U.S. patent application number 15/520799 was filed with the patent office on 2017-11-02 for substituted 1,2,3-triazol-1-yl-methyl-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazo- les as anti-mycobacterial agents and a process for the preparation thereof.
This patent application is currently assigned to COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH. The applicant listed for this patent is COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH. Invention is credited to Inshad Ali KHAN, Gurunadham MUNAGALA, Sumit SHARMA, Parvinder Pal SINGH, Samsher SINGH, Ram Asrey VISHWAKARMA, Kushalava Reddy YEMPALLA.
Application Number | 20170313721 15/520799 |
Document ID | / |
Family ID | 54361129 |
Filed Date | 2017-11-02 |
United States Patent
Application |
20170313721 |
Kind Code |
A1 |
YEMPALLA; Kushalava Reddy ;
et al. |
November 2, 2017 |
SUBSTITUTED
1,2,3-TRIAZOL-1-YL-METHYL-2,3-DIHYDRO-2-METHYL-6-NITROIMIDAZO[2,1-B]OXAZO-
LES AS ANTI-MYCOBACTERIAL AGENTS AND A PROCESS FOR THE PREPARATION
THEREOF
Abstract
The present invention relates to new generation of triazole
functionality containing 6-nitro-2,3-dihydroimidazooxazole agents
for general formula I, their method of preparation and their use as
drugs for treatment of tuberculosis, MDR-TB and XDR-TB either alone
or in combination with other anti-tubercular agents. In general
formula 1, X is selected from a group (CH.sub.2).sub.n or a direct
bond, where n is any number from 1-6, Y is selected from O, S or
direct bond, R.sub.1 is selected from the group consisting of H,
alkyl, substituted alkyl, aryl, substituted aryl, biaryl,
substituted biaryl, heterocyclic and substituted heterocyclic,
wherein the substituted heterocyclic is selected from any of the
following rings consisting of piperazinyl, morpholinyl, piperidyl,
pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl and benzothiazolyl and the
substitution on aryl and biaryl is selected from the group
consisting of F, CI, Br, I, CF.sub.3, OCF.sub.3, OR.sub.11,
NO.sub.2 and alkyl chain from C1 to C14, wherein R.sub.11 is
selected from the group consisting of H, alkyl, phenyl and
substituted phenyl. ##STR00001##
Inventors: |
YEMPALLA; Kushalava Reddy;
(Jammu, IN) ; MUNAGALA; Gurunadham; (Jammu,
IN) ; SINGH; Samsher; (Jammu, IN) ; SHARMA;
Sumit; (Jammu, IN) ; KHAN; Inshad Ali; (Jammu,
IN) ; VISHWAKARMA; Ram Asrey; (Jammu, IN) ;
SINGH; Parvinder Pal; (Jammu, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH |
New Delhi |
|
IN |
|
|
Assignee: |
COUNCIL OF SCIENTIFIC &
INDUSTRIAL RESEARCH
New Delhi
IN
|
Family ID: |
54361129 |
Appl. No.: |
15/520799 |
Filed: |
September 9, 2015 |
PCT Filed: |
September 9, 2015 |
PCT NO: |
PCT/IN2015/050111 |
371 Date: |
April 20, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 498/04 20130101;
A61P 31/06 20180101 |
International
Class: |
C07D 498/04 20060101
C07D498/04 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 21, 2014 |
IN |
3009/DEL/2014 |
Claims
1. A compound of general formula I, ##STR00056## wherein `X` is
selected from a group (CH.sub.2).sub.n or a direct bond, where n is
any number from 0, 1, 2 to 6, `Y` is selected from a group O, S or
direct bond, R.sub.I is selected from the group consisting of H,
alkyl, substituted alkyl, aryl, substituted aryl, biaryl,
substituted biaryl, heterocyclic and substituted heterocyclic,
wherein the substituted heterocyclic is selected from any of the
following rings consisting of piperazinyl, morpholinyl, piperidyl,
pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl and benzothiazolyl and the
substitution on aryl and biaryl is selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, OR.sub.I1,
NO.sub.2 and alkyl chain from C1 to C14, wherein R.sub.I1 is
selected from the group consisting of H, alkyl, phenyl, substituted
phenyl.
2. The compound of formula I as claimed in claim 1, wherein the
compound is selected from the group consisting of the following
compounds:
(R)-2-{[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.1)
(R)-2-{[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.2)
(R)-2-{[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.3)
(R)-2-{[4-(4-fluoro-3-methylphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.4)
(R)-2-{[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.5)
(R)-2-{[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihydro-2-m-
ethyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.6)
(R)-2-[(4-pentyl-1H-1,2,3-triazol-1-yl)methyl]-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound I.sub.7)
(R)-2-{[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.8)
(R)-2-{[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.9)
(R)-2-{[4-(3-chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.10)
(R)-2-{[4-(4-bromophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.11)
(R)-2-{[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.12)
(R)-2-{[4-(3-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.13)
(R)-2-{[4-(2-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.14)
(R)-2-{[4-(4-ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.15)
(R)-2-{[4-(3-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.16)
(R)-2-{[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.17)
(R)-2-{[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-d-
ihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.18)
(R)-2-methyl-6-nitro-2-((4-((pyridin-2-yloxy)methyl)-1H-1,2,3-triazol-1-y-
l)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.19)
(R)-2-methyl-6-nitro-2-((4-((p-tolylthio)methyl)-1H-1,2,3-triazol-1-yl)me-
thyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.20)
(R)-2-methyl-6-nitro-2-((4-(2-(p-tolyloxy)ethyl)-1H-1,2,3-triazol-1-yl)me-
thyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.21)
(R)-2-methyl-2-((4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-nit-
ro-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.22)
3. The compound of general formula I as claimed in claim 1, for use
in the treatment of tuberculosis.
4. The compound of formula I as claimed in claim 1, wherein said
compound exhibits an in vitro anti-tuberculosis activity against
replicating and non-replicating stages of Mycobacterium
tuberculosis with MIC values in the range of 0.12 to 32
.mu.g/ml.
5. The compound of formula I as claimed in claim 1, wherein said
compound exhibits an in vitro anti-tuberculosis activity against
XDR Mycobacterium tuberculosis (resistant to isoniazid, rifampicin,
amikacin and moxifloxacin), MDR-TB (resistant to isoniazid and
rifampicin) with MIC values in the range of 0.12 to 32 .mu.g/ml and
the compound does not exhibit any cytotoxicity up to 40 .mu.g/ml in
macrophage J774 cell line.
6. A process for preparation of the compound of formula I as
claimed in claim 1 wherein the said process comprising the steps:
i) reacting a compound of formula 8 in an organic solvent and in
the presence of an azide source at a temperature in the range of
25.degree. C. to 80.degree. C. for a period ranging between 1 h to
3 h to obtain a compound of formula 9; ##STR00057## ii) reacting
the compound of formula 9 in an organic solvent and in the presence
of a base at a temperature in the range of 10.degree. C.-25.degree.
