U.S. patent number RE48,105 [Application Number 16/103,823] was granted by the patent office on 2020-07-21 for compounds for the treatment of mycobacterial infections.
This patent grant is currently assigned to The Broad Institute, Inc., The General Hospital Corporation. The grantee listed for this patent is The Broad Institute, Inc., The General Hospital Corporation. Invention is credited to Deborah Hung, Noriaki Iwase, Tomohiko Kawate, Motohisa Shimizu, Sarah Stanley.
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United States Patent |
RE48,105 |
Hung , et al. |
July 21, 2020 |
**Please see images for:
( Certificate of Correction ) ** |
Compounds for the treatment of mycobacterial infections
Abstract
The invention relates to compounds of Formula I or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00001##
Inventors: |
Hung; Deborah (Lexington,
MA), Stanley; Sarah (Berkeley, CA), Kawate; Tomohiko
(Arlington, MA), Iwase; Noriaki (Yamaguchi, JP),
Shimizu; Motohisa (Yamaguchi, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
The Broad Institute, Inc.
The General Hospital Corporation |
Cambridge
Boston |
MA
MA |
US
US |
|
|
Assignee: |
The Broad Institute, Inc.
(Cambridge, MA)
The General Hospital Corporation (Boston, MA)
|
Family
ID: |
47996433 |
Appl.
No.: |
16/103,823 |
Filed: |
August 14, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
PCT/US2012/057913 |
Sep 28, 2012 |
|
|
|
|
61540943 |
Sep 29, 2011 |
|
|
|
Reissue of: |
14227372 |
Mar 27, 2014 |
9416121 |
Aug 16, 2016 |
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/37 (20130101); A61K 31/453 (20130101); A61K
31/453 (20130101); A61K 31/496 (20130101); A61K
31/5377 (20130101); C07D 311/16 (20130101); C07D
311/18 (20130101); C07D 405/04 (20130101); A61K
31/496 (20130101); C07D 311/16 (20130101); A61K
31/5377 (20130101); A61K 31/37 (20130101); C07D
405/04 (20130101); C07D 311/18 (20130101) |
Current International
Class: |
C07D
213/79 (20060101); C07D 405/04 (20060101); C07D
311/16 (20060101); C07D 311/18 (20060101); A61K
31/37 (20060101); A61K 31/5377 (20060101); A61K
31/496 (20060101); A61K 31/453 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Kawate, T., et al., "Synthesis and structure-activity relationships
of phenyl-substituted coumarins with anti-tubercular that target
FadD32," Bioorganic & Medicinal Chemistry Letters, 23:
6052-6059 (2013). cited by applicant .
Mashelkar et al. Indian Journal of Chemistry, Section B: Organic
Chemistry Including Medicinal Chemistry (2011),50B(3), 315-320.
cited by examiner .
Shi et al. Journal of Organic Chemistry (2004), 69(11), 3669-3671.
cited by examiner .
Moskvina et 31. Synthesis (2009), (8), 1279-1286. cited by examiner
.
Li, Journal of Organic Chemistry (2005), 70(16), 6515-6518. cited
by examiner .
Venkatesh et al., J. Pharm. Sci. 89, 145-54 (2000). cited by
examiner .
STN Abstrct of KUMGM (University of Kansas Molecular Graphics and
Modeling Laboratory), Dec. 19, 2007. cited by examiner .
Wolff, Burger's medicinal Chemistry and Drug Discovery, vol. 1,
Principles and Practice, John Wiley & sons, New York, 1997.
cited by examiner .
Moskvina et al. Synthesis 2009(8): 1279-1286. cited by examiner
.
Ananthan, NIH article 2009 89(5):334-353. cited by examiner .
Stanely et al. ACS Chem. Biol. 2612, 7, 1377-1384. cited by
examiner .
Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wil VCH,
Weinheim p. IX of Preface p. 1-15. cited by examiner .
PUBCHEM CID 6540169 (Create: date May 12, 2006) p. 1. cited by
applicant .
