, tautomers, polymorphs, hydrates, solvates and N-oxide, wherein R, R1 R , ,
R and X, are as defined above.
In another embodiment, the present invention provides novel compounds of formula
(I),
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers ,
conformers, tautomers, polymorphs, hydrates, solvates and N-oxide;
wherein
X is O or S(0)„;
R, Ri, R2, R8, R 9 and n are as defined above.
In a preferred embodiment, the present invention provides novel compounds of
formula (I),
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers ,
conformers, tautomers, polymorphs, hydrates, solvates and N-oxide;
Wherein,
X is O, NH or S(0)„;
Ri and R2 is independently selected from hydrogen, A, CHO, CH2OH, CH2R3, CH2-halogen,
N(R5)C0 2R4, C(0)NR 5R6, C0 2R and C(0)-A;
R is independently selected from CN, CHO, C(0)-A, NR5R6, N(R5)C(0)-A, N(R5)C(0)0-A,
N(R5)C(0)N(R 5)-A, C(0)N(R 5)-A, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (d-C 6)alkyl-
N3, (Ci-C6)alkyl-NR5R6, (Ci-C6)alkyl-N(R5)C(0)-A, (Ci-C6)alkyl-N(R5)C(0)0-A, (d-
C6)alkyl-N(R5)C(0)N(R 5)-A and (Ci-C6)alkyl-OC(0)N(R 5)-A;
A is independently selected from (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl and
heterocyclic, the said (Ci-C )alkyl, aryl or heteroaryl may be further substituted with 1-3
substituents independently selected from halogen, (Ci-C )alkyl, (C3-Cio)carbocycle, aryl,
heterocyclic, hydroxyl, CF3, 0(Ci-C 6)alkyl, N(R5)S(0) m-A and (Ci-C6)alkyl-OR , each aryl
may be further substituted with 1-3 substituents independently selected from halogen, (Ci-
C6)alkyl, hydroxyl, OS0 3H, 0(Ci-C 6)alkyl and
R3 is independently selected from O-A, NR5R6, S(0) -A, S(0) -(Ci-C6)alkyl-C0 2(Ci-
C6)alkyl and S(0) -(Ci-C6)alkyl-OH;
R4 is hydrogen or A;
R 5 is hydrogen or (Ci-C )alkyl;
R is independently selected from hydrogen, A, (Ci-C )alkyl-OH, CH(CH2OH)-aryl,
CH(CH2OH)2, (Ci-C6)alkyl-aryl, (Ci-C6)alkyl-heterocyclic and (Ci-C6)alkyl-heteroaryl;
R 5 and R together with the nitrogen to which they are attached may form a 3 to 8 membered
monocyclic heterocycle ring, which ring contains an additional heteroatom selected from O,
S and N and the said ring is substituted by R9; the nitrogen of said ring may also form Noxide;
R7 is hydrogen or A, which is (Ci-C )alkyl;
R is hydrogen or A, which is (Ci-C )alkyl;
R is hydrogen, hydroxyl or A, which is (Ci-C )alkyl;
n is 0;
is 2.
A family of specific compounds of particular interest within the scope of present
invention consists of compound and pharmaceutically acceptable salts thereof as follows:
Compd. Chemical Name
No.
1 7-[4-({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy] -N-[2-(morpholin-4-yl)ethyl]imidazo[2,1-
b][1,3]benzothiazole-2-carboxamide
2 7-[4-( {[3-tert-butyl- 1-(4-methylphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy] -N-[2-(morpholin-4-yl)ethyl]imidazo[2,1-
b][1,3]benzothiazole-2-carboxamide
3 7-[4-( {[3-tert-butyl- 1-(4-methylphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy] -N-(2-hydroxy- 1-phenylethyl)imidazo[2, 1-
b][1,3]benzothiazole-2-carboxamide
4 7-[4-( {[3-tert-butyl- 1-(4-methylphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy] -N-(2-hydroxyethyl)imidazo[2, 1-
b][1,3]benzothiazole-2-carboxamide
5 ethyl 7-[4-({ [3-tert-butyl-l-(3-chloro-4-methoxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
6 7-[4-( {[3-tert-butyl- 1-(3-chloro-4-methoxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylic acid
7 7-[4-( {[3-tert-butyl- 1-(3-chloro-4-methoxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy] -N-(2-hydroxyethyl)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxamide
7-[4-({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylic acid
7-{ [4-({ [3-tert-butyl-l-(4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenyl]sulfanyl}imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylic acid
7-{ [4-({ [3-tert-butyl-l-(4-methoxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenyl]sulfanyl}imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylic acid
7-{ [4-({ [3-tert-butyl-l-(4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenyl]sulfanyl}-N-(2-hydroxyethyl)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxamide
ethyl 7-{2-[({ [3-tert-butyl-l-(4-methoxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
7-{2-[( {[3-tert-butyl- 1-(4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylic acid
7-{2-[( {[3-tert-butyl- 1-(4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy}-N-(2-hydroxyethyl)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxamide
1-[3-tert-butyl- 1-(4-methoxyphenyl)- lH-pyrazol-5-yl] -3-(4- {[3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }phenyl)urea
1-[3-tert-butyl- 1-(4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(2- {[3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }benzyl)urea
Ethyl 7-{2-[( {[3-tert-butyl- 1-(4-hydroxyphenyl)- lH-pyrazol-5-yl]
carbamoyl }amino)methyl]phenoxy}imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate
1-[3-tert-butyl- 1-(4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(4- {[3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]sulfanyl }phenyl)urea
7-{2-[({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylic acid
7-{2-[( {[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy}-N-(2-hydroxyethyl)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxamide
7-{2-[( {[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy}-N-( 1,3-dihydroxypropan-2-
yl)imidazo [2, 1-b] [1,3]benzothiazole-3-carboxamide
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }benzyl)urea
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-{2-[(3-
{[(2-hydroxyethyl)sulfanyl]methyl }imidazo[2, 1-b] [1,3]benzothiazol-7-
yl)oxy]benzyl}urea
7-({2-[( {[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl}amino)methyl]phenyl}sulfanyl)imidazo[2,lb][
1,3]benzothiazole-3-carboxylic acid
ethyl 7-{2-[({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
ethyl 7-[4-({ [3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(4- {[3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }phenyl)urea
7-{2-[({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl}amino)methyl]phenoxy}-N-(2-hydroxyethyl)-Nmethylimidazo[
2, 1-b] [1,3]benzothiazole-3-carboxamide
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(thiomorpholin-4-ylmethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea
ethyl {[(7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazol-2-
yl)methyl] sulfanyl }acetate
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{ [3-
(methoxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }benzyl)urea
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-{2-[(3-
{[(2-hydroxyethyl)(methyl)amino]methyl }imidazo[2, 1-b] [1,3]benzothiazol-
7-yl)oxy]benzyl }urea
N-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-4-{[3-
(morpholin-4-ylcarbonyl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzamide
methyl {[(7- {2-[( {[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazol-3-
yl)methyl] sulfanyl }acetate
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{ [3-
(morpholin-4-ylmethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{ [3-
(morpholin-4-ylcarbonyl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(methoxymethyl)-2-methylimidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea
1-(3-tert-butyl- 1-phenyl- lH-pyrazol-5-yl)-3-(2- {[3-(hydroxymethyl)-2-
methylimidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
2-methoxyethyl (7-{2-[({ [3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1Hpyrazol-
5-yl]carbamoyl}amino)methyl]phenoxy}imidazo[2,lb][
1,3]benzothiazol-3-yl)carbamate
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[2-
methyl-3-(morpholin-4-ylmethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea
7-(4- {[(2-hydroxy- 1-phenylethyl)carbamoyl]amino }phenoxy)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxylic acid
ethyl 7-[2-({ [(2-hydroxy- l-phenylethyl)carbamoyl] aminojmethyl)
phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-(4-{[(5-methyl-3-phenyl-l,2-oxazol-4-yl)carbamoyl]
amino }phenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({[(3-chloro-4-methoxyphenyl)carbamoyl]
amino }methyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({[(3,5-dimethoxyphenyl)carbamoyl] aminojmethyl)
phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-(2- {[(cyclohexylcarbamoyl)amino]methyl }phenoxy)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxylate
ethyl 7-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl Jamino)
phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
1-(3-chloro-4-methoxyphenyl)-3-(2- {[3-(methoxymethyl)-2-
methylimidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
l-[4-chloro-3-(trifluoromethyl)phenyl]-3-(2-{[3-(methoxymethyl)-2-
methylimidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
1-(3-tert-butyl-1,2-oxazol-5-yl)-3-(2- {[3-(methoxymethyl)-2-
methylimidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
ethyl 7-(2-formylphenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-(hydroxymethyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
ethyl 7-[2-(chloromethyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
ethyl 7-[2-(azidomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate
ethyl 7-[2-(aminomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate hydrochloride
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-({ 3-
[(cyclopropylmethoxy)methyl]imidazo[2, 1-b] [1,3]benzothiazol-7-
yl}oxy)benzyl]urea
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(chloromethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
ethyl 7-[(4-nitrophenyl)sulfanyl]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate
ethyl 7-[(4-aminophenyl)sulfanyl]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate
Ethyl 7-{[4-( {[3-tert-butyl- 1-(4-methoxyphenyl)- lH-pyrazol-5-yl]
carbamoyl} amino) phenyl] sulfanyl} imidazo [2,l-b][l,3]benzothiazole-3-
carboxylate
ethyl 7-(4-nitrophenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-(4-aminophenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(ethoxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }benzyl)urea
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-(5-
methyl- 1,3-oxazol-2-yl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-({3-[(4-
hydroxypiperidin- l-yl)methyl] imidazo [2, 1-b] [1,3]benzothiazol-7-
yl}oxy)benzyl]urea
methyl 7-(2-{ [({5-tert-butyl-2-methoxy-3-[methyl(methylsulfonyl)
amino]phenyl} carbamoyl)amino] methyl} phenoxy)imidazo[2,lb][
1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({[(3-tert-butyl-l-phenyl-lH-pyrazol-5-yl)carbamoyl] amino}
methyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-(2- {[(propylcarbamoyl)amino]methyl}phenoxy)imidazo[2, 1-b] [1,3]
benzothiazole-3-carboxylate
ethyl 7-(2- {[(piperidin-4-ylcarbamoyl)amino]methyl }phenoxy)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
ethyl 7-{2-[( {[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl] -5-methylphenoxy }-5-methylimidazo[2, 1-
b][1,3]benzothiazole-3-carboxylate
ethyl 7-{ [3-({ [3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenyl]amino }imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate"
ethyl 7-{ [4-({ [3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl}amino)phenyl]amino}imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate
N-(5-tert-butyl-2-methoxy-3-{ [(2-{ [3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl) carbamoyl] aminojphenyl)
methanesulfonamide
N-(5-tert-butyl-2-methoxy-3-{ [(2-{ [3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)carbamoyl]amino} phenyl)
ethanesulfonamide
N-(5-tert-butyl-2-methoxy-3-{ [(2-{ [3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)carbamoyl]amino}phenyl)-Nmethylethanesulfonamide
N-(5-tert-butyl-2-methoxy-3-{ [(2-{ [3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)carbamoyl]amino}phenyl)-Nmethylmethanesulfonamide
Methyl 7-{4-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
ethyl 6- {2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl}amino)methyl]-4-fluorophenoxy}pyrrolo[2,lb][
1,3]benzothiazole- 1-carboxylate
ethyl 7-(2-{[(phenoxycarbonyl)amino] methyl Jphenoxy) imidazo[2,lb][
1,3]benzothiazole-3-carboxylate
4-(3-tert-butyl-5-{[(2-{[3-(morpholin-4-ylmethyl)imidazo[2,l-b]
[1,3]benzothiazol-7-yl]oxy }benzyl)carbamoyl]amino}-1H-pyrazol- 1-yl)-2-
chlorophenyl beta-D-glucopyranosiduronic acid
4-(3-tert-butyl-5-{[(2-{[3-(morpholin-4-ylmethyl)imidazo[2,lb][
1,3]benzothiazol-7-yl]oxy}benzyl)carbamoyl]amino }-1H-pyrazol- 1-yl)-
2-chlorophenyl hydrogen sulfate
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-({3-[(4
oxidomorpholin-4-yl)methyl]imidazo[2, 1-b] [1,3]benzothiazol-7-
yl}oxy)benzyl]urea
1-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(morpholin-4-ylmethyl)- 1-oxidoimidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea
1-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(morpholin-4-ylmethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea: Dihydrochloride
1-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-
(morpholin-4-ylmethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-
yl]oxy}benzyl)urea: Dimethanesulfonate
ethyl 6,8-bis(acetylamino)-7-(4-nitrophenoxy)imidazo[2,lb][
1,3]benzothiazole-3-carboxylate
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-
(imidazo[2, 1-b] [1,3]benzothiazol-7-yloxy)benzyl]urea
The following definitions apply to the terms as used throughout this specification,
unless otherwise limited in specific instances:
The term "compound" employed herein refers to any compound encompassed by the
generic formula disclosed herein. The compounds described herein may contain one or more
double bonds and therefore, may exist as isomers, stereoisomers, such as geometric isomers,
E and Z isomers, and may possess asymmetric carbon atoms (optical centres) and therefore
may exist as enantiomers, diastereoisomers. Accordingly, the chemical structures described
herein encompasses all possible stereoisomers of the illustrated compounds including the
stereoisomerically pure form (e.g., geometrically pure) and stereoisomeric mixtures
(racemates). The compound described herein, may exist as a conformational isomers such as
chair or boat form. The compound described herein may also exist as atropisomers. The
compounds may also exist in several tautomeric forms including the enol form, the keto form
and mixtures thereof. Accordingly, the chemical structures described herein encompass all
possible tautomeric forms of the illustrated compounds. The compounds described also
include isotopically labeled compounds where one or more atoms have an atomic mass
different from the atomic mass conventionally found in nature. Examples of isotopes that
may be incorporated into the compounds of the invention include, but are not limited to H,
3H, 13C, 14C, 15N, 18O, 17O, etc. Compounds may exist in unsolvated forms as well as solvated
forms, including hydrated forms. In general, compounds may be hydrated or solvated.
Certain compounds may exist in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated herein and are intended to be within
the scope of the present invention.
The use of the terms "a" & "an" & "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to be
construed to cover both the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context.
The nomenclature of the compounds of the present invention as indicated herein is
according to ACD/Lab's ChemDraw with "logD Suite" (Version 12.0)
"Pharmaceutically acceptable salt" refers to a salt of a compound, which possesses the
desired pharmacological activity of the parent compound. Such salts include: (1) acid
addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or formed with organic
acids such as acetic acid, propionic acid, isobutyric acid, hexanoic acid,
cyclopentanepropionic acid, oxalic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, phthalic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-
hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-
naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-
methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic
acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glucuronic acid, galactunoric acid, glutamic acid, hydroxynaphthoic acid, salicylic acid,
stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in
the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth
ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like. Also included are salts of
amino acids such as arginate and the like (see, for example, Berge, S.M., et al.,
"Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
As used herein, the term "polymorph" pertains to compounds having the same
chemical formula, the same salt type and having the same form of hydrate/solvate but having
different crystallographic properties.
As used herein, the term "hydrate" pertains to a compound having a number of water
molecules bonded to the compound.
As used herein, the term "solvate" pertains to a compound having a number of
solvent molecules bonded to the compound.
As used herein, "N-oxide" refers to compounds having oxidized nitrogen atom.
The present invention also encompasses compounds which are in a prodrug form.