C. for a period of 1 h to 12 h to obtain a compound of formula 10;
##STR00058## iii) reacting the compound of formula 10 with a
compound of formula selected from the group consisting of formula
13 (a-k) or 14 (a-g) or 15 (a-d) in 1:1 tert-BuOH/H.sub.2O mixture
in the presence of sodiumascorbate and CuSO.sub.4 at a temperature
in the range of 10.degree. C. to 25.degree. C. for a period of 1 h
to 12 h to obtain the compound of formula I. ##STR00059##
7. The process as claimed in step i) of claim 6, wherein the
organic solvent is selected from toluene, acetonitrile, DMF,
dichloroethane or any combination thereof.
8. The process as claimed in step i) of claim 6, wherein the azide
source is selected from sodiumazide, trimethylsilylazide,
tetrabutyl ammonium bromide or any combination thereof.
9. The process as claimed in step ii) of claim 6, wherein the base
is selected from sodium hydride, cesium carbonate, potassium
carbonate or any combination thereof.
10. The process as claimed in step ii) of claim 6, wherein the
organic solvent is selected from toluene, acetonitrile, DMF,
tetrahydrofuran or any combination thereof.
11. The compound of formula I as claimed in claim 2, wherein said
compound exhibits an in vitro anti-tuberculosis activity against
replicating and non-replicating stages of Mycobacterium
tuberculosis with MIC values in the range of 0.12 to 32
.mu.g/ml.
12. The compound of formula I as claimed in claim 2, wherein said
compound exhibits an in vitro anti-tuberculosis activity against
XDR Mycobacterium tuberculosis (resistant to isoniazid, rifampicin,
amikacin and moxifloxacin), MDR-TB (resistant to isoniazid and
rifampicin) with MIC values in the range of 0.12 to 32 .mu.g/ml and
the compound does not exhibit any cytotoxicity up to 40 .mu.g/ml in
macrophage J774 cell line.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to substituted
1,2,3-triazol-1-yl-methyl-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazo-
lesas anti-mycobacterial agents. The present invention particularly
relates to the compounds of 6-nitro-2,3-dihydroimidazooxazole
scaffold that have been designed, synthesized and their biological
evaluation result for anti-tuberculosis are presented. The present
invention relates to novel compounds of general formula I, their
method of preparations, and their use as drugs for treatment of
tuberculosis.
BACKGROUND OF THE INVENTION
[0002] Tuberculosis remains a leading infectious cause of death
worldwide and infects about one-third of the world's population.
The World Health Organization (WHO) has estimated that if the
present conditions remain unchanged, more than 30 million lives
will be claimed by TB between 2000 and 2020. In 2012, an estimated
8.6 million people developed TB and 1.3 million died from the
disease (including 320 000 deaths among HIV-positive people). TB
has also been declared as a global health emergency because of the
increase in secondary infections and/or co-infection in cancer and
immunocompromised patients (such as those infected with human
immunodeficiency virus). The existing lengthy TB therapy and
emergence of multidrug resistant TB (MDR-TB) and extensively drug
resistant TB (XDR-TB), [BemerMelchior, P.; Bryskier, A.; Drugeon,
H. B. J. Antimicrob. Chemother. 2000, 46, 571; Abubaker, J.;
Schraufnagel, D. J. Am. Med. Assoc. 2000, 283, 54; Dye. C.;
Scheele, S.; Dolin, P.; Pathania, V.; Raviglione, M. C. J. Am. Med.
Assoc. 1999, 282, 677] necessitates the development of new and
potent anti-tuberculosis agents.
[0003] In this direction, we have initiated a medicinal chemistry
programme on 6-nitro-2,3-dihydroimidazooxazole scaffold and
discovered new potent structures (2954/DEL/2013) and in
continuation, in the present invention, new generation triazole
functionality containing 6-nitro-2, 3-dihydroimidazooxazole is
synthesized and screened for anti-TB activity.
OBJECTIVE OF THE INVENTION
[0004] The main objective of the present invention is to provide
new generation triazole functionality containing 6-nitro-2,
3-dihydroimidazooxazoles agents for treatment of tuberculosis.
[0005] Still another object of the present invention is to provide
a process for the preparation of triazole functionality containing
6-nitro-2, 3-dihydroimidazooxazoles.
[0006] Still another object of the present invention is to provide
treatment against multi-drug resistant (MDR) and extensive drug
resistant (XDR) tuberculosis.
SUMMARY OF THE INVENTION
[0007] The present invention relates to new generation of triazole
functionality containing 6-nitro-2, 3-dihydroimidazooxazole agents,
their method of preparation and their use as drugs for treatment of
tuberculosis.
[0008] Accordingly the present invention provides a compound having
a general structure of formula I,
##STR00002##
[0009] wherein, [0010] `X` is selected from a group
(CH.sub.2).sub.n or a direct bond, where n is any number from 0, 1,
2 to 6, [0011] `Y` is selected from a group O, S or direct bond,
[0012] R.sub.I is selected from the group consisting of H, alkyl,
substituted alkyl, aryl, substituted aryl, biaryl, substituted
biaryl, heterocyclic and substituted heterocyclic, wherein the
substituted heterocyclic is selected from any of the following
rings consisting of piperazinyl, morpholinyl, piperidyl, pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl and benzothiazolyl and the
substitution on aryl and biaryl is selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, OR.sub.I1,
NO.sub.2 and alkyl chain from C1 to C14. [0013] wherein R.sub.I1 is
selected from the group consisting of H, alkyl, phenyl, substituted
phenyl. [0014] In an embodiment of the present invention, the
representative compound of general formula I comprising: [0015]
(R)-2-{[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.1, Table 1) [0016]
(R)-2-{[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.2, Table 1) [0017]
(R)-2-{[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.3, Table 1)
[0018]
(R)-2-{[4-(4-fluoro-3-methylphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.4, Table
1) [0019]
(R)-2-{[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-d-
ihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.5,
Table 1) [0020]
(R)-2-{[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.6, Table
1) [0021]
(R)-2-[(4-pentyl-1H-1,2,3-triazol-1-yl)methyl]-2,3-dihydro-2-methy-
l-6-nitroimidazo[2,1-b]oxazole (compound I.sub.7, Table 1) [0022]
(R)-2-{[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.8, Table 1) [0023]
(R)-2-{[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.9, Table 1) [0024]
(R)-2-{[4-(3-chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.10, Table
1) [0025]
(R)-2-{[4-(4-bromophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.11,
Table 1) [0026]
(R)-2-{[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.12, Table 1) [0027]
(R)-2-{[4-(3-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.13, Table
1) [0028]
(R)-2-{[4-(2-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.14, Table 1) [0029]
(R)-2-{[4-(4-ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.15, Table 1) [0030]
(R)-2-{[4-(3-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.16, Table
1) [0031]
(R)-2-{[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.17, Table 1) [0032]
(R)-2-{[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]met-
hyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.18, Table 1) [0033]
(R)-2-methyl-6-nitro-2-((4-((pyridin-2-yloxy)methyl)-1H-1,2,3-triazol-1-y-
l)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.19,
Table 1) [0034]
(R)-2-methyl-6-nitro-2-((4-((p-tolylthio)methyl)-1H-1,2,3-triazol--
1-yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.20,
Table 1) [0035]
(R)-2-methyl-6-nitro-2-((4-(2-(p-tolyloxy)ethyl)-1H-1,2,3-triazol--
1-yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.21,
Table 1) [0036]
(R)-2-methyl-2-((4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)methyl-
)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.22,
Table 1)
[0037] In an embodiment of the invention wherein the compound of
general formula I, for use in treatment of tuberculosis.