Ananthan, et al., "High Throughput Screening for Inhibitors of
Mycobacterium tuberculosis H37Rv," Tuberculosis (Edinb). Sep. 2009;
89(5): 334-353. Downloaded from
http://www.ncb.inlm.nih.gov/pmc/articles/PMC3255569/. cited by
applicant.
|
Primary Examiner: Jones; Dwayne C.
Attorney, Agent or Firm: Elmore Patent Law Group, P.C. Hoda;
Mahreen Chaudhry Elmore; Carolyn S.
Parent Case Text
RELATED APPLICATIONS
This application is a continuation of International Application No.
PCT/US2012/057913, which designated the United States and was filed
on Sep. 28, 2012, published in English, which claims the benefit of
U.S. Provisional Application No. 61/540,943, filed on Sep. 29,
2011. The entire teachings of the above applications are
incorporated herein by reference.
Claims
What is claimed is:
1. A compound of Formula Ia or a pharmaceutically acceptable salt
thereof: ##STR00097## wherein: R.sub.1 is selected from the group
consisting of phenyl, substituted phenyl, pyridinyl, and
substituted pyridinyl; R.sub.3 is hydrogen or unsubstituted
C.sub.1-C.sub.8 alkyl; R.sub.4 is hydrogen or unsubstituted
C.sub.1-C.sub.8 alkyl; R.sub.2 is: ##STR00098## each R.sub.6,
R.sub.7, R.sub.10 and R.sub.11 is independently selected from the
group consisting of hydrogen and unsubstituted C.sub.1-C.sub.8
alkyl; .Iadd.m is 0; .Iaddend. R.sub.5 is selected from the group
consisting of: ##STR00099## R.sub.100 is hydrogen or unsubstituted
C.sub.1-C.sub.8 alkyl; and R.sub.100' is hydrogen or unsubstituted
C.sub.1-C.sub.8 alkyl; wherein the substituted phenyl and the
substituted pyridinyl are each independently substituted with one
or more substituents independently selected from the group
consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,.[.-alkoxy.].
.Iadd.alkoxy.Iaddend., aryloxy, aralkoxy, aminocarbonyl,
alkylaminocarbonyl, arylaminocarbonyl,.[.-alkoxycarbonyl.].
.Iadd.alkoxycarbonyl.Iaddend., aryloxycarbonyl, haloalkyl, amino,
cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,
arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxy,
carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl,
aralkoxycarbonyl, and sulfonyl.
2. The compound .[.of claim 1.]. selected from the group consisting
of:
4-(3-aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen--
2-one; and
4-phenyl-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen-
-2-one, or a pharmaceutically acceptable salt of any of
thereof.
3. The compound of claim 1, wherein R.sub.5 is selected from the
group consisting of: ##STR00100## or a pharmaceutically acceptable
salt thereof.
4. The compound of claim 1, wherein R.sub.3 is unsubstituted
C.sub.1-C.sub.8 alkyl, and R.sub.4 is unsubstituted C.sub.1-C.sub.8
alkyl, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1, wherein R.sub.1 is phenyl or
substituted phenyl, or a pharmaceutically acceptable salt
thereof.
6. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and the compound of claim 1, or a
pharmaceutically acceptable salt thereof.
7. A compound selected from the table below, or a pharmaceutically
acceptable salt thereof: TABLE-US-00002 TABLE A No Structure 1
##STR00101##
5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-4-phenyl-2H-
chromen-2-one 2 ##STR00102##
5,7-dimethyl-4-phenyl-6-(4-(piperidin-l-ylmethyl)phenyl)-2H-
chromen-2-one 3 ##STR00103## 6-(4-((cyclohexylamino
)methyl)phenyl)-5,7-dimethyl-4-phenyl-2H- chromen-2-one 5
##STR00104##
5,7-dimethyl-6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-
phenyl-2H-chromen-2-one 6 ##STR00105##
4-(3-aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-
2H-chromen-2-one hydrochloride 7 ##STR00106##
4-(4-aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-
2H-chromen-2-one 8 ##STR00107##
5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-4-(3-nitrophenyl)-2H-
chromen-2-one 9 ##STR00108## methyl
3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-
chromen-4-yl)benzoate 10 ##STR00109##
N-(3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-
chromen-4-yl)phenyl)acetamide 11 ##STR00110##
N-(3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-
chromen-4-yl)phenyl)methanesulfonamide 12 ##STR00111## ethyl
(3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-
chromen-4-yl)phenyl)caxbamate 13 ##STR00112##
5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-4-(pyridin-
3-yl)-2H-chromen-2-one 43 ##STR00113## 44 ##STR00114##
8. The compound of claim 1, wherein R.sub.5 is: ##STR00115## or a
pharmaceutically acceptable salt thereof.