Prodrugs of the compounds described herein are those compounds that readily undergo
chemical changes under physiological conditions (in vivo) to provide the compounds of the
present invention. Additionally, prodrugs can be converted to the compounds of the present
invention by chemical or biochemical methods in an ex vivo environment, for example,
transdermal patch reservoir with a suitable enzyme or chemical. Prodrugs are, in some
situation, easier to administer than the parent drug. They may, for instance, be bioavailable
by oral administration whereas the parent drug is not. The prodrug may also have improved
solubility in pharmacological composition over the parent drug. Esters, peptidyl derivatives
and the like, of the compounds are the examples of prodrugs of the present invention. In vivo
hydrolysable (or cleavable) ester of a compound of the present invention that contains a
carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in
the human or animal body to produce the parent acid.
The present invention also encompasses compounds which are in an S-oxide form. As
used herein, "S-oxide" refers to compounds having oxidized sulfur atom.
The term "substituted", as used herein, includes mono- and poly-substitution by a
named substituent to the extent such single and multiple substitution (including multiple
substitution at the same site) is chemically allowed and which means that any one or more
hydrogen on the designated atom is replaced with a selection from the indicated group,
provided that the designated atom's normal valence is not exceeded, and that the
substitution results in a stable compound, for example, when a substituent is keto, then the
two hydrogens on the atom are replaced. All substituents (R, R1 R2 ... .) and their further
substituents described herein may be attached to the main structure at any heteroatom or
carbon atom which results in formation of stable compound.
As used herein, a "halogen" substituent is a monovalent halogen radical chosen from
chloro, bromo, iodo and fluoro.
The term "(Ci-C )alkyl" used either alone or in attachment with another group refers
to aliphatic hydrocarbon radical having the 1 to 6 carbon atoms and that is unsubstituted or
substituted. Said "(Ci-C )alkyl" may be straight (for example, methyl, ethyl, n-propyl, nbutyl,
n-pentyl, n-hexyl) or branched chain (for example, isopropyl, isobutyl, sec-butyl, tertbutyl)
and it may contain one or two double or triple bonds. The said (Ci-C )alkyl may also
contain (C3 -C )cycloalkyl ring in a spiro manner.
The term "(C 3-C10) carbocycle" used either alone or in attachment with another group
refers to a cyclic ring system having the 3 to 10 carbon atoms and that is unsubstituted or
substituted. The said "(C 3-Cio)carbocycle" means a cyclic ring system containing only
carbon atom in the ring system backbone such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl. Carbocycle may include bicyclic fused rings. Carbocycle may have any degree
of saturation provided that at least one ring in the ring system is not aromatic.
The term "aryl" refers to an aromatic group for example, which is a 6 to 10 membered
monocyclic or bicyclic carbon-containing ring system. The aryl groups include, but are not
limited to, phenyl, naphthyl, biphenyl, tetrahydronaphthyl and indane. Preferably, aryl is
phenyl which may be further substituted by (Ci-C6)alkyl, N(R5)S(0) m-A, N(R5)C(0)-A,
0(Ci-C 6)alkyl, halo, hydroxyl, CF3 or OCF3.
The term "heteroaryl" refers to an aromatic group for example, which is a 5 to 14
membered monocyclic or bicyclic ring system, which has at least one heteroatom. The term
"heteroatom" as used herein includes O, N, S. In bicyclic ring system, ring can be fused
through a bridge heteroatom. The heteroaryl groups include, but are not limited to pyrrolyl,
furanyl (furyl), thiophenyl (thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimdinyl,
pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl), indazolyl,
benzimidazol, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl or naphthyridinyl. Preferably heteroaryl
is pyrazolyl and isoxazolyl, most preferably heteroaryl is pyrazolyl.
The term "heterocyclic" or "heterocycle" refers to a fully or partially saturated cyclic
group, for example, which is a 3 to 14 membered monocyclic or bicyclic ring system, which
has at least one heteroatom. The term "heteroatom" as used herein includes O, N, S. In
bicyclic heterocyclic system, at least one ring is not aromatic and the rings can also be
attached to each other in a spiro manner. The heterocyclic or heterocycle groups include, but
are not limited, oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl,
imidazolidinyl, oxazohdinyl, isoxazoiidinyl, thiazoiidinyl, triazolidinyl, oxadiazolidinyl,
piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, dioxanyl,
morpholinyl, triazinanyl, azepanyl, diazepanyl, diazepinyi, oxepanyl, dioxepanyl,
oxazepanyl, oxazepinyl, indolinyl, benzomorpholinyl, tetrahydroquinolyl or
tetrahydrisoquinolyl.
As used herein, "hydroxyl" or "hydroxy" refers to -OH group.
As used herein, "room temperature" refers to a temperature between 20 C and 30 C.
As used herein, the term "mammal" means a human or an animal such as monkeys,
primates, dogs, cats, horses, cows, etc.
The terms "treating" or "treatment" of any disease or disorder as used herein to mean
administering a compound to a mammal, including human being, in need thereof. The
compound may be administered thereby providing a prophylactic effect in terms of
completely or partially preventing or delaying the onset of a disease or disorder or sign or
symptom thereof; and/or the compound may be administered thereby providing a partial or
complete cure for a disease or disorder and/or adverse effect attributable to the disorder.
The phrase "a therapeutically effective amount" means the amount of a compound
that, when administered to a patient for treating a disease, is sufficient to effect such
treatment for the disease. The "therapeutically effective amount" will vary depending on the
compound, mode of administration, the disease and its severity and the age, weight, etc., of
the patient to be treated.
Throughout this specification and the appended claims it is to be understood that the
words "comprise" and "include" and variations such as "comprises", "comprising",
"includes", "including" are to be interpreted inclusively, unless the context requires
otherwise. That is, the use of these words may imply the inclusion of an element or elements
not specifically recited.
In another embodiment, present invention provides the process for preparing the
compounds of formula (I).
The following reaction schemes are given to disclose the synthesis of the compounds
according to the present invention.
Accordingly, the compounds of formula (I) of the present invention may be prepared
as described in the schemes below.
Illustrative embodiments of compounds of formula (I) include compounds of formula
la, formula lb, formula Ic, formula Id, formula Ie, formula If, formula Ig, formula Ih, formula
Ii, formula Ii-1, formula Ij, formula laa, formula lab, formula lac, formula lad, formula lae,
formula laf, formula lag, formula Iba, formula Ibb, formula Ibc and formula Ibd. In which
the substituents are as defined in connection with general formula (I) and schemes 1-6.

Synthesis of various compounds of formula Ia-Ih, where R is L-N(R5)C(0)N(R5)-A is shown
in scheme 1, wherein L is defined in the scheme and R 5 is H. The compounds of formula la is
synthesized from the reaction of compound of formula Iaa or Iba, separately, with
compounds of formula of Ila or Ila' in the presence of a suitable base such as N,Ndiisopropylethylamine
(DIEA) and suitable solvent such as tetrahydrofuran (THF) or ethyl
acetate (EtOAc) at reflux temperature. Alternatively, compounds of formula la can be
synthesized by the reaction of other suitable carbamate using conventional synthetic
methods. Compound of formula Ila is synthesized from reaction of suitable substituted amine
(A-NH2) with trichloroethylchloroformate in the presence of aqueous basic solution such as
sodium bicarbonate / potassium bicarbonate in solvent such as ethylaceate (EtOAc) at room
temperature (RT) (J. Med. Chem., 2011, 54, 7797 or WO 2007/091152). Compound of
formula Ila' is synthesized from reaction of suitable phenyl chloroformate with amine (ANH
2) using the similar condition as described for synthesis of compound of formula Ila. The
compound of formula lb is prepared from the reduction of compound of formula la with
suitable reducing agent like metalborohydride such as lithium borohydride (LiBH4) or
lithium aluminium hydride (LAH) or vitride® in the presence of suitable solvent such as
tetrahydrofuran (THF) in an inert atmosphere at reflux or lower temperature, usually at reflux
temperature. Compound of formula Ic is synthesized from the compound of formula lb with
suitable chlorinating agent such as thionyl chloride in the presence of suitable solvent such as
dichloromethane (DCM) at a reflux temperature or lower. Compounds of formula Id is
synthesized from the reaction of compound of formula Ic with appropriate R3H. The reaction
is being carried out in a suitable solvent or mixture of solvent such as THF, dimethyl
formamide (DMF) at room temperature (RT) to the reflux temperature depending on the
nature of R3H. Oxidation of compounds of formula Id, when R3 is a sulfur (S) containing
group, can provide corresponding mono- or dioxide (S(0) m where m is 1 or 2) compounds of
formula Id. Compound of formula Ie and Ig can be prepared by hydrolysis of compound of
formula la. The hydrolysis reaction is being done with suitable base such as lithium
hydroxide monohydrate (LiOH. H20 ) using suitable solvent such as methanol (MeOH) at a
temperature between RT and reflux, usually at RT. Compound of formula If and H is
obtained from the coupling reaction of compound of formula Ie and Ig, separately, with
suitable amine (R5R NH) and suitable coupling reagent such as l-ethyl-3-(3-
dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl) in the presence of suitable
base such as ,-diisopropylethylamine (DIEA) and catalytic 4-dimethylaminopyridine
(DMAP) and suitable solvent such as THF in an inert atmosphere at 0°C to room
temperature. Some of the compounds of formula lb can also be synthesized from
demethylation of compounds of formula la, when R2 is CH2OCH 3. Demethylation is carried
out using boron tribromide (BBr3) in suitable solvent such as DCM at 0°C to RT.
Scheme - 2
Q = Ho rN0
The compounds of formula Id is also synthesized from either carbamate of formula Ii
or substituted isocynates (A-N=C=0) as shown in scheme 2. Compound of formula Id can be
prepared from the reaction of either compound of formula Ii or compound of formula Ii- 1
with appropriate amine (A-NH2) in the presence of suitable base such as DIEA and suitable
solvent such as toluene at temperature between RT and reflux, usually at reflux. Compounds
of formula Ii is synthesized from the reaction of either compound of formula Iaa or Iba, with
suitable chloroformate such as phenyl chloroformate or 4-nitrophenyl chloroformate in the
presence of suitable base such as pyridine and suitable solvent such as THF at 0°C to RT.
Compounds of formula Ii-1 can be synthesized from the reaction of either compound of
formula Iaa or Iba, with suitable chloroformate such as trichloroethylchloroformate in the
presence of suitable base such as sodium bicarbonate and suitable solvent such as EtOAc.
On the other hand, when compound of formula Iaa or Iba is treated with appropriate
substituted isocynate (A-N=C=0; wherein A is as defined above), it yields corresponding
compounds of formula Id in the presence of suitable solvent such as THF or toluene-DMF at
elevated temperature. Some of the substituted isocyanate has been prepared by reacting
substituted carboxylic acid with ethylchloroformate in the presence of sodium azide and
triethylamine (TEA) using DMF as solvent. In other method, substituted isocyanate is also
prepared by the reaction of substituted amine in the presence of triphosgene and TEA using
DCM as solvent at a temperature between 0°C and RT.
Scheme - 3
Synthesis of compound of formula Ij and Ibc, where X is O, is shown in scheme 3.
Compound of formula Ij is synthesized in two steps from compounds of formula Ibc .The
compound of formula Ibc is hydrolyzed to corresponding acid derivative (Ibd) using aqueous
sodium hydroxide (NaOH) as a base and MeOH as solvent at RT. The corresponding acid
derivative is coupled with suitable substituted amine (A-NH2) using suitable coupling reagent
such as EDCI.HC1 and suitable base such as DIEA and catalytic DMAP in solvent such as
THF in an inert atmosphere at 0°C to room temperature. Compound of formula Ibc is
prepared from the reaction of compound of formula-N with methyl 4-fluorobenzoate in the
presence of base such as potassium carbonate (K2CO3) or sodium carbonate using DMF as
solvent at elevated temperature. Compound of formula-N is synthesized from demethylation
of compound of formula-M using BBr3 in aprotic solvent such as DCM at 0°C to room
temperature. Compound of formula-M is prepared from basic hydrolysis of compound of
formula-C with lithium hydroxide monohydrate using aqueous MeOH. Further, the
hydrolysed product was coupled with appropriate substituted amine (R R NH) using suitable
coupling reagent such as EDCI.HC1 and suitable base such as DIEA and catalytic DMAP in
an aprotic solvent such as THF at 0°C to RT.
Scheme - 4
d . BF3.0(Et) , NaBH , THF, or Borane-THF, THF, or NaBH , TFA, THF
Several compounds of formula laa, lab, lac, lad, Iae, Iaf and Iba has been synthesized as
shown in scheme 4. The aminobenzyl compound of formula laa is prepared by different
synthetic methodologies. In the first method, compound of formula lag, where R is a nitrile
(CN) group at either position-2 or compound of formula Ibb, where R is a nitrile (CN) group
at position-4, undergoes reduction to provide respective 2- or 4- benzylic amino compounds
of formula laa using either sodium borohydride, boron trifluoride-etherate or borane-THF or
sodium borohydride, trifluoroacetic acid (TFA) in aprotic solvent such as THF at room
temperature to reflux. In the second method, compound of formula lag, where R is an
aldehyde (CHO) group at position-2, is reduced to compounds of formula lab by sodium
borohydride in protic solvent such as MeOH at 0°C to room temperature. Further, upon
reaction of compound of formula lab with diphenylphosphoryl azide (DPPA) in the presence
of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in aprotic solvent such as THF at 0°C to room
temperature, it provides respective 2-benzylic amino compound of formula Iaa. In the third
method, compound of formula lab is chlorinated with suitable chlorinating agents such as
thionyl chloride in an aprotic solvent such as methylene chloride at room temperature to
provide corresponding chloro derivative lac and which, after treatment with ammonia under
pressure to provide respective 2-benzylic amino compounds of formula Iaa. In the fourth
methodology, chloro derivative lac is reacted with sodium azide in solvent DMF to provide
respective azide derivatives lad, which was converted to respective 2-benzylic amino
compound of formula Iaa by triphenyl phosphine (TPP) in solvent such as aqueous
tetrahydrofuran. Compound of formula lag, where R is a CN group at position-2 and R2 is
C0 2Et group, upon hydrolysis by lithium hydroxide monohydrate in aqueous MeOH at RT,
yields corresponding acid compound of formula Iae. Compound of formula Iae is converted
to compound of formula Iaf using alkyl chloroformate such as ethylchloroformate in the
presence of sodium azide and TEA in solvent DMF followed by its treatment with
appropriate R4H in toluene. The nitrile group of compound of formula Iaf is reduced to get
corresponding 2-benzylic amino compound of formula Iaa using sodium borohydride, boron
trifluoride etherate in solvent THF at reflux temperature. On the other hand, 4-amino or 2-
amino compound of formula Iba is prepared from the compound of formula Ibb and lag
respectively. When R is a nitro (N0 2) group at either position-2 or position-4 in compound of
formula lag and Ibb respectively, it undergoes reduction by reducing agents such as stannous
chloride in alcoholic solvent such as MeOH to provide corresponding 4-amino or 2-amino
compound of formula Iba. Moreover, it is understood by those skilled in the art of organic
synthesis that the various other R functionalities can be synthesized.
Scheme - 5
Various compounds of formula lag and Ibb, where X is O, are synthesized as shown in
scheme 5. Some of the compound of formula lag, is prepared from the reaction of either
compound of formula-D or compound of formula-G, separately, with appropriate 2-
fluorophenyl compound such as substituted or unsubstituted 2-fluorobenzaldehyde or 2-
fluorobenzonitrile in presence of base such as potassium carbonate in solvent DMF at room
temperature to 100 °C. Using similar procedure, compounds of formula Ibb is synthesized
from the treatment of compound of formula-D or G, separately with appropriate 4-
fluorophenyl compound such as substituted or unsubstituted 4-fluoronitrobenzene.