[0038] In yet another embodiment of the invention of general
formula I, wherein said compound exhibits an in-vitro
anti-tuberculosis activity against H.sub.37Rv Mycobacterium
tuberculosis, MDR-TB (resistant to isoniazid and rifampicin) with
MIC values in the range of 0.12 to 32 .mu.g/ml.
[0039] In still another embodiment of the invention of general
formula I, wherein said compound exhibits an in vitro
anti-tuberculosis activity against XDR-TB (resistant to isoniazid,
rifampicin, amikacin and moxifloxacin) with MIC values in the range
of 0.12 to 32 (.mu.g/ml).
[0040] In another embodiment of the invention of general formula I,
wherein said compound does not exhibit any cytotoxicity upto 40
.mu.g/ml in macrophage J774 cell line.
[0041] The compound of formula I exhibits an in vitro
anti-tuberculosis activity against replicating and non-replicating
stages of Mycobacterium tuberculosis with MIC values in the range
of 0.12 to 32 .mu.g/ml.
[0042] The compound of formula I exhibits an in vitro
anti-tuberculosis activity against XDR Mycobacterium tuberculosis
(resistant to isoniazid, rifampicin, amikacin and moxifloxacin),
MDR-TB (resistant to isoniazid and rifampicin) with MIC values in
the range of 0.12 to 32 .mu.g/ml and the compound does not exhibit
any cytotoxicity upto 40 .mu.g/ml in macrophage J774 cell line.
[0043] The present invention also provides a process for
preparation of the compound of formula I wherein the said process
comprising the steps: [0044] i) reacting a compound of formula 8 in
an organic solvent selected from group consisting of toluene,
acetonotrile, DMF, dichloroethane or any combination thereof in the
presence of an azide source selected from sodiumazide,
trimethylsilylazide and tetrabutyl ammonium bromide at a
temperature in the range of 25.degree. C. to 80.degree. C. for a
period ranging between 1 h to 3 h to obtain the desired compound of
formula 9.
[0044] ##STR00003## [0045] ii) reacting the compound of formula 9
with a base selected from a group consisting of sodium hydride,
cesium carbonate, potassium carbonate or any combination thereof in
an organic solvent selected from a group consisting of toluene,
acetonotrile, DMF, tetrahydrofuran or any combination thereof in
the presence of at a temperature in the range of 10.degree.
C.-25.degree. C. for a period of 1 h to 12 h to obtain a desired
compound of formula 10.
[0045] ##STR00004## [0046] iii) reacting the compound of formula 10
with a compound of formula selected from the group consisting of
formula 13(a-k) or 14(a-g) or 15(a-d) in 1:1 tert-BuOH/H.sub.2O
mixture in the presence of sodiumascorbate and CuSO.sub.4 at a
temperature in the range of 10.degree. C. to 25.degree. C. for a
period of 1 h to 12 h to obtain the desired compound of formula
I.
##STR00005##
[0046] List of Abbreviations:
[0047] ATCC: american type culture collection [0048] AcOH: acetic
acid [0049] CFU: colony forming units [0050] DMAP:
4-dimethylaminopyridine [0051] DCM: dichloromethane [0052] d:
doublet [0053] dd: doublet of doublet [0054] Et: ethyl [0055] ESI:
electron spray ionisation [0056] FCS: fetal calf serum [0057]
H.sub.37Rv: a well characterised virulent strain of Mycobacterium
tuberculosis [0058] h: hours [0059] IC.sub.50: half maximal
inhibitory concentration [0060] J: coupling constant [0061] MIC:
minimum inhibitory concentration [0062] MS: mass spectrometry
[0063] ml: millilitre [0064] MHz: mega hertz [0065] m: multiplet
[0066] MDR-TB: Multi drug resistant tuberculosis [0067] Me: methyl
[0068] min: minutes [0069] m/z: mass to charge ratio [0070] MTB:
Mycobacterium tuberculosis [0071] NMP: N-methylpyrrolidinone [0072]
Rif.sup.R: rifampicin resistant tuberculosis [0073] RPMI: rosewell
park memorial institute medium [0074] R.sub.f: retention factor
[0075] s: singlet [0076] TFA: trifluoroacetic acid [0077] TLC: thin
layer chromatography [0078] TB: Tuberculosis [0079] TDR-TB: Total
drug resistant tuberculosis [0080] t: triplet [0081] tert: tertiary
[0082] WHO: world health organization [0083] XDR-TB: Extensive drug
resistant tuberculosis [0084] .mu.g: microgram [0085] .sup.1H NMR:
proton nuclear magnetic resonance
DETAILED DESCRIPTION OF THE INVENTION
[0086] The present invention relates to new generation of triazole
functionality containing 6-nitro-2, 3-dihydroimidazooxazole agents,
their method of preparation and their use as drugs for treatment of
tuberculosis.
[0087] The present invention describes a compound having general
structure of formula I
##STR00006##
[0088] wherein [0089] `X` is selected from a group (CH.sub.2).sub.n
or a direct bond, where n is any number from 0, 1, 2 to 6, [0090]
`Y` is selected from a group O, S or direct bond, [0091] RI is
selected from the group consisting of H, alkyl, substituted alkyl,
aryl, substituted aryl, biaryl, substituted biaryl, heterocyclic
and substituted heterocyclic, wherein the substituted heterocyclic
is selected from any of the following rings consisting of
piperazinyl, morpholinyl, piperidyl, pyridyl, triazolyl, triazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl,
thiophenyl, pyrrolyl, imidazoyl, thiazoyl, quinolinyl,
isoquinolinyl, benzooxazolyl and benzothiazolyl and the
substitution on aryl and biaryl is selected from the group
consisting of F, Cl, Br, I, CF3, OCF3, ORI1, NO2 and alkyl chain
from C1 to C14. [0092] wherein R.sub.I1 is selected from the group
consisting of H, alkyl, phenyl, substituted phenyl.