9. The compound of claim 1, wherein R.sub.5 is: ##STR00116##
##STR00117## or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1, wherein R.sub.5 is: ##STR00118## or a
pharmaceutically acceptable salt thereof.
11. The compound of claim 1, wherein R.sub.5 is: ##STR00119## or a
pharmaceutically acceptable salt thereof.
12. The compound of claim 8, wherein R.sub.100 is hydrogen, or a
pharmaceutically acceptable salt thereof.
13. The compound of claim 9, wherein R.sub.100 is hydrogen, or a
pharmaceutically acceptable salt thereof.
14. The compound of claim 10, wherein R.sub.100 is hydrogen, or a
pharmaceutically acceptable salt thereof.
15. The compound of claim 11, wherein R.sub.100 is hydrogen, or a
pharmaceutically acceptable salt thereof.
16. The compound of claim 15, wherein R.sub.100 ' is hydrogen or
methyl, or a pharmaceutically acceptable salt thereof.
17. The compound of claim 4, wherein R.sub.3 is unsubstituted
C.sub.1-C.sub.3 alkyl, and R.sub.4 is unsubstituted C.sub.1-C.sub.3
alkyl, or a pharmaceutically acceptable salt thereof.
18. The compound of claim 17, wherein R.sub.3 is methyl and R.sub.4
is methyl, or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 7, or a pharmaceutically
acceptable salt thereof.
Description
BACKGROUND
Tuberculosis (TB) is a disease caused by the bacterium
Mycobacterium tuberculosis (Mtb), and is spread from person to
person through the air. It is estimated that one-third of world's
population are latently infected by Mtb. Despite the availability
of effective anti-TB drugs, such as isoniazide and rifampin, TB is
still one of the world's deadliest diseases. According to World
Health Organization, there were 9.4 million new TB cases and 1.7
million people died from TB in 2009. [Global tuberculosis control:
WHO report 2010.WHO//HTM/TB/2010.7]. Development of new agents that
reduce the duration and complexity of current therapies, as well as
effectively kill emerging resistant mutants, multiple drug
resistant TB and extensively drug resistant TB, would have a major
impact on the TB therapy.
SUMMARY OF THE INVENTION
The invention relates to compounds of Formula I or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00002## Wherein, n is 0, 1, or 2; t is 0 or 1; R.sub.1 is
hydrogen, halogen, --OR.sub.20, --SR.sub.20, --NR.sub.20R.sub.21,
--CF.sub.3, --CN, --NO.sub.2, --N.sub.3, --C(O)OR.sub.20,
--C(O)R.sub.20, --C(O)NR.sub.20R.sub.21, acyl, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted aryl, heteroaryl or substituted heteroaryl;
Wherein each R.sub.20 and R.sub.21 is independently hydrogen,
halogen, alkyl, aliphatic, substituted aliphatic, aryl or
substituted aryl; R.sub.3 is hydrogen, halogen, --OR.sub.20,
--SR.sub.20, --NR.sub.20R.sub.21, --CF.sub.3, --CN, --NO.sub.2,
--N.sub.3, --C(O)OR.sub.20, --C(O)R.sub.20,
--C(O)NR.sub.20R.sub.21, acyl, alkyl, alkoxy, substituted alkoxy,
alkylamino, substituted alkylamino, dialkylamino, substituted
dialkylamino, substituted or unsubstituted alkylthio, substituted
or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic,
aryl or substituted aryl; Each R.sub.4 is independently selected
from hydrogen, halogen, --OR.sub.20, --SR.sub.20,
--NR.sub.20R.sub.21, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3,
--C(O)OR.sub.20, --C(O)R.sub.20, --C(O)NR.sub.20R.sub.21, acyl,
alkyl, alkoxy, substituted alkoxy, alkylamino, substituted
alkylamino, dialkylamino, substituted dialkylamino, substituted or
unsubstituted alkylthio, substituted or unsubstituted
alkylsulfonyl, aliphatic, substituted aliphatic, aryl or
substituted aryl; alternatively two R.sub.4 groups together with