Demethylation of compound of formula-C or F, separately, with demethylating agents such
as boron tribromide in aprotic solvents such as DCM yields compound of formula-D or G,
respectively. Compound of formula-C is synthesized from the reaction of substituted or
unsubstituted 2-amino-6-methoxybenzothiazole with N,N-dimethylformamide
dimethylacetal (DMF-DMA) in solvent toluene followed by its quaternisation with
ethylbromoacetate at elevated temperature and finally cyclisation using DBU in solvent such
as DMF at room temperature. While compound of formula-F is synthesized from the reaction
of substituted or unsubstituted 2-amino-6-methoxybenzothiazole with ethyl bromopyruvate
in an aprotic solvent such as DMF followed by its treatment with sodium hydroxide in
alcoholic solvent such as methanol and ethanol. Some of the compound of formula lag,
where R is CH2R3, is prepared from compound of formula-L in two steps. In the first step,
compound of formula-L is treated with appropriate R3H in a suitable solvent such as DMF to
provide corresponding derivative (compound of formula-Ll) at room temperature, where R2
is CH2R3. In case when R3H is an alcohol, the reagent (R3H) may also act as a solvent. The
reaction is done at room temperature to reflux. Further reaction of this intermediate
compound of formula-Ll with appropriate 2-fluorophenyl compound such as substituted or
unsubstituted 2-fluorobenzaldehyde or 2-fluorobenzonitrile in presence of base such as
potassium carbonate in solvent DMF at room temperature to 100 °C provide respective
compound of formula lag. Compound of formula-L is obtained from chlorination of
compound of formula-K using chlorinating agents such as thionyl chloride in aprotic solvent
such as DCM at room temperature. Demethylation of compound of formula-J, using
demethylating agents such as boron tribromide in aprotic solvents such as DCM to yield
compound of formula-K. Compound of formula-J when Ri=CH3 is synthesized from
reduction of compound of formula-H using metal hydrides such as sodium borohydride in a
protic solvent like MeOH at room temperature. Upon formylation of compound of formula-E
with suitable formylating agents such as POCI 3 in DMF, it gives rise to compound of
formula-H. Compound of formula-E is obtained from treatment of substituted or
unsubstituted 2-amino-6-methoxybenzothiazole with propargyl bromide in solvent DMF
followed by reaction with sodium alkoxide such as sodium methoxide in alcoholic solvent
such as MeOH. Compound of formula-J, is synthesized from reduction of compound of
formula-C, when R is H and R is C0 2Et using suitable reducing agent such as lithium
borohydride and suitable solvent such as THF. Some of the compounds of formula lag,
where R2 is CH2R3, is also prepared from compound of formula-J, where Ri is H.
Chlorination of compound of formula-J yields compound of formula-C 1, which was treated
with R3H to provide corresponding derivative C2 using similar condition as used for
preparation of compound of formula-L and of formula-Ll from compound of formula-K,
respectively. Demethylation of compound of formula-C2 provides corresponding phenolic
derivative LI using similar condition as used for preparation of compound of formula-K
from compound of formula-J.
Scheme - 5a
Some of compounds of formula lag, where X is O and R is heteroaryl, are synthesized as
shown in scheme 5a. Compound of formula lag, is prepared from the reaction of compound
of formula-D- 1 using the similar condition as discussed for compound of formula lag, where
X = O, as shown in scheme 5. Demethylation of compound of formula-C6 yields compound
of formula-D- 1 using similar condition as discussed for compound of formula-D in scheme 5.
Compound of formula-C4 is coupled with propargyl amine using suitable coupling reagent
such as EDCI and HOBt in the presence of suitable base such as triethylamine to provide
compound of formula-C5, which was converted to compound of formula-C6 using similar
condition as described in Organic Letters, 2012, 14, 4478-4481. Basic hydrolysis of
compound of formula-C3 gives to compound of formula-C4.
Scheme 6:
For R = H, R = C0 Et
Various compounds of formula lag or Ibb, where X is S, is synthesized as shown in scheme
6. Compounds of formula lag and Ibb, when R is H and R2 is C0 2Et, are obtained from
substituted or unsubstituted 2-amino-6-thiophenoxybenzothiazole B and B1 respectively
Compound of formula-B or Bi is, separately, treated with N,N-dimethylformamide
dimethylacetal (DMF-DMA) in solvent toluene followed by its quaternisation with ethyl
bromoacetate at elevated temperature and finally cyclisation using DBU in aprotic solvent
such as DMF at room temperature. Compounds of formula lag and Ibb, when Ri is C0 2Et
and R is H, are obtained from substituted or unsubstituted 2-amino-6-
thiophenoxybenzothiazole B and B1 respectively . Herein, compound of formula-B or Bi is,
separately, treated with ethyl bromopyruvate in aprotic solvent such as DMF followed by its
treatment with sodium hydroxide in alcoholic solvent such as methanol and ethanol.
Schemes 1-6 given herein above provide general method of preparation of compounds of
present invention. One of ordinary skill will recognize to appropriately substitute various
groups such as R, A, and R etc in starting material to prepare desired compounds
according to formula (I). Alternative to the given schemes, one of ordinary skill will readily
synthesize the compounds according to the present invention using conventional synthetic
organic techniques from suitable starting material which are either commercially available or
may be readily prepared.
The compounds of the present invention may have chiral centers and occur as
racemates, racemic mixtures and as individual diastereomers or enantiomers with all isomeric
forms being included in the present invention. Therefore, where a compound is chiral, the
separate enantiomers, substantially free of the other, are included within the scope of the
invention; further included are all mixtures of the two enantiomers.
The novel compounds of the present invention were prepared according to the
procedure of the schemes as described herein above, using appropriate materials and are
further exemplified by the following specific examples. The examples are not to be
considered or construed as limiting the scope of the invention set forth.
In present specification some general terms are used with their known intended
meaning which are defined herein below:
RT Room temperature
RM Reaction mixture
DCM Dichloromethane
DCE Dichloroethane
DMF Dimethyl formamide
THF Tetrahydrofuran
DIEA N,N-diisopropylethylamine
LAH Lithium aluminium hydride
EDCI l-ethyl-3-(3-dimethylaminopropyl)
carbodiimide
DMAP 4-dimethylaminopyridine
TEA Triethylamine
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
TPP Triphenyl phosphine
DMF-DMA ,-dimethylformamide dimethylacetal
TFA Trifluoroacetic acid
DPPA Diphenylphosphoryl azide
EtOAc Ethyl acetate
ESMS Electrospray Mass Spectrometry
ESI Electro spray ionization
APCI Atmospheric pressure chemical ionization
Micro Molar
nM Nano Molar
TS Tobacco smoke
COPD Chronic obstructive pulmonary disease
BALF Bronchoalveolar lavage fluid
Mg Milligram
PBS Phosphate buffer saline
NA Not applicable
Mass of compounds prepared according to present invention is measured using Single
quadrupole mass spectrometer (Water ZQ 2000 instrument) using APCI ionization technique
(Electro spray chemical ionization Probe) or Finnigan LXQ, thermo instrument Technique
using either ESI or APCI.
EXAMPLES:
Example 1: ethyl 7-(2-formylphenoxy)imidazo[2,l-b][l,3]benzothiazole-3-carboxylate
(Compound 51)
Ethyl 7-methoxyimidazo[2,l-b][l,3]benzothiazole-3-carboxylate (US 6191124) was
demethylated to provide ethyl 7-hydroxyimidazo[2,l-b][l,3]benzothiazole-3-carboxylate
compound using conventional O-demethylation methods e.g. BBr3/DCM.
To a stirred solution of ethyl 7-hydroxyimidazo[2,l-b][l,3]benzothiazole-3-carboxylate (85
gm, 320 mmol) in DMF (600 ml), potassium carbonate (132 gm, 960 mmol) and 2-
fluorobenzaldehyde (44.2 gm, 350 mmol) were added and reaction mixture (RM) was heated
at 100-105°C for 20-24 hrs. Reaction mixture was brought down to room temperature and
suspended solid was filtered, washed with DMF. The mother liquor (ML) was poured in
water and pH was adjusted to 6.0-6.5. The separated solid was filtered, washed with water
and dried and finally solid was stirred in methanol (300ml), at room temperature (RT) for 2-3
hrs. The stirred solid was filtered and dried under vacuum to get 80.0 gm of title compound
as white solid.
1H-NMR (400 MHz, DMSO-d 6) : 10.40 (1H, s), 8.96 (1H, d), 8.05 (1H, s), 7.94 (1H, s),
7.89 (1H, d), 7.70 (1H, t), 7.30-7.43 (2H, m), 7.06 (1H, d), 4.38 (2H, q), 1.36 (3H, t)
ESMS: 367.30
Example 2: ethyl 7-[2-(hydroxymethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate (Compound 52)
To a stirred solution of compound ethyl 7-(2-formylphenoxy)imidazo[2,lb][
l,3]benzothiazole-3-carboxylate,, (80 gm, 218 mmol) in methanol (600 ml), sodium
borohydride (24 gm, 655 mmol) was added at 0°C in portion-wise and stirred at room
temperature for 10-12 hrs. Methanol was removed under vacuum at 60°C and diluted with
water (500 ml) and pH was adjusted to 5.0-6.0 with dil. HC1. The separated solid, was
filtered washed with water and finally with 10% EtOAc/Hexane dried under vacuum at 60°C
to get title compound (80 gm) as white solid.
The product may also contain methyl ester derivative due to trans esterification. However
when reaction is performed using ethanol as a solvent, only ethyl ester is obtained.
1H-NMR (400 MHz, DMSO-d6) : 8.89 (1H, d), 8.04 (1H, s), 7.69 (1H, s), 7.58 (1H, d),
7.21-7.32 (3H, m), 6.94 (1H, d), 5.19 (1H, s), 4.54 (2H, s), 4.38 (2H, q), 1.35 (3H, t)
ESMS: 369.32
Example 3: ethyl 7-[2-(azidomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate (Compound 54)
To a stirred solution of compound ethyl 7-[2-(hydroxymethyl)phenoxy]imidazo[2,lb][
l,3]benzothiazole-3-carboxylate (80 gm, 217 mmol) in DCM (300 ml), thionyl chloride
(51 gm, 434 mmol) was added drop wise at 0-5°C. Reaction mixture was stirred at room
temperature for 6-8 hrs. Reaction mixture was concentrated to dryness under vacuum at 60°C
to provide ethyl 7-[2-(chloromethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate (Compound 53). The solid was suspended in DMF (400 ml) and stirred at 0-5°C.
Sodium azide (42 gm, 650 mmol) was added at 0°C and reaction mixture was stirred at room
temperature for 10-12 hrs. Reaction mixture was poured in cooled water and extracted with
ethyl acetate (300x2).The separated organic layer was washed with water, dried over sodium
sulfate and evaporated under vacuum at 60°C to get 80 gm title compound.
Example 4: ethyl 7-[2-(aminomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate hydrochloride (Compound 55)
To a stirred solution of compound ethyl 7-[2-(azidomethyl)phenoxy]imidazo[2,lb][
l,3]benzothiazole-3-carboxylate (80 gm, 203 mmol) in THF (400 ml), triphenylphosphine
(80 gm, 305 mmol) was added at 0-5°C along with water (100 ml). Reaction mixture was
stirred at room temperature for 10-12 hrs. Solvent was evaporated under vacuum at 60°C,
further diluted with water (-200 ml) and extracted with ethyl acetate (500 ml x2). Organic
layer was dried over sodium sulfate and concentrated under vacuum at 60°C to dryness to get
crude compound. This crude compound was dissolved in THF (800 ml) and purged HCI gas
at room temperature over 2 hrs. The solid, thus obtained, was filtered, washed with ethyl
acetate (500 ml) and hexane (500 ml) to get 55 gm title compound as white solid.
The product may also contain methyl ester derivative, if ethyl 7-[2-
(azidomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-carboxylate (compound 54) is
used along with methyl ester.
^-NMR (400 MHz, DMSO-d6) : 8.96 (IH, d), 8.51 (2H, bs), 8.07 (IH, s), 7.88 (IH, d),
7.65 (IH, d), 7.36-7.42 (2H, m), 7.25 (IH, t), 6.93 (IH, d) 4.38 (2H, q), 4.09-4.10 (2H, m),
1.35 (3H, t)
ESMS: 368.04
Compound 55 is also synthesized from ethyl 7-[2-(hydroxymethyl)phenoxy]imidazo[2,lb][
l,3]benzothiazole-3-carboxylate (compound 52) using DPPA, DBU and TPP in THF-H20
using standard procedure as known in the literature.
Example 5: ethyl 7-[2-({[(2-hydroxy-l-phenylethyl) carbamoyl] aminojmethyl)
phenoxy]imidazo[2,l-b][l,3]benzothiazole-3-carboxylate (Compound 42)
To a stirred solution of ethyl 7-[2-(aminomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-
3-carboxylate hydrochloride ( 1 gm, 2.72 mmol) in THF (20 ml) and pyridine (0.260 gm, 3.27
mmol), 4-nitrophenyl carbonochloridate (0.66 gm, 3.27 mmol) was added at around 0-5 °C.
Reaction mixture was stirred at room temperature for 4-6 hrs. Solvent was evaporated under
vacuum at 60°C. The resulted carbamate derivative (0.3 gm, 0.56 mmol) was suspended in
toluene (20 ml). To this, (R)-phenyl glycinol (0.0078 gm, 0.56 mmol) and DIEA (0.150 gm,
1.12 mmol) were added and refluxed for 4-6 hrs. Reaction mixture was cooled to room
temperature and poured into water and extracted with ethyl acetate (10 mlx2). The organic
layer was dried over sodium sulfate and evaporated under vacuum at 60°C to get crude
compound, which was purified by column chromatography to get 0.1 10 gm as a solid.
1H-NMR (400 MHz, DMSO-d ) : 8.90 (IH, d), 8.04 (IH, s), 7.71 (IH, bs), 7.36 (IH, d),
716-7.30 (7H, m), 6.94 (IH, d), 6.53 (IH, d), 6.46 (IH, t), 4.87 (IH, t), 4.65-4.66 (IH, q),
4.37 (2H, q), 4.23 ( 2H, d), 3.54 (2H, m), 1.35 (3H, t)
ESMS: 531.45
Example 6 : ethyl 7-(2-{[(cyclohexylcarbamoyl)amino]methyl} phenoxy)imidazo[2,lb][
l,3]benzothiazole-3-carboxylate (Compound 46)
To a stirred solution of ethyl 7-[2-(aminomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-
3-carboxylate hydrochloride (0.7 gm, 1.9 mmol) in THF (20 ml), isocyanatocyclohexane (0.8
gm, 6.4 mmol) was added. Reaction mixture was refluxed for 18-20 hrs. Reaction mixture
was cooled to room temperature. Solvent was evaporated under vacuum at 60°C, sticky mass
was quenched with cold water and extracted with ethyl acetate (10 ml x 2) and organic layer
was evaporated to get crude compound. The material was purified by column
chromatography to get 0.05 gm title compound as solid.
1H-NMR (400 MHz, CDC13) 9.03 (IH, d), 8.00 (IH, s), 7.48 (IH, d), 7.26 (IH, merged
with solvent signal), 7.09-7.21 (3H, m), 6.90 (IH, d), 4.73 (IH, t), 4.38-4.43 (4H, m), 4.26
(IH, d), 3.42 (IH, m), 1.85-1.87 (2H, m), 1.54-1.57 (IH, merged with water signal), 1.43
(3H, t), 1.23-1.32 (3H, m), 0.99-1.14 (4H, m)
ESMS: 493.33
Example 7: ethyl 7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]
carbamoyl} amino) methyl] phenoxy} imidazo [2,l-b][l,3] benzothiazole-3-carboxylate
(Compound 25)
Step 1; 2,2,2-trichloroethyl [3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamate (Intermediate 1)
To a stirred solution of 4-(5-amino-3-tert-butyl-lH-pyrazol-l-yl)-2-chlorophenol (60 gm,
225.5 mmol) in ethyl acetate (1500 ml) and 2N aq. sodium bicarbonate solution (500 ml),
trichloro ethylchloroformate (119.32 gm, 563.90 mmol) was added at room temperature and
stirred at room temperature till reaction completion . Ethyl acetate layer was separated, dried
over sodium sulfate and evaporated under vacuum at 60°C to get crude compound. The crude
compound was suspended in hexane (100 ml), stirred at 0-5°C and solid, thus appeared, was
filtered and dried to get 85 gm of title compound as solid.