[0093] The most preferred compounds of general formula I are:
[0094]
(R)-2-{[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.1,
Table 1) [0095]
(R)-2-{[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]methyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.2, Table 1) [0096]
(R)-2-{[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.3,
Table 1) [0097]
(R)-2-{[4-(4-fluoro-3-methylphenyl)-1H-1,2,3-triazol-1-yl]methyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.4, Table 1) [0098]
(R)-2-{[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.5,
Table 1) [0099]
(R)-2-{[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-d-
ihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.6,
Table 1) [0100]
(R)-2-[(4-pentyl-1H-1,2,3-triazol-1-yl)methyl]-2,3-dihydro-2-methy-
l-6-nitroimidazo[2,1-b]oxazole (compound I.sub.7, Table 1) [0101]
(R)-2-{[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.8, Table 1) [0102]
(R)-2-{[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.9, Table 1) [0103]
(R)-2-{[4-(3-chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.10, Table
1) [0104]
(R)-2-{[4-(4-bromophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.ii,
Table 1) [0105]
(R)-2-{[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.12, Table 1) [0106]
(R)-2-{[4-(3-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.13, Table
1) [0107]
(R)-2-{[4-(2-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.14, Table 1) [0108]
(R)-2-{[4-(4-ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.15, Table 1) [0109]
(R)-2-{[4-(3-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound I.sub.16, Table
1) [0110]
(R)-2-{[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]methyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.17, Table 1) [0111]
(R)-2-{[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]met-
hyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
I.sub.18, Table 1) [0112]
(R)-2-methyl-6-nitro-2-((4-((pyridin-2-yloxy)methyl)-1H-1,2,3-triazol-1-y-
l)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.19,
Table 1) [0113]
(R)-2-methyl-6-nitro-2-((4-((p-tolylthio)methyl)-1H-1,2,3-triazol--
1-yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.20,
Table 1) [0114]
(R)-2-methyl-6-nitro-2-((4-(2-(p-tolyloxy)ethyl)-1H-1,2,3-triazol--
1-yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.21,
Table 1) [0115]
(R)-2-methyl-2-((4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)methyl-
)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (compound I.sub.22,
Table 1)
[0116] The compounds of general formula I, are useful in treatment
of tuberculosis. The compound of general formula I, exhibits an in
vitro anti-tuberculosis activity against H.sub.37Rv Mycobacterium
tuberculosis, MDR-TB (resistant to isoniazid and rifampicin) with
MIC values in the range of 0.12 to 32 .mu.g/ml.
[0117] The compound of general formula I, exhibits an in vitro
anti-tuberculosis activity against XDR-TB (resistant to isoniazid,
rifampicin, amikacin and moxifloxacin) with MIC values in the range
of 0.12 to 32 (.mu.g/ml).
[0118] The compound of general formula I does not exhibit any
cytotoxicity upto 40 .mu.g/ml in macrophage J774 cell line.
[0119] An embodiment of the invention; provides a process for the
preparation of a compound of formula 9, wherein the process step
comprising of the reaction of compound of formula 8 in an organic
solvent selected from toluene, acetonotrile, DMF, dichloroethaneor
any combination thereof in the presence of azide source selected
from sodiumazide, trimethylsilylazide, tetrabutyl ammonium bromide
or any combination thereof at a temperature in the range of
25.degree. C. to 80.degree. C. for a period of 1 h to 3 h to obtain
the desired compound of formula 9.
[0120] In another embodiment of the invention a process for the
preparation of the compound of formula 10, wherein the process step
comprising of the reaction of compound of formula 9 in an organic
solvent selected from toluene, acetonotrile, DMF, tetrahydrofuran
or any combination thereof in the presence of base selected from
sodium hydride, cesium carbonate, potassium carbonate or any
combination thereof at a temperature in the range of 10.degree. C.
to 25.degree. C. for a period of 1 h to 12 h to obtain the desired
compound of formula 10.
[0121] In another embodiment of the invention, a process for the
preparation of the compound of general formula I, wherein the
process step comprising the reacting compound of formula 10 with a
compound of formula selected from the group consisting of formula
13 or 14 or 15 in 1:1 tert-BuOH/H.sub.2O mixture in the presence of
sodium ascorbate and CuSO.sub.4 at a temperature in the range of
10.degree. C. to 25.degree. C. for a period of 1 h to 12 h to
obtain the desired compound of general formula I.
The present invention discloses process for synthesis of the
fragments A and B which in turn can be used for synthesis of
compounds of general formula I. The entire synthesis of compound I
is illustrated by Reaction Schemes 1 to 4 as given below: --
##STR00007##
##STR00008##
##STR00009##
##STR00010##
##STR00011##
EXAMPLES
Synthesis of Compounds:
[0122] The following examples are given by way of illustrating the
present invention and should not be construed to limit the scope of
the invention:
R)-3-(2-Chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxy-2-methylpropylmethanesu-
lfonate (8)
[0123] The synthesis of compound 8 was successfully synthesized
from a starting material 4-Nitroimidiazole 1 as shown in scheme 1
by following known procedure (Sasaki, H.; Haraguchi, Y.; Itotani,
M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.;
Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49,
7854.
Example 1
(R)-1-Azido-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methylpropan-2-ol
(9)
[0124] To a solution of
(R)-3-(2-Chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxy-2-methylpropyl
methanesulfonate (8) (10 mmol) in DMF (20 mL) was added sodium
azide (30 mmol) and tetrabutyl ammonium bromide (1 mmol). After the
solution was stirred at 80.degree. C. for 3 h, the reaction mixture
was extracted with ethyl acetate twice, and the combined organic
layer was washed with brine, dried over sodium sulphate, and
filtered. The filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography in 5%
DCM/Ethyl acetate to give the compound 9 as yellow colour solid.
The compound 9 is also prepared using the process as described
above using different solvents such as toluene, acetonitrile or
dichloroethane at 60-80.degree. C. for a period of 2-4 hr as given
in the following table.