the atoms to which they are attached and any intervening atoms may
form an additional optionally substituted, 3, 4, 5, 6 or 7 membered
ring; R.sub.2 is aryl, substituted aryl, heterocyclic, substituted
heterocyclic, alkyl substituted with aryl, alkenyl substituted with
aryl, alkynyl substituted aryl, --[C(R.sub.20)(R.sub.21)].sub.a-Cy,
--[C(R.sub.20)(R.sub.21)].sub.a.dbd.[C(R.sub.20)(R.sub.21)].sub.a-Cy,
--O[C(R.sub.20)(R.sub.21)].sub.a-Cy,
--S[C(R.sub.20)(R.sub.21)].sub.a-Cy, or
--N(R.sub.20)[C(R.sub.20)(R.sub.21)].sub.a-Cy; Wherein Cy is aryl,
substituted aryl, heterocyclic, substituted heterocyclic,
carbocyclic or substituted carbocyclic; Each a is independently 0,
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19
or 20.
The invention further relates to the use of a compound of Formula I
in the manufacture of a medicament. The invention further relates
to the use of a compound of Formula I for the treatment of a
bacterial infection, in particular, mycobacterial infection. The
compounds of the invention can be used for anti-mycobacterial
activity against clinically sensitive as well as resistant strains
of Mycobacterium tuberculosis. Compounds of Formula I are useful
for the treatment of mycobacterial diseases, particularly those
caused by pathogenic mycobacteria.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to compounds of Formula I or a
pharmaceutically acceptable salt, ester of prodrug thereof:
##STR00003## Wherein, n is 0, 1, or 2; t is 0 or 1; R.sub.1 is
hydrogen, halogen, --OR.sub.20, --SR.sub.20, --NR.sub.20R.sub.21,
--CF.sub.3, --CN, --NO.sub.2, --N.sub.3, --C(O)OR.sub.20,
--C(O)R.sub.20, --C(O)NR.sub.20R.sub.21, --S(O)R.sub.20,
--S(O)NR.sub.20, --S(O).sub.2R.sub.20, acyl, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted aryl, heteroaryl or substituted heteroaryl;
Wherein each R.sub.20 and R.sub.21 is independently hydrogen,
halogen, alkyl, aliphatic, substituted aliphatic, aryl or
substituted aryl; R.sub.3 is hydrogen, halogen, --OR.sub.20,
--SR.sub.20, --NR.sub.20R.sub.21, --CF.sub.3, --CN, --NO.sub.2,
--N.sub.3, --C(O)OR.sub.20, --C(O)R.sub.20,
--C(O)NR.sub.20R.sub.21, acyl, alkyl, alkoxy, substituted alkoxy,
alkylamino, substituted alkylamino, dialkylamino, substituted
dialkylamino, substituted or unsubstituted alkylthio, substituted
or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic,
aryl or substituted aryl; Each R.sub.4 and R.sub.9 is independently
selected from hydrogen, halogen, --OR.sub.20, --SR.sub.20,
--NR.sub.20R.sub.21, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3,
--C(O)OR.sub.20, --C(O)R.sub.20, --C(O)NR.sub.20R.sub.21, acyl,
alkyl, alkoxy, substituted alkoxy, alkylamino, substituted
alkylamino, dialkylamino, substituted dialkylamino, substituted or
unsubstituted alkylthio, substituted or unsubstituted
alkylsulfonyl, aliphatic, substituted aliphatic, aryl or
substituted aryl; alternatively two R.sub.4 groups together with
the atoms to which they are attached and any intervening atoms may
form an additional optionally substituted, 3, 4, 5, 6 or 7 membered
ring; R.sub.2 is aryl, substituted aryl, heterocyclic, substituted
heterocyclic, --[C(R.sub.20)(R.sub.21)].sub.a-Cy,
--[C(R.sub.20)(R.sub.21)].sub.a[C(R.sub.20)(R.sub.21)].sub.a-Cy,
--O[C(R.sub.20)(R.sub.21)].sub.a-Cy,
--S[C(R.sub.20)(R.sub.21)].sub.a-Cy,
--N(R.sub.20)[C(R.sub.20)(R.sub.21)].sub.b-Cy; Wherein Cy is aryl,
substituted aryl, heterocyclic, substituted heterocyclic,
carbocyclic or substituted carbocyclic; Each a is independently 0,
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19
or 20.