1H-NMR (400 MHz, CDC13 ) : 7.44 (IH, s), 7.22-7.24 (IH, m), 7.03 (IH, d), 6.70 (IH, bs),
6.39 (2H, bs), 4.81 (2H, s), 1.34 (9H, s)
ESMS: 442.24/444.21
Using the similar procedure as described for Intermediate 1, 2,2,2-trichloroethyl [3-tertbutyl-
l-(3-chloro-4-methoxyphenyl)-lH-pyrazol-5-yl]carbamate (Intermediate 2), 2,2,2-
trichloroethyl [3-tert-butyl- 1-(4-methoxyphenyl)- lH-pyrazol-5-yl] carbamate (Intermediate
3) and 2,2,2-trichloroethyl [3-tert-butyl- l-(4-methylphenyl)-lH-pyrazol-5-yl] carbamate
(Intermediate 4) are synthesized from corresponding aminopyrazole compound.
Step 2: ethyl 7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]
carbamoyl} amino) methyl] phenoxy} imidazo [2,l-b][l,3] benzothiazole-3-carboxylate
(Compound 25)
To a stirred solution of ethyl 7-[2-(aminomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-
3-carboxylate hydrochloride (Compound 55) (55 gm, 136 mmol) in THF (600 ml), N,Ndiisopropyethylamine
(70.33 gm, 545 mmol) and intermediate 1 (60 gm, 136 mmol) were
added. Reaction mixture was refluxed for 8-12 hrs. Solvent was evaporated under vacuum at
60UC, sticky mass was quenched with cold water, and pH was adjusted to 4-5 using HC1.
The solid, thus obtained, was filtered, washed with hexane (500 ml), dried under vacuum and
crystallized by using EtOAc to get 72 gm title compound as white solid.
1H-NMR (400 MHz, DMSO-d 6) : 10.50 (IH, s), 8.90 (IH, d), 8.15 ( IH, s), 8.04 ( IH, s),
7.69 (IH, d), 7.39 (IH, d), 7.29-7.31 (2H, m), 7.17-7.24 (3H, m), 7.04 (IH, d), 6.94-6.96
(IH, m), 6.89 (IH, t), 6.15 (IH, s) 4.37 (2H, q), 4.27 (2H, d), 1.35 (3H, t), 1.21 (9H, s)
ESMS: 656.74/657.98
The product may also contain methyl ester derivative, if compound 55 is used along with
methyl ester.
Example 8 : 7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl}amino)methyl]phenoxy}imidazo[2,l-b][l,3]benzothiazole-3-carboxylic
acid (Compound 19)
To a stirred solution of ethyl 7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-
5-yl] carbamoyl} amino) methyl] phenoxy} imidazo [2,l-b][l,3] benzothiazole-3-
carboxylate (0.2 gm, 0.3 mmol) in MeOH (10 ml), lithium hydroxide monohydrate (0.063
gm, 1.51 mmol) was added by dissolving in water (2 ml). Reaction mixture was stirred at
room temperature for 2-4 hrs. Reaction mixture was quenched into cold water, acidified, and
stirred. The solid, thus obtained, was filtered and dried to get 0.080 gm title compound as
white solid.
1H-NMR (400 MHz, DMSO-d ) : 13.21 ( IH, bs), 10.50 (IH, s), 8.98 (IH, d), 8.17 ( IH, s),
7.99 (IH, s), 7.68 (IH, d), 7.40 (IH, d), 7.29-7.30 (2H, m), 7.16-7.24 (3H, m), 7.04 (IH, d),
6.89-6.95 (2H, m), 6.15 (IH, s), 4.27 (2H, d), 1.21 (9H, s)
ESMS: 631.50/633.42
Example 9 : 7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino) methyl] phenoxy}-N- (2-hydroxyethyl) imidazo[2,lb][
l,3]benzothiazole-3-carboxamide (Compound 20)
To a stirred solution of 7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylic acid
(0.8 gm, 1.26 mmol) in THF (20 ml), N,N-diisopropyethylamine (0.49 gm, 3.8 mmol), 1-
hydroxy benzotriazole (0.342 gm, 2.56 mmol) and l-ethyl-3-(3-dimethylamino)
propylcarbodiimide hydrochloride (0.486 gm, 2.65 mmol) were added at 0-5 °C and stirring
was continued for 45 min. Ethanolamine (0.152 gm, 2.53 mmol) was added. Reaction
mixture was stirred at room temperature for 20-24 hrs. Reaction mixture was quenched into
cold water, acidified to pH 4-5 and stirred. It was extracted by ethyl acetate (10 ml x2) and
organic layer was evaporated to get crude compound, which was further purified by column
chromatography to get 0.1 gm title compound.
1H-NMR (400 MHz, DMSO-d ) : 10.53 ( 1H, s), 8.94 ( 1H, d), 8.53 (1H, t), 8.18 (1H, s),
7.95 (1H, s), 7.65 (1H, m), 7.39 (1H, m), 7.29 (2H, bs), 7.16-7.23 (3H, m), 7.04 (1H, d),
6.91-6.93 (2H, m), 6.17 (1H, s), 4.78 (1H, t), 4.28 (2H, d), 3.54-3.55 (2H, m), 3.33 (2H,
hidden under signal of water), 1.22 (9H, s)
ESMS: 674.62/676.45
Example 10: l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-
(hydroxymethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea (Compound 22)
To a stirred solution of ethyl 7-{2-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-
5-yl] carbamoyl} amino) methyl] phenoxy} imidazo [2,l-b][l,3] benzothiazole-3-
carboxylate (40 gm, 60.69 mmol) in THF (400 ml), lithium borohydride (4.2 gm, 182 mmol)
was added in portion-wise at 0-5 °C and reaction mixture was refluxed for 4-5 hrs. The
reaction mixture was quenched in cold water and acidified by using 33% HBr in acetic acid
(50 ml) and heated at 60-65°C for 4-5 hrs. Reaction mixture was cooled to room temperature,
diluted with water and extracted in EtOAc (250 ml x2). Organic layer was washed with brine
and dried over sodium sulfate and evaporated under vacuum at 60°C. The solid, thus
obtained, was suspended in EtOAc (150 ml), stirred and filtered to get 27 gm title compound
as white solid.
1H-NMR (400 MHz, DMSO-d6) : 8.23 ( 1H, s), 8.01 ( 1H, d), 7.66 (1H, d), 7.42 (1H, d),
7.14-7.30 (6H, m), 7.06 (1H, d), 6.94 (1H, t), 6.89 (1H, d), 6.21 (1H, s), 5.52 (1H, bs) 4.81
(2H, s), 4.30 (2H, d), 1.23 (9H, s)
ESMS: 615.08/617.08
Example 11: l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-
(methoxymethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea (Compound 31)
To a stirred solution of l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-
{[3-(hydroxymethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea (10 gm, 16
mmol) in a mixture of DCM (100 ml) and chloroform (10 ml), thionyl chloride (9.5 ml) was
added drop-wise at 5- 10°C. Reaction mixture was stirred under cooling and then stirred at
room temperature for 2-4 hrs. Thionyl chloride was evaporated under vacuum at 50°C to get
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-yl]-3-(2- {[3-(chloromethyl)
imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl) (compound 57). To this, methanol (60 ml)
was added under cooling and reaction mixture was then refluxed for 2 hrs. The suspended
solid was filtered in hot, further washed with methanol and dried well under vacuum to get 8
gm title compound as white solid.
1H-NMR (400 MHz, DMSO-d 6) : 10.49 (1H, bs), 8.20 ( 1H, s), 7.82 ( 1H, d), 7.69 (1H, d),
7.40 (1H, d), 7.27-7.30 (3H, m), 7.14-7.23 (3H, m), 7.05 (1H, d), 6.90-6.92 (2H, m), 6.19
(1H, s), 4.77 (2H, s), 4.28 (2H, d), 3.30 (3H, partially merged with water signal), 1.23 (9H, s)
ESMS: 629.62/630.45
Example 12: l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-
(morpholin-4-ylmethyl) imidazo [2,l-b][l,3] benzothiazol-7-yl] oxy} benzyl) urea
(Compound 35)
To a stirred solution of l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-
{[3-(hydroxymethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea (5 gm, 8.1
mmol) in a mixture of DCM (50 ml) and chloroform (5 ml) and thionyl chloride (1.75 ml)
was added drop wise at 5- 10°C. Reaction mixture was stirred under cooling and then stirred
at room temperature for 2-4 hrs. Thionyl chloride was evaporated under vacuum at 50 C to
get l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-(chloromethyl)
imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl) (compound 57). To this, DMF (50 ml)
and morpholine (7.04 gm, 8 1 mmol) were added under cooling (5- 10°C) and reaction
mixture was then stirred at room temperature for 2-4 hrs. Reaction mixture was quenched
into cold water, stirred and solid was filtered and dried to get crude compound, which was
crystallized in methylene chloride to get ~ 3 gm title compound as white solid.
1H-NMR (400 MHz, DMSO-d ) : 10.51 (1H, s), 8.20 ( 1H, s), 8.01 ( 1H, d), 7.65 (1H, bs),
7.40 (1H, bs), 7.28-7.30 (2H, m), 7.03-7.24 (5H, m), 6.92-6.94 (2H, m), 6.18 (1H, s), 4.28
(2H, d), 3.79 (2H, s), 3.52 (4H, s), 2.44 (4H, partially merged with solvent signal) 1.22 (9H,
s)
ESMS: 686.50/688.45
Example 13: ethyl 7-[(4-aminophenyl)sulfanyl]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate (Compound 59)
To a stirred solution of ethyl 7-[(4-nitrophenyl)sulfanyl]imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate (1.2 gm, 3 mmol) (Compound 58), in methanol (20 ml), stannous chloride
dihydrate (2.7 gm, 12 mmol) was added at room temperature and reaction mixture was
refluxed for 4-5 hrs. Solvent was evaporated under vacuum at 60°C, further diluted with
water, basified, extracted with ethyl acetate, dried over sodium sulfate and concentrated
under vacuum to dryness to get 0.9 gm title compound.
Compound 58 is synthesized from 4-[(4-nitrophenyl)sulfanyl]aniline, using the similar
procedure as described in Journal of Current Pharmaceutical Research, 2010, 3(1), 13 to get
corresponding benzothiazole compound and which was cyclised using the similar procedure
as described in US6191 124.
Example 14: ethyl 7-{[4-({[3-tert-butyl-l-(4-methoxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino) phenyl] sulfanyl} imidazo [2,l-b][l,3]benzothiazole-3-carboxylate
(Compound 60)
Compound 60 was synthesized from the reaction of ethyl 7-[(4-
aminophenyl)sulfanyl]imidazo[2,l-b][l,3]benzothiazole-3-carboxylate and intermediate 3
using the similar procedure as described for synthesis of compound 25 in Example 7.
Example 15: 7-{[4-({[3-tert-butyl-l-(4-methoxyphenyl)-lH-pyrazol-5-yl]carbamoyl}
amino)phenyl]sulfanyl}imidazo[2,l-b][l,3]benzothiazole-3-carboxylic acid (Compound
10)
Compound 10 was synthesized from the hydrolysis of ethyl 7-{[4-({[3-tert-butyl-l-(4-
methoxyphenyl)-lH-pyrazol-5-yl]carbamoyl} amino) phenyl] sulfanyl} imidazo [2,1-
b][l,3]benzothiazole-3-carboxylate, using the similar procedure as described for the
synthesis of compound 19 in example 8.
1H-NMR (400 MHz, DMSO-d6) : 9.40 ( 1H, s), 9.00 (1H, d), 8.55 (1H, s), 7.93-7.96 (2H,
m), 7.39-7.57 (8H, m), 7.06-7.09 (2H, m), 6.35 (1H, s), 3.81 (3H, s),1.28 (9H, s)
ESMS: 613.16
Example 16: ethyl 7-(4-aminophenoxy)imidazo[2,l-b][l,3]benzothiazole-3-carboxylate
(Compound 62)
Step 1: ethyl 7-(4-nitrophenoxy)imidazo[2,l-b][l,3]benzothiazole-3-carboxylate
(Compound 61)
Compound 6 1 was synthesized from ethyl 7-hydroxyimidazo[2,l-b][l,3]benzothiazole-3-
carboxylate and 4-nitro fluorobenzene using the similar procedure as described for the
synthesis of compound 51 in Example 1.
Step 2: ethyl 7-(4-aminophenoxy)imidazo[2,l-b][l,3]benzothiazole-3-carboxylate
(Compound 62)
Compound 62 was synthesized from reduction of ethyl 7-(4-nitrophenoxy)imidazo[2,lb][
l,3]benzothiazole-3-carboxylate, using the similar procedure as described for the
synthesis of compound 59 in Example 13.
Example 17: ethyl 7-[4-({[3-tert-butyl-l-(3-chloro-4-methoxyphenyl)-lH-pyrazol-5-
yl]carbamoyl}amino) phenoxy] imidazo [2,l-b][l,3] benzothiazole-3-carboxylate
(Compound 5)
vrYxx J
Compound 5 was synthesized from the reaction of ethyl 7-(4-aminophenoxy)imidazo[2,lb][
l,3]benzothiazole-3-carboxylate, and intermediate 2 using the similar procedure as
described for the synthesis of compound 25 in Example 7.
1H-NMR (400 MHz, DMSO-d 6) : 1H-NMR (400 MHz, CDC13 ) 9.06 ( 1H, d), 7.97 (1H, s),
7.50 (1H, d), 7.31-7.34 (3H, m), 7.22-7.26 (2H, m), 7.16 (1H, dd), 7.01 (2H, d), 6.89 (1H,
d), 6.82 (1H, s), 6.41 (1H, s), 4.43 (2H, q), 3.88 (3H, s), 1.45 (3H t), 1.31 (9H, s)
ESMS: 657.45/659.37
Example 18: ethyl 7-(4-{[(5-methyl-3-phenyl-l,2-oxazol-4-yl)carbamoyl]amino}
phenoxy)imidazo[2,l -b][ ound 43)
To a stirred solution of ethyl 7-(4-aminophenoxy)imidazo[2,l-b][l,3]benzothiazole-3-
carboxylate, (0.75 gm, 2.14 mmol) in toluene (15 ml), 4-isocyanato-5-methyl-3-phenyl-l,2-
oxazole (0.5 gm, 2.5 mmol)) was added and reaction mixture was refluxed for 4-6 hrs. The
reaction mixture was cooled to room temperature. Reaction mixture was quenched with cold
water, and extracted with ethyl acetate to get crude compound, which was purified by solvent
treatment using diisopropylether and then dried to get 0.5 gm title compound as solid.