TABLE-US-00001 Reactant Solvent Temp .degree. C. Time Reagents
Product (R)-3-(2-Chloro-4- Toluene 60 2 Sodium azide
(R)-1-Azido-3-(2- nitro-1H-imidazol-1- chloro-4-nitro-1H-
yl)-2-hydroxy-2- imidazol-1-y1)-2- methylpropyl methylpropan-2-ol
(9) methanesulfonate (8) (R)-3-(2-Chloro-4- Acetonitrile 60 4
Trimethylsily (R)-1-Azido-3-(2- nitro-1H-imidazol-1- lazide
chloro-4-nitro-1H- y1)-2-hydroxy -2- imidazol-1-y1)-2- methylpropyl
methylpropan-2-ol (9) methanesulfonate (8) (R)-3-(2-Chloro-4-
dichloroethane 80 2 Sodium azide (R)-1-Azido-3-(2-
nitro-1H-imidazol-1- chloro-4-nitro-1H- yl)-2-hydroxy-2-
imidazol-1-y1)-2- methylpropyl methylpropan-2-ol (9)
methanesulfonate (8)
Example 2
(R)-2-(Azidomethyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole
(10)
[0125] To a solution of
(R)-1-Azido-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methylpropan-2-ol
9)(10 mmol) in DMF (20 mL) was added cesium carbonate (30 mmol) at
below 15.degree. C. portion wise, After the solution was stirred
for 12 h at 25.degree. C., The reaction mixture was poured into the
ice water and extracted with ethyl acetate twice, and the combined
organic layer was washed with brine, dried over sodium sulphate,
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography to
give the compound 10 as yellow colour solid.
[0126] The reaction is also carried out by using the different
solvent such as toluene, acetonitrile or tetrahydrofurane at
25.degree. C. for a period of 6-12 hr. to produce the compound
10.
TABLE-US-00002 Reactant Solvent Tem. .degree. C. Time Reagents
Product (R)-1-Azido-3-(2- DMF 25 6 Sodium (R)-2-(Azidomethyl)-
chloro-4-nitro-1H- hydride 2-methy1-6-nitro-2,3- imidazol-1-y1)-2-
dihydroimidazo [2,1- methylpropan-2-ol (9) b] oxazole (10)
(R)-1-Azido-3-(2- Toluene 25 6 Sodium (R)-2-(Azidomethyl)-
chloro-4-nitro-1H- hydride 2-methy1-6-nitro-2,3- imidazol-1-y1)-2-
dihydroimidazo [2,1- methylpropan-2-ol (9) b] oxazole (10)
(R)-1-Azido-3-(2- Acetonitrile 25 12 Potassium (R)-2-(Azidomethyl)-
chloro-4-nitro-1H- carbonate 2-methy1-6-nitro-2,3-
imidazol-1-y1)-2- dihydroimidazo [2,1- methylpropan-2-ol (9) b]
oxazole (10) (R)-1-Azido-3-(2- tetrahydro- 25 12 Sodium
(R)-2-(Azidomethyl)- chloro-4-nitro-1H- furan carbonate
2-methy1-6-nitro-2,3- imidazol-1-y1)-2- dihydroimidazo [2,1-
methylpropan-2-ol (9) b] oxazole (10)
Example 3
[0127] General Procedure for the Preparation of Compounds (I.sub.1
to I.sub.22):
[0128]
(R)-2-(Azidomethyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazo-
le (10) (1 mmol) and 13 (a-k) or 14 (a-g) or 15 (a-d) suspended in
6 mL of a 1:1 tert-BuOH/H.sub.2O mixture. While the mixture was
being stirred, sodium ascorbate (0.1 mmol) was added, followed by
CuSO.sub.4 pentahydrate (0.02 mmol). Left stirring for 12 h at
25.degree. C., after which time it was diluted with water, and the
solid was filtered off. The crude was purified by silica gel column
chromatography to give the compounds I.sub.1 to I.sub.22.
(R)-2-Methyl-6-nitro-2-((4-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-
-yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.1, Table 1,
Scheme 3)
##STR00012##
[0130] TLC (EtOAc:DCM 1:9): R.sub.f=0.3; .sup.1H NMR (400 MHz,
Acetone) .delta. 8.50 (s, 2H), 8.01 (t, J=4.5 Hz, 7H), 7.39 (d,
J=8.0 Hz, 5H), 5.10 (q, J=14.9 Hz, 6H), 4.66 (d, J=11.2 Hz, 3H),
4.42 (d, J=11.2 Hz, 3H), 1.79 (s, 7H); MS (ESI+): m\z 410.0950.
(R)-2-Methyl-6-nitro-2-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1--
yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.2, Table 1,
Scheme 3)
##STR00013##
[0132] TLC (EtOAc:DCM 1:9): R.sub.f=0.45; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.74 (s, 1H), 8.07 (t, J=4.0 Hz, 3H), 7.81 (d, J=8.3
Hz, 2H), 5.05 (d, J=14.8 Hz, 1H), 4.98 (d, J=14.8 Hz, 1H), 4.44 (d,
J=11.3 Hz, 1H), 4.26 (d, J=11.3 Hz, 1H), 1.63 (s, 3H); MS (ESI+):
m\z 394.1001.
(R)-2-((4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl-6nitro-2-
,3-dihydro imidazo[2,1-b]oxazole (I.sub.3, Table 1, Scheme 3)
##STR00014##
[0134] TLC (EtOAc:DCM 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.54 (s, 1H), 8.05 (s, 1H), 7.87 (dd, J=8.7, 5.5 Hz,
2H), 7.28 (t, J=8.9 Hz, 2H), 5.01 (d, J=14.8 Hz, 1H), 4.95 (d,
J=14.8 Hz, 1H), 4.42 (d, J=11.3 Hz, 1H), 4.24 (d, J=11.2 Hz, 1H),
1.63 (s, 3H); MS (ESI+): m\z 344.1033.
(R)-2-((4-(4-Fluoro-3-methylphenyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl-
-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.4, Table 1, Scheme
3)
##STR00015##
[0136] TLC (EtOAc:DCM 1:9): R.sub.f=0.5; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.47 (s, 1H), 8.02 (s, 1H), 7.72 (d, J=7.0 Hz, 1H),
7.69-7.60 (m, 1H), 7.19 (t, J=9.1 Hz, 1H), 5.00 (d, J=14.8 Hz, 1H),
4.93 (d, J=14.8 Hz, 1H), 4.41 (d, J=11.3 Hz, 1H), 4.23 (d, J=11.3
Hz, 1H), 2.27 (s, 3H), 1.63 (s, 3H); MS (ESI+): m\z 358.1190.
(R)-2-((4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl-6-ni-
tro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.5, Table 1, Scheme
3)
##STR00016##
[0138] TLC (EtOAc:DCM 1:9): R.sub.f=0.25; .sup.1H NMR (500 MHz,
Acetone) .delta. 8.35 (d, J=3.6 Hz, 2H), 8.21 (dd, J=15.5, 8.8 Hz,
2H), 7.81 (s, 2H), 7.20-7.11 (m, 4H), 5.15 (q, J=14.9 Hz, 6H), 4.68
(d, J=11.1 Hz, 3H), 4.43 (d, J=11.1 Hz, 3H), 1.79 (s, 8H); MS
(ESI+): m\z 362.0939.