1H-NMR (400 MHz, DMSO-d ) : 8.94 (1H, bs), 8.89 (1H, d), 8.03 (1H, s), 7.84 (1H, s),
7.71-7.76 (3H, m), 7.47-7.52 (5H, m), 7.23 (1H, dd), 7.02 (2H, d), 4.36 (2H, q), 2.37 (3H, s),
1.35 (3H, t)
ESMS: 554.25
Example 19: ethyl 7-(2-{[(phenoxycarbonyl)amino] methyljphenoxy) imidazo[2,lb][
l,3]benzothiazole-3-carboxylate (Compound 80)
To a stirred solution of ethyl 7-[2-(aminomethyl)phenoxy]imidazo[2,l-b][l,3]benzothiazole-
3-carboxylate ( 1 gm, 2.72 mmol) (Compound 55) in THF (10 ml), DIEA (0.7 gm, 5.44
mmol) was added and reaction mixture was cooled at 0°C. To this cooled reaction mixture,
phenylchloroformate (0.42 gm, 2.72 mmol) was added and reaction mixture was further
stirred at RT for around 1 hr. Reaction mixture was poured into water, extracted with ethyl
acetate, dried over sodium sulfate and concentrated under vacuum to dryness to get 1.2 gm
title compound as a white solid .
Example 20: ethyl 7-(2-{[(propylcarbamoyl)amino] methyl Jphenoxy) imidazo [2,1-b]
[l,3]benzothiazole-3-carboxylate (Compound 68)
To a stirred solution of ethyl 7-(2-{[(phenoxycarbonyl) amino]methyl}phenoxy)imidazo[2,lb][
l,3]benzothiazole-3-carboxylate (0.5 gm, 1.02 mmol) (Compound 80) in toluene (10 ml),
DIEA (0.26 gm, 2.05 mmol) and n-propylamine (0.12 gm, 2.05 mmol) were added at room
temperature and reaction mixture was refluxed for 4-5 hrs. Reaction mixture was poured into
water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under vacuum
to dryness to get crude compound, which was purified by column chromatography to get 0.
gm title compound as a white solid.
The following representative compounds of the present invention were prepared
analogous manner by using the synthetic schemes as described above:
Table 1
p.No.

7.50 (4H, m), 7.20-7.23 (2H, m), 6.99-7.09 (4H, m), 6.23 32.73
(IH, d), 3.56-3.57 (4H, m, partially overlapped by water
signal), 2.41-2.48 (8H, m, partially merged with DMSO
signal), 1.26 (9H, s)
2 1H-NMR (400 MHz, CDC13) 8.21 ( IH, bs), 7.71 ( IH, 693.3
bs), 7.43-7.59 (IH, m), 7.33-7.43 (3H, m), 7.19-7.21
(2H, m), 7.07 (IH, dd), 6.90-7.00 (2H, m), 6.71-6.76 (4H,
m), 6.39 (IH, s), 3.77 (4H, bs), 3.51-3.52 (2H m), 2.57-
2.64 (4H, m), 2.38 (3H, s), 2.01-2.08 (2H, m), 1.35 (9H,
s)
3 9.10 ( IH, s), 8.97 ( IH, s), 8.35-8.62 (2H, m), 8.13 700.27
(IH, d), 7.72 (IH, d), 7.20-7.46 (10H, m), 7.0 (2H, d),
6.35 (IH, s), 5.83 (IH, bs), 5.02-5.05 (2H, m), 3.73 (2H,
m), 2.95-3.00 (IH, m), 2.38 (3H s), 1.27 (9H, s)
4 9.12 ( IH, s), 8.85 ( IH, s), 8.38 (IH, s), 8.30 (IH, d), 624.16
8.13 (IH, t), 7.74-7.77 (IH, m), 7.34-7.51 (6H, m), 7.28
(IH, dd), 7.07 (2H, d), 6.40 (IH, s), 4.84 (IH, t), 3.54-
3.58 (2H, m), 3.34 (2H, hidden under signal of water),
2.43 (3H s), 1.33 (9H, s)
6 10.50 ( IH, bs), 10.04 (IH, bs), 9.50 (IH, d), 7.67 (IH, 631.14/6
d), 7.62 (IH, d), 7.49-7.53 (3H, m), 7.40 (IH, s), 7.20 33.03
(IH, d), 6.8-7.05 (3H, m), 6.88 (IH, s), 6.30 (IH, s), 3.81
(3H, s), 1.28 (9H, s)
(DMSO-d +D20 ) 8.75 ( IH, d), 7.91 (IH, s), 7.48-7.53 674.22/6
(2H, m), 7.37 (3H, t), 7.21 (IH, d), 7.05-7.12 (IH, m), 76.01
6.98 (2H, d), 6.27 (IH, s), 3.86 (3H, s), 3.53-3.56 (2H,
m), 3.35-3.42 (2H, m), 1.22 (9H, s)
11.97 ( IH, bs), 10.57 (IH, s), 9.00-9.03 (2H, m), 8.30 617.13/6
(IH, s), 7.95 (IH, s), 7.71 (IH, s), 7.43-7.45 (2H, m), 18.79
7.22-7.28 (2H, m), 7.01-7.09 (2H, m), 6.86 (IH, s), 6.54
(IH, s), 6.16 (IH, s) 1.25 (9H, s)
10.05 ( IH, s), 9.32 (IH, s), 9.04 (IH, bs), 8.41 (IH, s), (ES-)
7.94 (IH, s), 7.39-7.52 (5H, m), 7.28 (2H, d), 6.89 (2H, 597.29
d), 6.34 (IH, s), 1.24 (9H, )
9.40 ( IH, s), 9.00 (IH, d), 8.55 (IH, s), 7.93-7.96 (2H, 613.16
m), 7.39-7.57 (8H, m), 7.06-7.09 (2H, m), 6.35 (IH, s),
3.81 (3H, s),1.28 (9H, s)
1H-NMR (400 MHz, CDC13 ) 9.05 ( IH, s), 7.89 (IH, 639.27
s), 7.07-7.38 (6H, m), 6.88 (2H, d), 6.19 (IH, s), 5.99
(IH, s), 5.41-5.44 (IH, m), 4.48 (2H, d), 4.42 (2H, q),
3.80 (3H, s), 1.44 (3H t), 1.31 (9H, s)
9.45 ( IH, d), 8.21 ( IH, s), 7.66 (IH, d), 7.55 (IH, bs), 597.16
7.00-7.33 (7H, m), 6.82-6.89 (3H, m), 6.16 (IH, s), 4.28
(2H, d), 1.22 (9H, s)
9.85 ( IH, bs), 9.01 ( IH, d), 8.54 (IH, m), 8.09 (IH, s), (ES-
7.96 (IH, s), 7.65-7.71 (2H, m), 7.28-7.33 (2H, m), 7.16- )638.22
7.21 (3H, m), 6.91-6.93 (2H, m), 6.84 (2H, d), 6.17 (IH,
s), 4.78 (IH, t), 4.28 (2H, d), 3.53-3.56 (2H, m), 3.43
(2H, hidden under signal of water), 1.23 (9H, s)
9.07 ( IH, s), 8.32 (IH, s), 8.01 (IH, bs), 7.69 (IH, s), (ES-)
7.42-7.45 (4H, m), 7.18 (2H, m), 7.09 (2H, m), 7.01 (2H, 581.13
m), 6.33 (IH, s), 5.49 (IH, bs), 4.81 (2H, bs), 3.82 (3H,
s),1.26 (9H, s)
7.97 ( IH, d), 7.59 ( IH, d), 7.27-7.30 (2H, m), 7.12- (ES-)
7.17 (4H, m), 6.82-6.92 (4H, m), 6.14 (IH, s), 4.79 (2H, 581.26
s), 4.25 (2H, d), 3.34-3.49 (IH, m), 1.20 (9H, s)
9.73 ( IH, s), 8.91 ( IH, d), 8.05 (2H, d), 7.70 (IH, s), 625.16
7.30-7.33 (2H, m), 7.17-7.24 (4H, m), 6.93-6.96 (2H, m),
6.83 (2H, d), 6.14 (IH, s), 4.37 (2H, q), 4.26 (2H, d), 1.35
(3H, t), 1.20 (9H, s)
9.79 ( IH, bs), 9.21 (IH, bs), 8.30 (IH, bs), 7.93-7.96 585.1
(2H, m), 7.20-7.46 (8H, m), 6.89 (2H, bs), 6.32 (IH, bs),
5.48 (IH, bs), 4.79 (2H, s), 1.25 (9H, s)
(DMSO-d +D20 ) 8.82 ( IH, d), 7.95 ( IH, d), 7.56 (IH, 704.58/6
s), 7.28-7.37 (3H, m), 7.15-7.20 (3H, m), 7.05 (IH, d), 7706.37
6.93 (IH, d), 6.10 (IH, s), 4.26 (2H, s), 3.88-4.06 (3H,
merged with water signal), 3.53-3.64 (2H, m), 1.21 (9H,
s)
8.27 ( IH, bs), 7.94 ( IH, bs), 7.67 (IH, bs), 6.92-7.38 (ES-)
(10 H, m), 6.18 (IH, bs), 4.26 (4H, bs), 3.51(2H, partially 675.54/6
merged with water signal), 3.35 (2H, hidden under signal 77.52
of water), 1.22 (9H, s)
9.45 (IH, bs), 8.43 (IH, bs), 7.98 ( IH, bs), 7.61 (IH, 647.52/6
bs), 7.41 (2H, bs), 7.1 1-7.30 (8H, m), 6.20 (IH, s), 4.35 49.43
(2H, s), 1.23 (9H, s)
10.58 ( IH, bs), 9.04 (IH, s), 8.90 (IH, d), 8.30 (IH, s), (ES-)
8.04 (IH, s), 7.74 (IH, s), 7.44-7.46 (3H, m), 7.26 (2H, t), 643.61/6
7.02-7.09 (3H, m), 6.32 (IH, s), 4.36 (2H, q), 1.35 (3H t), 44.57
1.26 (9H, s)
10.56 ( IH, bs), 9.02 (IH, s), 8.29 (IH, s), 7.99 (IH, m), (ES-)
7.69 (IH, s), 7.44 (3H, bs), 7.01-7.27 (6H, m), 6.32 (IH, 601.77/6
s), 5.49 (IH, bs), 4.80 (2H, s), 1.26 (9H, s) 03.24
10.50 ( IH, bs), 8.21 ( IH, s), 8.02 (IH, m), 7.71 (IH, 688.32/6
s), 7.66 (IH, bs), 7.40 (IH, bs), 7.14-7.28 (5H, m), 7.05 90.33
(IH, d), 6.88-6.92 (2H, m), 6.18 (IH, s), 4.86 (IH, bs),
4.27 (2H, d), 3.63 (3H, bs), 3.10-3.20 (4H, bs), 1.22 (9H,
s)
10.50 (1H, bs), 8.21 ( 1H, bs), 7.97 ( 1H, bs), 7.65 (1H, (ES-)
bs), 7.41 (1H, bs), 7.18-7.29 (6H, m), 7.04-7.06 (1H, m), 700.48/7
6.92 (2H, bs), 6.18 (1H, bs), 4.28 (2H, bs), 3.82 (2H, bs), 02.48
2.72 (4H, bs), 2.56 (4H, partially merged with solvent
signal), 1.23 (9H, s)
10.51 (1H, s), 8.20 (1H, s), 7.99 ( 1H, d), 7.67 ( 1H, bs), 719.33/7
7.41 (1H, d), 7.28-7.29 (2H, m), 7.12-7.23 (4H, m), 7.04 21.33
(1H, d), 6.91-6.92 (2H, m), 6.19 (1H, s) 4.32 (2H, s),
4.28 (2H, d), 4.03 (2H, q), 3.30 (2H, merged with water
signal), 1.22 (9H, s), 1.14 (3H, t)
10.51 ( 1H, bs), 8.22 ( 1H, s), 8.14 (1H, d), 7.65 (1H, (ES-)
d), 7.41 (1H, d), 7.17-7.29 (5H, m), 7.04-7.07 (2H, m), 672.40/6
6.91-6.93 (2H, m), 6.19 (1H, s), 4.48 (1H, bs), 4.28 (2H, 74.75
d), 3.82 (2H, s), 3.51 (2H, bs), 2.54 (2H, partially merged
with solvent signal), 2.18 (3H, s), 1.23 (9H, s)
8.16-8.21 (3H, m), 8.02 (1H, d), 7.83 (1H, d), 7.68- 670.95/6
7.72 (2H, m), 7.53-7.55 (1H, m), 7.40-7.43 (1H, m), 72.88
7.21-7.23 (2H, m), 5.41-5.43 (1H, m), 3.80 (4H, bs), 3.64
(4H, bs), 1.22 (9H, s)
8.45 (1H, s), 8.18 ( 1H, d), 7.81 ( 1H, d), 7.60 (1H, s), 705.04/7
7.44 (1H, d), 7.20-7.35 (5H, m), 7.10-7.12 (2H, m), 6.97- 07.04
6.99 (1H, m), 6.22 (1H, s), 4.39 (2H, s), 4.27 (2H, d),
3.56 (3H, s), 3.42 (2H, s), 1.23 (9H, s)
10.53 (1H, bs), 8.20 ( 1H, bs), 7.98-8.06 ( 1H, m), 7.69 700.30/7
(2H, bs), 7.40-7.52 (3H, m), 7.17-7.29 (4H, m), 6.91-7.06 02.31
(2H, m), 6.18 (1H, bs), 4.28 (2H, bs), 3.67-3.74 (8H, m),
1.22 (9H, s)
10.50 (1H, s), 8.20 ( 1H, s), 7.77 ( 1H, d), 7.66 (1H, d), 645.31/6
7.40 (1H, d), 7.26-7.29 (2H, m), 7.21-7.23 (1H, m), 7.12- 47.20
7.17 (2H, m), 7.03-7.05 (1H, m), 6.88-6.90 (2H, m), 6.19
(1H, s), 4.75 (2H, s), 4.28 (2H, d), 3.28 (3H, partially
merged with water signal), 2.29 (3H, s), 1.22 (9H, s)
10.52 (IH, bs), 8.21 ( IH, s), 7.96 ( IH, d), 7.65 (IH, 631.27/6
d), 7.41 (IH, d), 7.21-7.29 (3H, m), 7.14-7.16 (2H, m), 33.28
7.05 (IH, d), 6.93 (IH, t), 6.87 (IH, d), 6.19 (IH, s), 5.34
(IH, bs), 4.77 (2H, s), 4.29 (2H, d), 2.25 (3H, s) 1.23
(9H, s)
10.52 (IH, s), 8.22 ( IH, s), 7.69 ( IH, d), 7.62 (IH, d), 704.33/7
7.42 (IH, d), 7.14-7.28 (6H, m), 7.04-7.09 (2H, m), 6.89- 06.34
6.93 (2H, m), 6.20 (IH, s), 4.27-4.28 (4H, m), 3.57-3.63
(2H, m), 2.54 (3H, merged with solvent signal), 1.23 (9H,
s)
10.51 (IH, s), 8.20 ( IH, s), 7.90 ( IH, d), 7.63 (IH, s), 699.94/7
7.40 (IH, s), 7.03-7.29 (6H, m), 6.91 (2H, bs), 6.18 (IH, 01.94
s), 4.28 (2H, bs), 3.74 (2H, s), 3.51 (4H, bs), 2.45 (4H,
partially merged with solvent signal), 2.24 (3H, s), 1.22
(9H, s)
8.97 (IH, d), 8.70 (IH, s), 7.92 (IH, s), 7.67 (IH, d), 489.02
7.41 (2H, d), 7.16-7.33 (7H, m), 6.99 (IH, d), 6.69 (2H,
d), 4.98 (IH, bs), 4.73-4.77 (IH, m), 3.59-3.83 (2H, m)
8.88 (IH, d), 8.45 (IH, s), 8.02 (IH, s), 7.69 (IH, d), 551.28/5
7.53 (IH, d), 7.45 (IH, d), 7.33 (IH, t), 7.21-7.23 (2H, 53.10
m), 7.05-7.07 (IH, m), 6.99 (IH, d), 6.92 (IH, d), 6.49
(IH, t), 4.31-4.39 (4H, m), 3.75 (3H, s), 1.35 (3H, t)
8.90 (IH, d), 8.50 (IH, s), 8.03 (IH, s), 7.71 (IH, bs), 547.31
7.44 (IH, d), 7.33 (IH, t), 7.23-7.24 (2H, m), 6.99 (IH,
d), 6.54 (2H, s), 6.49 (IH, t), 6.00 (IH, s), 4.31-4.39 (4H,
m), 3.65 (6H, s), 1.35 (3H, t)
9.96 (IH, bs), 9.56 (IH, bs), 8.90 (IH, d), 8.12 (IH, s), (ES-)
8.03 (IH, s), 7.76 (IH, bs), 7.59-7.64 (2H, m), 7.52 (2H, 573.26/5
d), 7.26 (IH, d), 7.06 (2H, d), 4.37 (2H, q), 1.35 (3H, t) 75.34
8.52 (IH, s), 7.77 (IH, d), 7.67 (IH, d), 7.58 (IH, d), (ES-)
7.42 (IH, d), 7.30 (IH, t), 7.10-7.21 (3H, m), 6.92-9-98 535.41/5
(2H, m), 6.52 (IH, t), 4.74 (2H, s), 4.31 (2H, d), 3.76 37.43
(3H, s), 3.29 (3H, partially merged with water signal),
2.19 (3H, s)
9.05 (IH, s), 8.02 (IH, s), 7.76 (IH, d), 7.66 (IH, s), 575.23/5
7.42-7.49 (3H, m), 7.30 (IH, m), 7.17-7.19 (2H, m), 6.94 77.21
(IH, d), 6.74 (lH,bs), 4.73 (2H, s), 4.36 (2H, bs), 3.29
(3H, partially merged with water signal), 2.29 (3H, s)
9.45 (IH, s), 7.78 (IH, d), 7.69 (IH, s), 7.40 (IH, d), 520.35
7.30 (IH, t), 7.18 (2H, m), 6.92 (2H, m), 6.29 (IH, s),
4.75 (2H, s), 4.36 (2H, d), 3.29 (3H, partially merged
with water signal), 2.29 (3H, s), 1.24 (9H, s)
10.51 (IH, bs), 8.20 ( IH, bs), 7.88 (IH, d), 7.68 (IH, 671.06/6
d), 7.4 (IH, d), 7.30-7.28 (3H, m), 7.22 (IH, dd), 7.14- 73.01
7.19 (2H, m), 7.04 (IH, d), 6.90-6.92 (2H, m), 6.18 (IH,
s), 4.81 (2H, s), 4.28 (2H, d), 3.36 (2H, partially
overlapped by water signal), 1.22 (9H, s), 1.02 (IH, m),
0.43-0.46 (2H, m), 0.14-0.16 (2H, m)
10.60 (IH, bs), 8.33 ( IH, bs), 7.98 (IH, d), 7.77 (IH, 645.05/6
d), 7.64 (IH, s), 7.41 (IH, d), 7.32-7.18 (5H, m), 7.08 46.98
(IH, d), 7.02 (IH, t), 6.96 (IH, d), 6.19 (IH, s), 4.86 (2H,
bs), 4.26 (2H, d), 3.57 (2H, q), 1.22 (9H, s), 1.13 (3H, t)
10.49 (IH, bs), 9.39 ( IH, d), 8.16 (IH, s), 7.91 (IH, s), 667.95/6
7.68 (IH, s), 6.90-7.39 (10H, m), 6.15 (IH, s), 4.27 (2H, 69.91
d), 2.41 (3H, s), 1.21 (9H, s)
10.51 (IH, bs), 8.21 ( IH, bs), 8.02 (IH, d), 7.64 (IH, 699.99/7
s), 7.41 (IH, s), 7.28-7.15 (6H, m), 7.05 (IH, d), 6.93 00.99
(IH, d), 6.18 (IH, s), 5.75 (IH, s), 4.54 (IH, s), 4.28 (2H,
d), 3.74 (IH, s), 3.47 (IH, bs), 2.74 (2H, bs), 2.12 (2H,
bs), 1.67 (2H, bs), 1.37 (2H, m), 1.22 (9H, s)
8.89 ( IH, d), 8.24 (lH,bs), 8.02 (IH, s), 7.68 (IH, s), 608.97
7.46-7.20 (9H, m), 6.95 (2H, m), 6.20 (IH, s), 4.36-4.29
(4H, m), 1.35 (3H, s), 1.23 (9H, s)
68 8.90 ( IH, d), 8.02 (IH, s), 7.70 (IH, s), 7.39 (IH, d), 453.01
7.29 (IH, t), 7.22-7.19 (2H, m), 6.96 (IH, d), 6.21 (IH,
bs), 5.97 (IH, bs), 4.37 (2H, q), 4.24 (2H, d), 2.93 (2H,
d), 1.37-1.34 (5H,m), 0.81 (3H, t)
69 8.98 ( IH, bs), 8.91 (IH, d),8.04 (IH, s), 7.74 (IH, s), 494.01
7.39 (IH, d), 7.29- 7.18 (3H, m), 6.94 (IH, d), 6.62 (IH,
d), 6.43 (IH, bs), 4.37 (2H, q), 4.24 (2H, d), 3.63 (IH,
bs), 3.17 (2H, m), 2.90 (2H, t), 1.89-1.86 (2H, m), 1.56-
1.53 (2H, m), 1.35 (3H, t)
70 10.50 ( IH, bs), 8.95-8.91 (2H, m),8.82 (IH, s), 8.22 (ES-)
(IH, d), 8.04 (IH, s), 7.84 (IH, s), 7.41 (IH, s), 7.32 (IH, 643.05
d), 7.24 (IH, d), 7.12 (IH, t), 7.05- 6.97 (2H, m), 6.87
(IH, d), 6.33 (IH, s), 4.37 (2H, q), 1.35 (3H, t), 1.25 (9H,
s)
74 8.96 ( IH, bs), 8.19 (IH, s), 8.07 (IH, s), 8.03 (IH, d), 692.95
7.69 (IH, s), 7.46 (IH, d), 7.32-7.18 (7H, m), 6.97 (IH,
d), 6.91 ( IH, s), 4.36 (2H, s), 3.79 (2H, s), 3.65 (3H, s),
3.53 (4H, bs), 3.03 (3H, s), 2.45 (4H, bs), 1.21 (9H, s)
78 10.49 (IH, bs), 8.89 (IH, d), 8.17 (IH, s), 8.04 (IH, s), 644.94/6
7.76 ( IH, d), 7.42 (IH, d), 7.27-7.23 (4H, m), 7.07-6.96 46.89
(4H, m), 6.24 (IH, s), 4.24 (2H, d), 3.89 (3H, s), 1.25
(9H, s)
79 10.36 (IH, bs), 8.89 (IH, d), 8.20 ( IH, s), 8.03 ( IH, s), 677.08/6
7.66 (IH, d), 7.38 (IH, d), 7.22-7.13 (4H, m), 7.04-7.02 78.28
(2H, m), 6.95 (IH, m), 6.15 (IH, s), 4.37 (2H, q), 4.24
(2H, d), 1.36 (3H, t), 1.33 (9H, s)
Pharmaceutical compositions
In another embodiment present invention provides a pharmaceutical composition
comprising a therapeutically effective amount of one or more of a compound of formula (I).
While it is possible to administer therapeutically effective quantity of compounds of formula
(I) either individually or in combination, directly without any formulation, it is common
practice to administer the compounds in the form of pharmaceutical dosage forms comprising
pharmaceutically acceptable excipient(s)/adjuvant(s) or carrier and at least one active
ingredient. These dosage forms may be administered by a variety of routes including oral,
topical, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, intranasal,
pulmonary etc.
Oral compositions may be in the form of solid or liquid dosage form. Solid dosage
form may comprise pellets, pouches, sachets or discrete units such as tablets, multi
particulate units, capsules (soft & hard gelatin) etc. Liquid dosage forms may be in the form
of elixirs, suspensions, emulsions, solutions, syrups etc. Composition intended for oral use
may be prepared according to any method known in the art for the manufacture of the
composition and such pharmaceutical compositions may contain in addition to active
ingredients, excipients such as diluents, disintegrating agents, binders, solubilizers,
lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers,
flavours, sweeteners, colours etc. Some example of suitable excipients include lactose,
cellulose and its derivatives such as microcrystalline cellulose, methylcellulose, hydroxy
propyl methyl cellulose & ethylcellylose, dicalcium phosphate, mannitol, starch, gelatin,
polyvinyl pyrolidone, various gums like acacia, tragacanth, xanthan, alginates & its
derivatives, sorbitol, dextrose, xylitol, magnesium stearate, talc, colloidal silicon dioxide,
mineral oil, glyceryl mono stearate, glyceryl behenate, sodium starch glycolate, cross
povidone, crosslinked carboxymethylcellulose, various emulsifiers such as polyethylene
glycol, sorbitol, fatty acid esters, polyethylene glycol alkylethers, sugar esters,
polyoxyethylene polyoxypropyl block copolymers, polyethoxylated fatty acid monoesters,
diesters and mixtures thereof.
Intranasal or pulmonary compositions according to present invention can be in the
form of liquid or solid or semisolid composition suitable for nasal administration. Liquid
composition can be aqueous, non-aqueous composition, suspension or emulsion, solid
composition can be in the form of powder and the like and semi solid composition can be in
form of gel and the like. Nasal/pulmonary compositions may also form in-situ gel. Said nasal
or pulmonary composition comprises compounds of formula (I) optionally with one or more
suitable excipients selected from in-situ gelling agent, mucoadhesive agent, polymer,
humectant, buffering agent, stabilizer, surfactant, preservative, thickening agent, solvents, cosolvents,
permeation enhancer, chelating agent, viscosity modifying agent, sweetener, taste
masking agent, solubilizer, flavoring agent, emulsifier and isotonicity agent.
Sterile compositions for injection can be formulated according to conventional
pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as
water for injection, N -Methyl-2-Pyrrolidone, propylene glycol and other glycols, alcohols, a
naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton seed oil or a
synthetic fatty vehicle like ethyl oleate or the like. Buffers, anti-oxidants, preservatives,
complexing agents like cellulose derivatives, peptides, polypeptides and cyclodextrins and
the like can be incorporated as required.
The dosage form can have a slow, delayed or controlled release of active ingredients
in addition to immediate release dosage forms.
The amount of active ingredient which is required to achieve a therapeutic effect will,
of course, vary with the particular compound, the route of administration, the subject under
treatment, and the particular disorder or disease being treated. The compounds of the
invention may be administered by oral, inhalation or parenteral route at a dose of from
0.0005 to 100 mg/kg per day, preferably from 0.0005 to 50 mg/kg per day, more preferably
from 0.001 to 20 mg/kg per day, most preferably from 0.001 to 10 mg/kg per day. The dose
range for adult humans is generally from 5 g to 5 g per day, preferably dose range is 10g
to 2 g per day.
Dosage forms of presentation provided in discrete units may conveniently contain an
amount of compound of the invention which is effective at such dosage or as a multiple of
the same, for example units containing 5 g to 1000 mg.
In another embodiment present invention provides method of treating allergic and
non-allergic airway disease by administering a therapeutically effective amount of a
compound of formula (I) to a mammal, including human being, in need thereof. Allergic and
non-allergic airway diseases include allergic and non-allergic asthma, chronic obstructive
pulmonary disease (COPD), rhinitis, chronic bronchitis, emphysema, or asthma-like
syndrome such as coughing, wheezing or dyspnea.
A preferred embodiment of the present invention is a method for treating chronic
obstructive pulmonary disease and asthma by administering a therapeutically effective
amount of a compound of formula (I) to a mammal, including human being, in need thereof.
A most preferred embodiment of the present invention is a method for treating
chronic obstructive pulmonary disease by administering a therapeutically effective amount of
a compound of formula (I) to a mammal, including human being, in need thereof.
Another embodiment of the present invention is the use of a compound of formula (I)
for the preparation of a medicament for treating allergic and non-allergic airway disease.
A preferred embodiment of the present invention is the use of a compound of formula
(I) for the preparation of a medicament for treating chronic obstructive pulmonary disease
and asthma.
A most preferred embodiment of the present invention is the use of a compound of
formula (I) for the preparation of a medicament for treating chronic obstructive pulmonary
disease.
Biological testing:
Biological example 1: in-vitro studies
Inhibition of p38 alpha MAPK activity: Time-resolved fluorescence resonance energy
transfer kinase standard assay (TR-FRET assay)
Compounds of present invention at various concentrations were premixed with DMSO. The
experiment was initiated by mixing 0.5% - 1.0% DMSO as vehicle/ compounds with
purified recombinant human p38 alpha MAPK (Millipore, USA) in the wells and 15 min
incubation at RT. Thereafter, 30nM of Biotinylated GST-ATF2 (Activation Transcription
Factor2) and 100 of ATP were added in to the wells containing reaction mixture,
followed by reincubation for 60 minutes at RT. Reaction was terminated by addition of 10
mM of EDTA and detection reagent containing anti-phosphotheronine ATF2 antibody
(Perkin Elmer, USA) labelled with europium chelate and APC (AUophycocyanin) labeled
streptavidin, into the reaction mixture which was further incubated for 60 minutes at room
temperature. The degree of phosphorylation of the substrate (GST-ATF2) was measured
using Envision multimode reader (Perkin Elmer). Percentage inhibition of p38 kinase activity
was calculated by determining ratio of specific europium 665nm energy transfer signal to
reference 615nm signal. Results are summarized in the table 2.
Table 2
Compound Concentration 38Inhibition
No
1 +++
2 ++++
3 +++
4 +++++
5 ++
6 +++++
7 ++++
8 +++++
9 +++++
10 +++++
11 ++
12 +++++
13 +++++
14 +++++
15 ++++
16 +++++
17 +++++
18 +++
19 +++++
20 +++++
2 1 +++++
22 +++++
23 +++++
24 +++
25 ++++
26 +
27 ++++
28 +++++
29 +++++
30 +++++
3 1 +++++
35 +++++
37 +++++
38 +++++
40 +++++
4 1 +
42 +
43 +
44 +++
45 +
46 +
47 +
48 ++++
49 +++++
50 +++++
56 ++++
64 ++++
65 ++++
67 ++++
74 ++++
Criteria: +++++ = Inhibition >80% <100%; ++++ = Inhibition >60% <80%;
+++= Inhibition >40% <60%; ++ = Inhibition >20% <40%; + = Inhibition <20%
Observation: in-vitro data shows that compounds of present invention effectively inhibits p38
MAPK activity.
Biological example 2: in vivo studies
In vivo efficacy evaluation of compounds in animal model of airway inflammation:
The tobacco smoke induced airway inflammation model is used for in vivo efficacy of
compound. Many investigators have used acute tobacco smoke (TS) exposure in rodents as
models of airway inflammation for quick screening of anti-inflammatory therapies for COPD
(J Pharmacol Exp Ther. 2008; 324(3):921-9; J Pharmacol Exp Ther. 2010; 332(3):764-75;
Journal of Inflammation 2013, 10(Suppl 1):31 and Eur Respir J Suppl 2006; 663s:3850).
Given its position as predominant cause of COPD, animal models using TS exposure would
appear to be the logical choice for investigation (Respir Res. 2004; 2;5: 18).
A: Efficacy studies in acute mouse model of airway inflammation
Mice were exposed to tobacco smoke (TS) in an acrylic chamber. Animals were exposed to
TS from 8, 12, 16 cigarettes on dayl, day2, day 3 respectively. From day 4 onwards till day
11, animals were exposed to TS from 20 cigarettes per day. On 11 days of exposure of mice
to TS, significant inflammatory cell recruitment, predominantly neutrophils, to lungs was
observed as compared to air exposed control mice (BALF neutrophil levels, nil in air control
group vs 93.8+1 1.7 * 10 cells/animal in smoke exposed vehicle group).