(R)-2-Methyl-6-nitro-2-((4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)-
-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.6, Table 1, Scheme 3)
##STR00017##
[0140] TLC (EtOAc:DCM 1:9): R.sub.f=0.25; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.47 (s, 1H), 8.02 (s, 1H), 7.82 (d, J=8.7 Hz, 2H),
7.41 (t, J=7.9 Hz, 2H), 7.16 (t, J=7.4 Hz, 1H), 7.05 (dd, J=8.1,
6.0 Hz, 4H), 5.00 (d, J=14.8 Hz, 1H), 4.93 (d, J=14.8 Hz, 1H), 4.42
(d, J=11.3 Hz, 1H), 4.24 (d, J=11.3 Hz, 1H), 1.63 (s, 3H); MS
(ESI+): m\z 418.1390.
(R)-2-[(4-Pentyl-1H-1,2,3-triazol-1-yl)methyl]-2,3-dihydro-2-methyl-6-nitr-
oimidazo[2,1-b]oxazole (I.sub.7, Table 1, Scheme 3)
##STR00018##
[0142] TLC (EtOAc:DCM 1:9): R.sub.f=0.5; .sup.1H NMR (400 MHz,
Acetone) .delta. 8.18 (s, 1H), 7.80 (s, 1H), 4.62 (d, J=11.2 Hz,
2H), 4.40 (d, J=11.2 Hz, 2H), 2.25 (t, 2H), 1.75 (s, 3H), 1.21 (m,
4H), 1.15 (m, 2H), 0.91 (m, 3H); MS (ESI+): m\z 320.1579.
(R)-2-Methyl-6-nitro-2-((4-((4-(trifluoromethoxy)phenoxy)methyl)-1H-1,2,3--
triazol-1-yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.8,
Table 1, Scheme 4)
##STR00019##
[0144] TLC (EtOAc:DCM 1:9): R.sub.f=0.45; .sup.1H NMR (400 MHz,
Acetone) .delta. 8.18 (s, 1H), 7.79 (s, 1H), 7.28 (d, J=9.2 Hz,
2H), 7.14 (d, J=9.2 Hz, 2H), 5.22 (s, 2H), 5.08 (q, J=14.9 Hz, 2H),
4.65 (d, J=11.2 Hz, 1H), 4.42 (d, J=11.2 Hz, 1H), 1.78 (s, 3H); MS
(ESI+): m\z 440.1056.
(R)-2-Methyl-6-nitro-2-((4-((4-(trifluoromethyl)phenoxy)methyl)-1H-1,2,3-t-
riazol-1-yl)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.9,
Table 1, Scheme 4)
##STR00020##
[0146] TLC (EtOAc:DCM 1:9): R.sub.f=0.15; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.23 (s, 1H), 8.05 (s, 1H), 7.65 (d, J=8.7 Hz, 2H),
7.20 (d, J=8.5 Hz, 2H), 5.23 (s, 2H), 4.97 (q, J=14.8 Hz, 2H), 4.39
(d, J=11.3 Hz, 1H), 4.23 (d, J=11.3 Hz, 1H), 1.59 (s, 3H); MS
(ESI+): m\z 424.1107.
(R)-2-((4(3-Chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl-6-
-nitro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.10, Table 1, Scheme
4)
##STR00021##
[0148] TLC (EtOAc:DCM 1:9): R.sub.f=0.25; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.21 (s, 1H), 8.05 (s, 1H), 7.30 (t, J=8.2 Hz, 1H),
7.11 (t, J=2.0 Hz, 1H), 6.99 (ddd, J=10.4, 8.2, 1.6 Hz, 2H), 5.14
(s, 2H), 4.96 (q, J=14.8 Hz, 2H), 4.39 (d, J=11.3 Hz, 1H), 4.22 (d,
J=11.3 Hz, 1H), 1.59 (s, 3H); MS (ESI+): m\z 390.0843.
(R)-2-(4-((4-Bromophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl-6-
-nitro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.11, Table 1, Scheme
4)
##STR00022##
[0150] TLC (EtOAc:DCM 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.20 (s, 1H), 8.04 (s, 1H), 7.44 (d, J=8.6 Hz, 2H),
6.98 (d, J=8.4 Hz, 2H), 5.11 (s, 2H), 4.96 (q, J=14.8 Hz, 2H), 4.38
(d, J=11.3 Hz, 1H), 4.22 (d, J=11.2 Hz, 1H), 1.58 (s, 3H); MS
(ESI+): m\z 434.0338.
(R)-2-Methyl-6-nitro-2-((4-((p-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)meth-
yl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.12, Table 1, Scheme
4)
##STR00023##
[0152] TLC (EtOAc:DCM 1:9): R.sub.f=0.3; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.17 (s, 1H), 8.05 (s, 1H), 7.08 (d, J=8.2 Hz, 2H),
6.88 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 5.02-4.88 (m, 2H), 4.38 (d,
J=11.3 Hz, 1H), 4.22 (d, J=11.3 Hz, 1H), 2.23 (s, 3H), 1.59 (s,
3H); MS (ESI+): m\z 370.1390.
(R)-2-Methyl-6-nitro-2-((4-((m-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)meth-
yl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.13, Table 1, Scheme
4)
##STR00024##
[0154] TLC (EtOAc:DCM 1:9): R.sub.f=0.3; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.17 (s, 1H), 8.03 (s, 1H), 7.15 (t, J=7.8 Hz, 1H),
6.77 (dd, J=16.5, 7.7 Hz, 3H), 5.07 (s, 2H), 4.95 (q, J=14.8 Hz,
2H), 4.38 (d, J=11.3 Hz, 1H), 4.22 (d, J=11.3 Hz, 1H), 2.26 (s,
3H), 1.58 (s, 3H); MS (ESI+): m\z 370.1390.
(R)-2-Methyl-6-nitro-2-((4-((o-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)meth-
yl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.14, Table 1, Scheme
4)
##STR00025##
[0156] TLC (EtOAc:DCM 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone) .delta. 8.14 (s, 7H), 7.78 (s, 6H), 7.12 (dt, J=22.2, 7.9
Hz, 26H), 6.85 (t, J=6.9 Hz, 8H), 5.17 (s, 21H), 5.07 (q, J=14.9
Hz, 27H), 4.62 (d, J=11.2 Hz, 12H), 4.40 (d, J=11.2 Hz, 12H), 2.13
(s, 20H), 1.77 (s, 36H); MS (ESI+): m\z 370.1390.