Lung delivery of test compound was achieved by whole body aerosol exposure for 25
minutes in a chamber. Mice were divided in different dose groups and exposed in a chamber
for 25 minutes with vehicle or Compound No. 22 (0.3mg/ml) or Compound No. 22 (3mg/ml)
) or Compound No. 31(0.3mg/ml) or Compound No. 31(1.0 mg/ml). A total quantity of
3.5ml of either vehicle or test compound formulation (suspension formulation with D90 <
5, with Malvern Mastersizer®) was nebulized in a chamber to respective groups over 25
mins period. Test compounds were administered 2 hr prior to TS exposure from day 6 to day
11. Bronchoalveolar lavage (BAL) was performed 24 hr post last TS exposure.
Trachea of animal was cannulated using catheter. Phosphate Buffer Saline (PBS) was used as
lavage fluid. A volume of 0.5ml was gently instilled and withdrawn and collected in
microcentrifuge tube placed on ice. This procedure was repeated further 2 times.
Lavage fluid was separated from cells by centrifugation and supernatant separated.
The cell pallet was resuspended in known volume of PBS. Cells in aliquot were stained using
Turk solution and total cell numbers were calculated by counting Turk stained aliquot under
microscope using haemocytometer.
The residual cell suspension was resuspended and slides prepared using cyto
centrifuge technique (Cytospin 4, Thermo Shandon). The slides were then fixed with
methanol, air dried and stained with May Grunwald Giemsa stain. Up to 300 cells were
counted and differentiated using standard morphometric techniques under light microscopy.
All results are presented at individual data for each animal and mean value calculated
for each group. Percentage inhibition for the neutrophil was calculated for Compound No. 22
& 3 1 treatment group against vehicle group. Results are summarized herein below:
The effect of treatment Compound No. 22 & 3 1 on cigarette smoke induced Neutrophil
accumulation in BAL Fluid.
Table 3
Treatment Concentration Exposure Neutrophil %Inhibition
Duration
(*103 (Minutes) cells/animal)
Vehicle NA 25 93.8+11.7
Compound No. 0.3 mg/ml 25 71.2+13.6 24
22
3 mg/ml 25 35.2±3.7 62
Vehicle NA 25 100.0+18.7
0.3 mg/ml 25 40.3±6.2 60
Compound 31
1.0 mg/ml 25 20.4±3.8 80
Values are Mean±SEM; NA: Not applicable
Observation: It was observed that compounds of present invention were found effective in
inhibition of neutrophil influx, an index of pulmonary inflammation. These results indicate
that compounds of present invention possess pulmonary anti-inflammatory activity.
B. (I) Efficacy studies in acute Guinea Pig model of airway inflammation
Guinea pigs were exposed to tobacco smoke (TS) in an acrylic chamber. Animals were
exposed to TS from 5, 10, 15 cigarettes on day 1, day 2, day 3 respectively. From day 4
onwards till day 11, animals were exposed to TS from 15 cigarettes per day. On 11 days of
exposure of guinea pig to TS, significant inflammatory cell recruitment, predominantly
neutrophils, to lungs was observed as compared to air exposed control guinea pig (BALF
neutrophil levels, 0.23±0.052*106 cells/animal in air control group vs 3.5±0.62 * 106
cells/animal in smoke exposed vehicle group).
Lung delivery of test compound was achieved by whole body aerosol exposure for 75
minutes in a chamber. Guinea pig were divided in different dose groups and exposed in a
chamber for 75 minutes with vehicle or Compound No. 3 1 (6 mg/ml). A total quantity of 7.0
ml of either vehicle or test compound formulation (suspension formulation with D90 < 5,
with Malvern Mastersizer®) was nebulized in chambers to respective groups over 75 mins
period. Test compound was administered 2 hr prior to TS exposure from day 6 to day 11.
Bronchoalveolar lavage (BAL) was performed 24 hr post last TS exposure.
Trachea of animal was cannulated using catheter. Phosphate Buffer Saline (PBS) was
used as lavage fluid. A volume of 5.0 ml was gently instilled and withdrawn and collected in
microcentrifuge tube placed on ice. This procedure was repeated further 5 times.
Lavage fluid was separated from cells by centrifugation and supernatant separated.
The cell pallet was resuspended in known volume of PBS. Cells in aliquot were stained using
Turk solution and total cell numbers were calculated by counting Turk stained aliquot under
microscope using haemocytometer.
The residual cell suspension was resuspended and slides prepared using cyto
centrifuge technique (Cytospin 4, Thermo Shandon). The slides were then fixed with
methanol, air dried and stained with May Grunwald Giemsa stain. Up to 300 cells were
counted and differentiated using standard morphometric techniques under light microscopy.
All results are presented at individual data for each animal and mean value calculated
for each group. Percentage inhibition for the neutrophil was calculated for Compound No 3 1
treatment group against vehicle group. Results are summarized herein below:
The effect of treatment Compound No 3 1 on cigarette smoke induced neutrophil
accumulation in BAL Fluid.
Table 4
Treatment Concentration Exposure Neutrophil %Inhibition
Duration
(Minutes) *1 0 ^ells/animal)
— ----- 3 5 6
Compound No. 6 mg/ml 75 1.8+0.28 48
3 1
Values are Mean±SEM; NA: Not applicable
Observation: It was observed that compounds of present invention were found effective in
inhibition of neutrophil, an index of pulmonary inflammation in guinea pig model of airway
inflammation. These results indicate that compounds of present invention possess pulmonary
anti-inflammatory activity.
(II) Efficacy studies in chronic model of COPD in Guinea Pigs.
Guinea pigs were exposed to tobacco smoke (TS) and LPS in an acrylic chamber. Exposure
to TS and LPS is given in following manner in a week for a total of 18 weeks.
wk 1
wk 18
Lung delivery of test material was achieved by whole body aerosol exposure for 75
minutes in a chamber. Guinea pig were divided in different dose groups and exposed to
vehicle or Compound No. 3 1 (2 mg/ml). A total quantity of 7.0 ml of either vehicle or
Compound No. 3 1 (suspension formulation with D90 < 5, with Malvern Mastersizer®) was
nebulized in chambers to respective groups over 75 mins period. Compound No 3 1 was
administered 2 hr prior to TS/LPS exposure once daily from week 9 to week 18. Control
animals were exposed to room air instead of TS and PBS instead of LPS. Lung function and
bronchoalveolar lavage (BAL) for each animal was performed 24 hr post last TS exposure.
Lung function assessment in anesthetized and tracheotomized animal was carried out
using PFT maneuvers (BUXCO, USA) for determination of various parameters such as
Functional Residual Capacity (FRC), Residual volume (RV), Pressure volume and flow
volume relationships.
Trachea of animal was cannulated using catheter. Phosphate Buffer Saline (PBS) was
used as lavage fluid. A volume of 5.0 ml was gently instilled and withdrawn and collected in
microcentrifuge tube placed on ice. This procedure was repeated further 5 times.
Lavage fluid was separated from cells by centrifugation and supernatant separated.
The cell pallet was resuspended in known volume of PBS. Cells in aliquot were stained using
Turk solution and total cell numbers were calculated by counting Turk stained aliquot under
microscope using haemocytometer.
The residual cell suspension was resuspended and slides prepared using cyto
centrifuge technique (Cytospin 4, Thermo Shandon). The slides were then fixed with
methanol, air dried and stained with May Grunwald Giemsa stain. Up to 300 cells were
counted and differentiated using standard morphometric techniques under light microscopy.
After collection of BALF lung was fixed under constant pressure using neutral
buffered formaline, which is to be used further for histopathological analysis. Hematoxylin
and eosin stained slides were used for assessment of lung inflammatory cell influx and
alveolar & epithelial inflammatory changes. Periodic acid-Schiff-diastase stained slides
were used to evaluate mucin secreting cells and Masson's trichome stained slides were used
for assessment of collagen fibers in parenchyma.
All results are presented at individual data for each animal and mean value calculated
for each group. Percentage inhibition for the neutrophil was calculated for compound no 31
group against vehicle group. Results are summarized herein below:
A. Effect of treatment of compound no 31, on BALF fluid inflammatory cell influx in guinea
pigs.
Table 5
Treatment Concentration Exposure Duration Neutrophil %
(mg/ml) (Minutes) (*10 cells) inhib"
Vehicle NA 75 6.9+1.3
Compound no 2 75 3.3±0.71 52
3 1
Values are Mean±SEM; NA: Not applicable
B. Effect of treatment of Compound no 31, on lung function parameters, Functional Residual
Capacity (FRC), Residual Volume (RV), Inspiratory Capacity (IC) to Total Lung Capacity
(TLC) ratio and Total lung resistance (R L) is given in Fig 1 and 2. (Values are Mean±SEM)
C. Effect of treatment of Compound No 3 1 on lung remodeling, assessed by composite score
using histopathological analysis of lung tissue and mucus secretion, by number of mucin
secreting cells.
Table 6
Concentration Composite Average number of
(mg/ml) score (Range) mucin secreting
cells/10 high power
field (Range)
Compound No 3 1 2 0.4 (0.1 to 0.5) 301 (190-420)
(2mg/ml)
NA: Not applicable
Observation: In a chronic COPD model, Compound of present invention exerted significant
effect in reduction of neutrophil influx to lung tissue, significantly improves lung function
and prevents lung remodeling aspects associated with COPD.
A Compound of formula (I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, atropisomers,
conformers, tautomers, polymorphs, hydrates, solvates and N-oxide;
wherein,
X is selected from O, S(0) , NH and N( -C3)alkyl;
Ri and R2 is independently selected from hydrogen, A, CHO, C=N-OH, C=N-0-(Ci-
C6)alkyl, CH2OH, CH2R3, N(R5)C0 2R4, CH2-halogen, NR5R6, N(R5)C(0)-A, N(R5)S(0) m-A,
N(R5)C(0)N(R 5)-A, N(R5)C(S)N(R5)-A, C(0)NR 5R6, C0 2R , C(0)-A, CH(OH)-A
C(CH3)=N-OH, C(CH3)=N-0-(Ci-C 6)alkyl, C(0)CH 2-halogen and C(0)CH 2R3;
R is independently selected from hydrogen, (Ci-C )alkyl, (C3-Cio)carbocycle, CN, CHO,
C(0)-A, C(CH3)=N-OH, C(CH3)=N-0-(Ci-C 6)alkyl, C(0)CH 2-halogen, C(0)CH 2R3,NR5R6,
N(R5)C(0)-A, N(R5)S(0) -A, N(R5)C(0)0-A, N(R5)C(0)N(R 5)-A, N(R5)C(S)N(R5)-A,
C0 2R , C(0)N(R 5)-A, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (Ci-C6)alkyl-N3, (d-
C6)alkyl-NR5R6, (Ci-C6)alkyl-N(R5)C(0)-A, (Ci-C6)alkyl-N(R5)S(0) m-A, (Ci-C6)alkyl-
N(R5)C(0)0-A, (Ci-C6)alkyl-N(R5)C(0)N(R 5)-A, (Ci-C6)alkyl-N(R5)C(S)N(R5)-A and (QC
6)alkyl-OC(0)N(R 5)-A;
A is independently selected from (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl and
heterocyclic, the said (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl or heterocyclic may
be optionally substituted with 1-3 substituents independently selected from halogen, (Ci-
C )alkyl, (C3 -Cio)carbocycle, aryl, heteroaryl, heterocyclic, hydroxyl, CF3, OCF3, 0(Ci-
C6)alkyl, O-(C3-Ci0)carbocycle, N0 2, C(0)-(Ci-C 6)alkyl, C(0)CH 2-halogen, C(0)CH 2R3,
NR5R6, C0 2R , C(0)N(R 5)-A, N(R5)S(0) m-A, SH, S(0) (Ci-C6)alkyl, S(0) mN(R5)-A, CN,
CHO, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen and (Ci-C6)alkyl-NR5R 6 wherein each aryl or
heteroaryl may be further optionally substituted with 1-3 substituents independently selected
from halogen, (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl, heterocyclic, hydroxyl, CF3,
OCF3, 0(Ci-C 6)alkyl, O-(C3-Ci0)carbocycle, N0 2, C(0)-(Ci-C 6)alkyl, C(0)CH 2-halogen,
C(0)CH 2R3, NR5R , C0 2R , C(0)N(R 5)-A, N(R5)S(0) m-A, SH, S(0) (C1-C )alkyl,
-A, CN, OS0 3H, CHO, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (Ci-C6)alkyl-
NR5R6 and
R3 is independently selected from O-A, NR5R6, S(0) -A, S(0) -(Ci-C6)alkyl-C0 2(Ci-
C6)alkyl, S(0) -(Ci-C6)alkyl-OH, S(0) -(Ci-C6)alkyl-C0 2H, N(R5)C(0)-A, N(R5)C(0)0-A,
N(R5)C(0)N(R 5)-A, N(R5)S(0) m-A, N(R5)C(0)-heterocyclic and N(R5)C(S)N(R5)-A;
R4 is hydrogen or A;
R 5 and R 5 is independently selected from hydrogen, (Ci-C )alkyl, (Ci-C )alkyl-(C3-
Cio)carbocycle and (C3-Cio)carbocycle;
R and R is independently selected from hydrogen, A, (Ci-C )alkyl-OH, (Ci-C )alkyl-
NR5
'R6
'
, CH(CH2OH)-aryl, CH(CH2OH)2, (Ci-C6)alkyl-aryl, (Ci-C6)alkyl-heterocyclic and
(Ci-C )alkyl-heteroaryl;
R5 and R or R 5 and R together with the nitrogen to which they are attached may form a 3 to
8 membered monocyclic or 8 to 12 membered bicyclic heterocycle ring, which ring
optionally contains an additional heteroatom selected from O, S or N and the said ring is
optionally substituted by one or more R 9 or Rio substituent. The nitrogen of said ring may
also form N-oxide. In bicyclic heterocyclic system, the rings can be attached to each other in
a spiro or fused manner;
R is hydrogen or A;
Each s is independently 1-2 substituents and each selected from hydrogen, halogen, A, CN,
CHO, C(0)-A, C(0)CH 2-halogen, C(0)CH 2R3, hydroxyl, CF3, OCF3, NR5R6, N(R5)C(0)-A,
N(R5)S(0) m-A, C(0)N(R 5)-A, 0-(Ci-C 6)alkyl, O-(C3-Ci0)carbocycle, S(0) -A and
S(0) mN(R5)-A, wherein R and R are simultaneously not hydrogen;
R is independently selected from hydrogen, halogen, A, hydroxyl, CF3, OCF3, 0(Ci-
C6)alkyl, O-(C3-Ci0)carbocycle, N0 2, C(0)-A, C(0)CH 2-halogen, C(0)CH 2R3, NR5R6,
N(R5)C(0)0-A, N(R5)C(0)N(R 5)-A, N(R5)C(S)N(R5)-A, C0 2R , C(0)N(R 5)-A, CN, CHO,
(Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (Ci-C6)alkyl-aryl, (Ci-C6)alkyl-NR5R6, ( -
C6)alkyl-N(R5)C(0)0-A, (Ci-C6)alkyl-N(R5)C(0)N(R 5)-A, (Ci-C6)alkyl-N(R5)C(S)N(R5)-A,
(Ci-C6)alkyl-OC(0)N(R 5)-A and N(R5)S(0) m-A;
Rio is selected from hydrogen, halogen, A, hydroxyl, (Ci-C )alkyl-(C3-Cio)carbocycle, (Ci-
C6)alkyl-aryl, C(0)-A, C0 2R , C(0)N(R 5)-A, C(0)(Ci-C 6)alkyl-A, oxo, thio, =N-OH, =N-
0-(Ci-C 6)alkyl, 0-(Ci-C 6)alkyl, O-(C3-Ci0)carbocycle, O-aryl, O-heteroaryl, S(0) -A,
NR5R6, N(R5)C(0)-A, N(R5)C(0)0-A, N(R5)C(0)N(R 5)-A, N(R5)S(0) m-A, N(R5)C(0)-
heterocyclic and N(R5)C(S)N(R5)-A;
m is 1 or 2;
n is 0, 1 or 2.
2. A compound of formula (I) according to claim 1, wherein;
X is O, NH or S(0) ;
Ri and R2 is independently selected from hydrogen, A, CHO, CH2OH, CH2R3, CH2-halogen,
N(R5)C0 2R4, C(0)NR 5R6, C0 2R and C(0)-A;
R is independently selected from CN, CHO, C(0)-A, NR5R6, N(R5)C(0)-A, N(R5)C(0)0-A,
N(R5)C(0)N(R 5)-A, C(0)N(R 5)-A, (Ci-C6)alkyl-OR , (Ci-C6)alkyl-halogen, (Ci-C6)alkyl-
N3, (Ci-C6)alkyl-NR5R6, (Ci-C6)alkyl-N(R5)C(0)-A, (Ci-C6)alkyl-N(R5)C(0)0-A, (d-
C6)alkyl-N(R5)C(0)N(R 5)-A and (Ci-C6)alkyl-OC(0)N(R 5)-A;
A is independently selected from (Ci-C )alkyl, (C3-Cio)carbocycle, aryl, heteroaryl and
heterocyclic, the said (Ci-C )alkyl, aryl or heteroaryl may be further substituted with 1-3
substituents independently selected from halogen, (Ci-C )alkyl, (C3-Cio)carbocycle, aryl,
heterocyclic, hydroxyl, CF3, 0(Ci-C 6)alkyl, N(R5)S(0) m-A and ( -C6)alkyl-OR , each aryl
may be further substituted with 1-3 substituents independently selected from halogen, (Ci-
C6)alkyl, hydroxyl, OS0 3H, 0(Ci-C 6)alkyl and
R3 is independently selected from O-A, NR5R6, S(0) -A, S(0) -(Ci-C6)alkyl-C0 2(Ci-
C6)alkyl and S(0) -(Ci-C6)alkyl-OH;
R4 is hydrogen or A;
R5 is hydrogen or (Ci-C )alkyl;
R is independently selected from hydrogen, A, (Ci-C )alkyl-OH, CH(CH2OH)-aryl,
CH(CH2OH)2, (Ci-C6)alkyl-aryl, (Ci-C6)alkyl-heterocyclic and (Ci-C6)alkyl-heteroaryl;
R 5 and R together with the nitrogen to which they are attached may form a 3 to 8 membered
monocyclic heterocycle ring, which ring contains an additional heteroatom selected from O,
S and N and the said ring is substituted by R9; the nitrogen of said ring may also form Noxide;
R7 is hydrogen or A, which is (Ci-C )alkyl;
R s is hydrogen or A, which is (Ci-C )alkyl;
R9 is hydrogen, hydroxyl or A, which is (Ci-C )alkyl;
n is 0;
m is 2.
3. A compound selected from the group consisting of:
7-[4-( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)phenoxy] -N-[2-(morpholin-4-yl)ethyl]imidazo [2,1-
b][1,3]benzothiazole-2-carboxamide
7-[4-({ [3-tert-butyl- l-(4-methylphenyl)-lH-pyrazol-5-yl]carbamoyl} amino)phenoxy]-N-[2
(moholin-4-yl)ethyl]imidazo[2, 1-b] [1,3]benzothiazole-2-carboxamide
7-[4-({ [3-tert-butyl- l-(4-methylphenyl)-lH-pyrazol-5-yl]carbamoyl} amino)phenoxy]-N-(2
hydroxy- 1-phenylethyl)imidazo[2, 1-b] [1,3]benzothiazole-2-carboxamide
7-[4-({ [3-tert-butyl- l-(4-methylphenyl)-lH-pyrazol-5-yl]carbamoyl} amino)phenoxy]-N-(2
hydroxyethyl)imidazo[2, 1-b] [1,3]benzothiazole-2-carboxamide
ethyl 7-[4-( {[3-tert-butyl- 1-(3-chloro-4-methoxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
7-[4-( {[3-tert-butyl- 1-(3-chloro-4-methoxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylic acid
7-[4-( {[3-tert-butyl- 1-(3-chloro-4-methoxyphenyl)- lH-pyrazol-5-
yl]carbamoyl}amino)phenoxy]-N-(2-hydroxyethyl)imidazo[2,l-b][l,3]benzothiazole-3-
carboxamide
7-[4-( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylic acid
7-{[4-({ [3-tert-butyl- l-(4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)phenyl]sulfanyl }imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylic acid
7-{[4-( {[3-tert-butyl- 1-(4-methoxyphenyl)- -pyrazol-5-
yl]carbamoyl}amino)phenyl]sulfanyl}imidazo[2,l-b][l,3]benzothiazole-3-carboxylic acid
7-{[4-({ [3-tert-butyl- 1-(4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl}amino)phenyl]sulfanyl}-N-(2-hydroxyethyl)imidazo[2,l-b][l,3]benzothiazole
3-carboxamide
ethyl 7-{2-[({ [3-tert-butyl-l-(4-methoxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
7-{2-[( {[3-tert-butyl- 1-(4-hydroxyphenyl)- 1H-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylic acid
7-{2-[( {[3-tert-butyl- 1-(4-hydroxyphenyl)- 1H-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }-N-(2-hydroxyethyl)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxamide
1-[3-tert-butyl- 1-(4-methoxyphenyl)- lH-pyrazol-5-yl] -3-(4- {[3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }phenyl)urea
1-[3-tert-butyl- 1-(4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(2- {[3-(hydroxymethyl)imidazo[2, 1
b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
Ethyl 7-{2-[({[3-tert-butyl-l-(4-hydroxyphenyl)-lH-pyrazol-5-yl]
carbamoyl }amino)methyl]phenoxy}imidazo[2,l-b][l,3]benzothiazole-3-carboxylate
1-[3-tert-butyl- 1-(4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(4- {[3-(hydroxymethyl)imidazo[2, 1
b][1,3]benzothiazol-7-yl] sulfanyl }phenyl)urea
7-{2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylic acid
7-{2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }-N-(2-hydroxyethyl)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxamide
7-{2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }-N-( 1,3-dihydroxypropan-2-yl)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxamide
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{ [3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }benzyl)urea
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-{2-[(3-{[(2-
hydroxyethyl)sulfanyl] methyl }imidazo[2, 1-b] [1,3]benzothiazol-7-yl)oxy]benzyl}urea
7-({2-[({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl }amino)methyl]phenyl }sulfanyl)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxyl
acid
ethyl 7-{2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[4-( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-
yl]carbamoyl} amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(4-{ [3-
(hydroxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy }phenyl)urea
7-{2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl}amino)methyl]phenoxy}-N-(2-hydroxyethyl)-N-methylimidazo[2,lb][
1,3]benzothiazole-3-carboxamide
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-yl]-3-(2- {[3-(thiomorpholin-4-
ylmethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
ethyl {[(7- {2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazol-2-
yl)methyl]sulfanyl} acetate
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{ [3-
(methoxymethyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy}benzyl)urea
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-{2-[(3-{[(2-
hydroxyethyl)(methyl)amino]methyl }imidazo[2, 1-b] [1,3]benzothiazol-7-yl)oxy]benzyl}urea
N-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-4-{[3-(morpholin-4-
ylcarbonyl)imidazo[2, 1-b] [1,3]benzothiazol-7-yl]oxy Jbenzamide
methyl {[(7- {2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazol-3-
yl)methyl]sulfanyl} acetate
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(2- {[3-(morpholin-4-
ylmethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(2- {[3-(morpholin-4-
ylcarbonyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-yl]-3-(2- {[3-(methoxymethyl)-2-
methylimidazo [2, 1-b] [1,3]benzothiazol-7 -yl]oxy}benzyl)urea
1-(3-tert-butyl- 1-phenyl- 1H-pyrazol-5-yl)-3-(2- {[3-(hydroxymethyl)-2-methylimidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
2-methoxyethyl (7- {2-[({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazol-3-yl)carbamate
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[2-methyl-3-
7-(4- {[(2-hydroxy- 1-phenylethyl)carbamoyl] amino }phenoxy)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxylic acid
ethyl 7-[2-({ [(2-hydroxy- l-phenylethyl)carbamoyl] aminojmethyl) phenoxy]imidazo[2,lb][
1,3]benzothiazole-3-carboxylate
ethyl 7-(4-{ [(5-methyl-3-phenyl-l,2-oxazol-4-yl)carbamoyl] amino }phenoxy)imidazo [2,1-
b][1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({ [(3-chloro-4-methoxyphenyl)carbamoyl] amino }methyl)phenoxy]imidazo[2,lb][
1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({[(3,5-dimethoxyphenyl)carbamoyl] aminojmethyl) phenoxy]imidazo[2,lb][
1,3]benzothiazole-3-carboxylate
ethyl 7-(2-{[(cyclohexylcarbamoyl)amino]methyl}phenoxy)imidazo[2,lb][
1,3]benzothiazole-3-carboxylate
ethyl 7-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl} amino) phenoxy]imidazo[2,lb][
,3]benzothiazole-3-carboxylate
1-(3-chloro-4-methoxyphenyl)-3-(2- {[3-(methoxymethyl)-2-methylimidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
l-[4-chloro-3-(trifluoromethyl)phenyl]-3-(2-{[3-(methoxymethyl)-2-methylimidazo[2,lb][
l,3]benzothiazol-7-yl]oxy}benzyl)urea
1-(3-tert-butyl-1,2-oxazol-5-yl)-3-(2- {[3-(methoxymethyl)-2-methylimidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
ethyl 7-(2-formylphenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-(hydroxymethyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-(chloromethyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-(azidomethyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-(aminomethyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
hydrochloride
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-({ 3-
[(cyclopropylmethoxy)methyl]imidazo[2, 1-b] [1,3]benzothiazol-7-yl }oxy)benzyl]urea
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-
(chloromethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
ethyl 7-[(4-nitrophenyl)sulfanyl]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[(4-aminophenyl)sulfanyl]imidazo[2,l-b][l,3]benzothiazole-3-carboxylate
Ethyl 7-{[4-({[3-tert-butyl-l-(4-methoxyphenyl)-lH-pyrazol-5-yl] carbamoyl} amino)
phenyl] sulfanyl} imidazo [2,l-b][l,3]benzothiazole-3-carboxylate
ethyl 7-(4-nitrophenoxy)imidazo[2,l-b][l,3]benzothiazole-3-carboxylate
ethyl 7-(4-aminophenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-
(ethoxymethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(2-{[3-(5-methyl-l,3-
oxazol-2-yl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
l-[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-({3-[(4-
hydroxypiperidin-l-yl)methyl]imidazo[2,l-b][l,3]benzothiazol-7-yl}oxy)benzyl]urea
methyl 7-(2-{ [({5-tert-butyl-2-methoxy-3-[methyl(methylsulfonyl) amino]phenyl}
carbamoyl)amino]methyl } phenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({ [(3-tert-butyl-l-phenyl-lH-pyrazol-5-yl)carbamoyl] amino}
methyl)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-(2-{ [(propylcarbamoyl)amino]methyl}phenoxy)imidazo[2,l-b][l,3] benzothiazole-3-
carboxylate
ethyl 7-(2- {[(piperidin-4-ylcarbamoyl)amino]methyl }phenoxy)imidazo[2, 1-
b][1,3]benzothiazole-3-carboxylate
ethyl 7-[2-({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino)phenoxy]imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-{2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl] -5-methylphenoxy }-5-methylimidazo[2, 1-b] [1,3]benzothiazole-
3-carboxylate
ethyl 7-{[3-({ [3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino)phenyl]amino}imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 7-{[4-( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl} amino)phenyl]amino}imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
N-(5-tert-butyl-2-methoxy-3- {[(2- {[3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl) carbamoyl] amino }phenyl) methanesulfonamide
N-(5-tert-butyl-2-methoxy-3- {[(2- {[3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)carbamoyl]amino} phenyl) ethanesulfonamide
N-(5-tert-butyl-2-methoxy-3- {[(2- {[3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)carbamoyl]amino}phenyl)-N-methylethanesulfonamide
N-(5-tert-butyl-2-methoxy-3- {[(2- {[3-(morpholin-4-ylmethyl)imidazo[2, 1-
b][l,3]benzothiazol-7-yl]oxy}benzyl)carbamoyl]amino}phenyl)-Nmethylmethanesulfonamide
Methyl 7-{4-[({[3-tert-butyl-l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-
yl]carbamoyl} amino)methyl]phenoxy }imidazo[2, 1-b] [1,3]benzothiazole-3-carboxylate
ethyl 6-{2-[( {[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- lH-pyrazol-5-
yl]carbamoyl }amino)methyl] -4-fluorophenoxy }pyrrolo[2, 1-b] [1,3]benzothiazole- 1-
carboxylate
ethyl 7-(2-{[(phenoxycarbonyl)amino] methyl Jphenoxy) imidazo[2,l-b][l,3]benzothiazole-
3-carboxylate
4-(3-tert-butyl-5- {[(2- {[3-(moholin-4-ylmethyl)imidazo[2, 1-b] [ 1,3]benzothiazol-7-
yl]oxy}benzyl)carbamoyl]amino}-lH-pyrazol-l-yl)-2-chlorophenyl beta-Dglucopyranosiduronic
acid
4-(3-tert-butyl-5-{[(2-{[3-(mo holin-4-ylmethyl)imidazo[2,l-b][l,3]benzothiazol-7-
yl]oxy}benzyl)carbamoyl] amino }-1H-pyrazol- 1-yl)-2-chlorophenyl hydrogen sulfate
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-({3-[(4-
oxidomorpholin-4-yl)methyl]imidazo[2, 1-b] [1,3]benzothiazol-7-yl}oxy)benzyl]urea
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(2- {[3-(morpholin-4-
ylmethyl)-l-oxidoimidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl] -3-(2- {[3-(morpholin-4-
ylmethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea: Dihydrochloride
1-[3-tert-butyl- 1-(3-chloro-4-hydroxyphenyl)- 1H-pyrazol-5-yl]-3-(2- {[3-(morpholin-4-
ylmethyl)imidazo[2,l-b][l,3]benzothiazol-7-yl]oxy}benzyl)urea: Dimethanesulfonate
ethyl 6,8-bis(acetylamino)-7-(4-nitrophenoxy)imidazo[2, 1-b] [1,3]benzothiazole-3-
carboxylate
1-[3-tert-butyl- l-(3-chloro-4-hydroxyphenyl)-lH-pyrazol-5-yl]-3-[2-(imidazo[2,lb][
l,3]benzothiazol-7-yloxy)benzyl]urea and pharmaceutically acceptable salts thereof.
4. A pharmaceutical composition comprising a therapeutically effective amount of one or
more compound of claim 1 to 3, in admixture with a pharmaceutically acceptable adjuvant or
carrier.
5. A method of treating allergic and non-allergic airway diseases in a mammal, including
human being, the method comprising administering a therapeutically effective amount of a
compound of claim 1 to 3.
6. A method according to claim 5, wherein allergic and non-allergic airway disease is
selected from chronic obstructive pulmonary disease and asthma.
7. Use of a compound as claimed in claim 1 to 3 for the preparation of a medicament for
treating allergic and non-allergic airway diseases.
8. Use according to claim 7, wherein allergic and non-allergic airway disease is selected from
chronic obstructive pulmonary disease and asthma.
9. A compound of formula (I), its process for the preparation and pharmaceutical
composition, as herein described with reference to the examples accompanying the
specification.