(R)-2-((4-((4-Ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl--
6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.15, Table 1, Scheme
4)
##STR00026##
[0158] TLC (EtOAc:DCM 1:9): R.sub.f=0.5; .sup.1H NMR (400 MHz,
Acetone) .delta. 8.11 (s, 1H), 7.79 (s, 1H), 7.13 (d, J=8.4 Hz,
2H), 6.92 (d, J=8.5 Hz, 2H), 5.19-4.98 (m, 6H), 4.63 (d, J=11.2 Hz,
2H), 4.40 (d, J=11.1 Hz, 2H), 2.58 (dd, J=15.1, 7.5 Hz, 2H), 1.76
(s, 3H), 1.18 (t, J=7.6 Hz, 14H); MS (ESI+): m\z 384.1546.
(R)-2-((4-((3-Fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl-
-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.16, Table 1,
Scheme 4)
##STR00027##
[0160] TLC (EtOAc:DCM 1:9): R.sub.f=0.2; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.21 (s, 1H), 8.03 (s, 1H), 7.30 (dd, J=15.3, 7.7 Hz,
1H), 6.93-6.72 (m, 3H), 5.12 (s, 2H), 4.96 (q, J=14.7 Hz, 2H), 4.38
(d, J=11.1 Hz, 1H), 4.22 (d, J=11.2 Hz, 1H), 1.59 (s, 3H); MS
(ESI+): m\z 374.1139.
(R)-2-((4-((2-Fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-methyl-
-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.17, Table 1,
Scheme 4)
##STR00028##
[0162] TLC (EtOAc:DCM 1:9): R.sub.f=0.3; .sup.1H NMR (400 MHz,
Acetone) .delta. 8.18 (s, 1H), 7.80 (s, 1H), 7.29 (td, J=8.6, 1.6
Hz, 1H), 7.17-7.09 (m, 2H), 6.96 (ddd, J=7.8, 7.0, 1.5 Hz, 1H),
5.26 (s, 3H), 5.07 (q, J=14.9 Hz, 4H), 4.62 (d, J=11.2 Hz, 2H),
4.40 (d, J=11.2 Hz, 2H), 1.75 (s, 5H); MS (ESI+): m\z 374.1139.
(R)-2-((4-((4-Isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-met-
hyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.18, Table 1,
Scheme 4)
##STR00029##
[0164] TLC (EtOAc:DCM 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.18 (s, 1H), 8.07 (s, 1H), 7.14 (d, J=8.5 Hz, 2H),
6.91 (d, J=8.6 Hz, 2H), 5.07 (s, 2H), 4.96 (q, J=14.8 Hz, 2H), 4.39
(d, J=11.3 Hz, 1H), 4.22 (d, J=11.2 Hz, 1H), 2.83 (dt, J=13.8, 6.8
Hz, 1H), 1.58 (s, 3H), 1.17 (d, J=6.9 Hz, 6H); MS (ESI+): m\z
398.1703.
(R)-2-Methyl-6-nitro-2-((4-((pyridin-2-yloxy)methyl)-1H-1,2,3-triazol-1-yl-
)methyl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.19, Table 1,
Scheme 5)
##STR00030##
[0166] TLC (EtOAc:DCM 1:9): R.sub.f=0.4; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.19 (s, 1H), 8.04 (s, 1H), 7.98 (m, 1H), 7.25-7.38
(m, 3H), 5.10 (s, 2H), 4.95 (q, J=14.8 Hz, 2H), 4.38 (d, J=11.3 Hz,
1H), 4.22 (d, J=11.3 Hz, 1H), 1.58 (s, 3H); MS (ESI+): m\z
357.1186.
(R)-2-Methyl-6-nitro-2-((4-((p-tolylthio)methyl)-1H-1,2,3-triazol-1-yl)met-
hyl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.20, Table 1, Scheme
5)
##STR00031##
[0168] TLC (EtOAc:DCM 1:9): R.sub.f=0.3; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.17 (s, 1H), 8.05 (s, 1H), 7.08 (d, J=8.2 Hz, 2H),
6.88 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 5.02-4.88 (m, 2H), 4.38 (d,
J=11.3 Hz, 1H), 4.22 (d, J=11.3 Hz, 1H), 2.23 (s, 3H), 1.59 (s,
3H); MS (ESI-F): m\z 386.1161.
(R)-2-Methyl-6-nitro-2-((4-(2-(p-tolyloxy)ethyl)-1H-1,2,3-triazol-1-yl)met-
hyl)-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.21, Table 1, Scheme
5)
##STR00032##
[0170] TLC (EtOAc:DCM 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.17 (s, 1H), 8.05 (s, 1H), 7.08 (d, J=8.2 Hz, 2H),
6.88 (d, J=8.4 Hz, 2H), 5.02-4.88 (m, 2H), 4.38 (d, J=11.3 Hz, 1H),
4.22 (d, J=11.3 Hz, 1H), 4.12 (d, J=4.8 Hz, 2H), 2.32 (d, J=4.8 Hz,
2H), 2.23 (s, 3H), 1.59 (s, 3H); MS (ESI+): m\z 384.1546.
(R)-2-Methyl-2-((4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-nitr-
o-2,3-dihydroimidazo[2,1-b]oxazole (I.sub.22, Table 1, Scheme
5)
##STR00033##
[0172] TLC (EtOAc:DCM 1:9): R.sub.f=0.25; .sup.1H NMR (400 MHz,
DMSO) .delta. 8.16 (s, 1H), 8.06 (s, 1H), 5.04 (s, 2H), 5.02-4.88
(m, 2H), 4.38 (d, J=11.3 Hz, 1H), 4.22 (d, J=11.3 Hz, 1H),
4.09-4.18 (d, 4H), 3.36-3.48 (m, 4H), 1.58 (s, 3H); MS (ESI+): m\z
349.1499.
Biological Evaluation
Example 1
[0173] In Vitro Activity of Compounds I.sub.I to I.sub.22 Against
M. tuberculosis H.sub.37Rv and Two Clinical Isolates (M.
tuberculosis MDR & M. tuberculosis XDR)
[0174] MIC Determination:
[0175] MIC was determined by broth dilution method against M.
tuberculosis H.sub.37Rv (ATCC 27294; American Type Culture
Collection, Manassas, Va.), M. tuberculosis MDR (resistant to
isoniazid and rifampicin) and M. tuberculosis XDR (resistant to
isoniazid, rifampicin, amikacin and moxifloxacin). The bacterial
strains were grown for 10 to 15 days in Middlebrook 7H9 broth
(Difco Laboratories, Detroit, Mich.) supplemented with 0.5% (v/v)
glycerol, 0.25% (v/v) Tween 80 (Himedia, Mumbai India), and 10% ADC
(albumin dextrose catalase, Becton Dickinson, Sparks, Md.) under
shaking conditions at 37.degree. C. in 5% CO.sub.2 to facilitate
exponential-phase growth of the organism. Bacterial suspension was
prepared by suspending M. tuberculosis growth in normal saline
containing 0.5% tween 80 and turbidity was adjusted to 1 McFarland
standard which is equivalent to 1.5.times.10.sup.7 CFU/ml. The
2-fold serial dilutions of compounds I.sub.1 to I.sub.22 were
prepared in Middle brook 7H9 (Difco laboratories) for M.
tuberculosis in 100 .mu.l per well in 96-well U bottom microtitre
plates (Tarson, Mumbai, India). The above-mentioned bacterial
suspension was further diluted in the growth media and 100 .mu.l
volume of this diluted inoculum was added to each well of the plate
resulting in the final inoculum of 5.times.10.sup.5 CFU/ml in the
well and the final concentrations of compound I.sub.I to I.sub.22
ranged from 0.015 to 32 .mu.g/ml (0.015, 0.03, 0.06, 0.12, 0.25,
0.5, 1, 2, 4, 8, 16, 32). The plates were incubated at 37.degree.
C. for 3-weeks in 5% CO.sub.2. The plates were read visually and
the minimum concentration of the compound showing no turbidity was
recorded as MIC.
Results:
[0176] i) The compounds of general formula I (compounds I.sub.1 to
I.sub.22), were screened against both replicating &
non-replicating stages of M. tuberculosis, wherein 7 compounds
I.sub.10, I.sub.11, I.sub.13, I.sub.14, I.sub.17, I.sub.18 and
I.sub.21 showed MIC value of <1.0 .mu.g/ml (results provided in
Table 2). Three compounds I.sub.11, I.sub.17 and I.sub.21 showed
very potent MIC of 0.12, 0.25 and 0.25 .mu.g/ml against replicating
stages of M. Tuberculosis and MIC of 0.25, 0.5 and 0.25 against
non-replicating stages of M. Tuberculosis. The results are given in
Table 2. ii) The compounds of general formula I (compounds I.sub.1
to I.sub.22), were screened against both multi-drug and
extensive-drug resistant strains of M. tuberculosis, wherein five
compounds I.sub.11, I.sub.17, I.sub.19, I.sub.20 and I.sub.21
showed MIC value of <1.0 .mu.g/ml. Three compounds I.sub.11,
I.sub.17 and I.sub.21 showed very potent MIC of 0.12, 0.5 and 0.25
.mu.g/ml against multi and extensive-drug resistant strains of M.
Tuberculosis. The results are given in Table 2.
Example 2
[0177] Cytotoxicity Assay of Compounds I.sub.1 to I.sub.22:
Cell Culture:
[0178] The study was carried out using macrophage J774 cells line
(ATCC-USA). Cells were grown in Rosewell Park Memorial Institute
Medium (RPMI) containing 10% fetal calf serum (FCS) and
supplemented with 75 mg/litre penicillin, 100 mg/litre
streptomycin, 110 mg/litre Sodium pyruvate, 2.38 gm/litre HEPES,
0.05 mM 2 .beta.-mercaptoethanol, and 2 gm/litre NaHCO.sub.3, in a
humidified atmosphere in 5% CO.sub.2 at 37.degree. C., and were
sub-cultured at 1:4 ratio once a week.
Cell Treatment:
[0179] Cells were plated at a density of 3.times.10.sup.4
cells/cm.sup.2 and maintained in culture medium for 12 hours. Cells
were seeded onto 96-well flat bottom plates and FCS was reduced to
5% for the experiment. Stock solutions of compounds 9 to 37 were
prepared fresh to avoid oxidation. Cells were incubated with the
compounds (40 .mu.g/ml) for 24 hrs.
Cytotoxicity Assays:
[0180] After the completion of incubation, the medium was removed
and cell viability was evaluated by assaying for the ability of
functional mitochondria to catalyze the reduction of
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
to form formazan salt by mitochondrial dehydrogenases, and
determined by Elisa reader at 450 nm (Multiskan Spectrum; Thermo
Electron Corporation, USA). Percentage cytotoxicity was calculated
with respect to the untreated cells.
Results:
[0181] Compounds I.sub.1 to I.sub.22 were not toxic up to 40
.mu.g/ml concentration and the cytotoxicity assay results are shown
in Table 2.
TABLE-US-00003 TABLE 1 Structure of representative compounds
I.sub.1 to I.sub.22 of general formula I Entries Codes Structures 1
I.sub.1 ##STR00034## 2 I.sub.2 ##STR00035## 3 I.sub.3 ##STR00036##
4 I.sub.4 ##STR00037## 5 I.sub.5 ##STR00038## 6 I.sub.6
##STR00039## 7 I.sub.7 ##STR00040## 8 I.sub.8 ##STR00041## 9
I.sub.9 ##STR00042## 10 I.sub.10 ##STR00043## 11 I.sub.11
##STR00044## 12 I.sub.12 ##STR00045## 13 I.sub.13 ##STR00046## 14
I.sub.14 ##STR00047## 15 I.sub.15 ##STR00048## 16 I.sub.16
##STR00049## 17 I.sub.17 ##STR00050## 18 I.sub.18 ##STR00051## 19
I.sub.19 ##STR00052## 20 I.sub.20 ##STR00053## 21 I.sub.21
##STR00054## 22 I.sub.22 ##STR00055##
TABLE-US-00004 TABLE 2 Anti-tuberculosis activity and cytotoxicity
of representative compounds of general formula I (I.sub.1 to
I.sub.22) MIC (.mu.g/ml) Compound M. tb Non-replicating MIC
Cytotoxicity S. No. code H.sub.37Rv strain (Rif.sup.R) MDR XDR
(.mu.g/ml) 1. I.sub.1 2 4 2 2 1 >40 2. I.sub.2 2 8 4 2 2 >40
3. I.sub.3 1 2 2 2 2 >40 4. I.sub.4 2 4 1 4 2 >40 5. I.sub.5
1 8 4 1 4 >40 6. I.sub.6 2 2 1 1 1 >40 7. I.sub.7 2 4 8 2 8
>40 8. I.sub.8 2 4 2 2 2 >40 9. I.sub.9 1 2 4 4 4 >40 10.
I.sub.10 0.5 1 2 2 4 >40 11. I.sub.11 0.12 0.25 0.12 0.12 0.25
>40 12. I.sub.12 1 2 8 2 8 >40 13. I.sub.13 0.5 0.5 1 1 2
>40 14. I.sub.14 0.5 2 1 1 1 >40 15. I.sub.15 2 2 4 2 4
>40 16. I.sub.16 1 2 2 2 2 >40 17. I.sub.17 0.25 0.5 1 0.5 1
>40 18. I.sub.18 0.5 1 2 1 4 >40 19. I.sub.19 1 2 0.5 0.25
0.5 >40 20. I.sub.20 2 1 0.25 0.5 2 >40 21. I.sub.21 0.25
0.25 1 0.25 0.25 >40 22. I.sub.22 2 1 2 2 2 >40
* * * * *