In a preferred embodiment, R.sub.1 is alkyl, aryl, substituted
aryl, heteroaryl or substituted heteroaryl.
In a preferred embodiment, R.sub.2 is selected from:
##STR00004## ##STR00005## ##STR00006## Wherein m is 0, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11 or 12; q is 0, 1, 2, 3 or 4; Each R.sub.6,
R.sub.7, R.sub.10 and R.sub.11 is independently selected from
absent, hydrogen, halogen, --OR.sub.20, --SR.sub.20,
--NR.sub.20R.sub.21, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3, --OH,
--SH, --C(O)OR.sub.20, --C(O)R.sub.20, --C(O)NR.sub.20R.sub.21,
--S(O)R.sub.20, --S(O)NR.sub.20, --S(O).sub.2R.sub.20, acyl, alkyl,
alkenyl, alkoxy, oxo, substituted alkoxy, alkylamino, substituted
alkylamino, dialkylamino, substituted dialkylamino, substituted or
unsubstituted alkylthio, substituted or unsubstituted
alkylsulfonyl, aliphatic, substituted aliphatic, aryl or
substituted aryl; alternatively two R.sub.10 and R.sub.11 groups
together with the atoms to which they are attached and any
intervening atoms may form an additional optionally substituted, 3,
4, 5, 6 or 7 membered ring; R.sub.5 is selected from absent,
hydrogen, halogen, --NR.sub.20R.sub.21, OR.sub.20, SR.sub.20,
--CF.sub.3, --CN, --NO.sub.2, --N.sub.3, --C(O)OR.sub.20,
--C(O)R.sub.20, --C(O)NR.sub.20R.sub.21, --S(O)R.sub.20,
--S(O)NR.sub.20, --S(O).sub.2R.sub.20, alkyl, substituted alkyl,
aryl, substituted aryl, heterocyclic and substituted heterocyclic;
Wherein when R.sub.21 is hydrogen, R.sub.20 is other than H,
CH.sub.3 or --C(O)CH.sub.3; R.sub.8 is absent, --O--, --S--,
--NR.sub.10--, --C(O)--, --C(O)O--, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl or substituted alkynyl
alkynyl. In a preferred embodiment, R.sub.5 is NR.sub.22R.sub.23;
Wherein R.sub.22 is selected from hydrogen, C.sub.1-C.sub.20 alkyl,
substituted C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl,
substituted C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20 alkynyl,
substituted C.sub.2-C.sub.20 alkynyl, C.sub.3-C.sub.20 cycloalkyl;
substituted C.sub.3-C.sub.20 cycloalkyl; Wherein R.sub.23 is
selected from absent, C.sub.2-C.sub.20 alkyl, substituted
C.sub.2-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, substituted
C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20 alkynyl, substituted
C.sub.2-C.sub.20 alkynyl, C.sub.3-C.sub.20 cycloalkyl; substituted
C.sub.3-C.sub.20 cycloalkyl; Alternatively R.sub.22 and R.sub.23
together with the nitrogen atom to which they are attached may form
an additional optionally substituted, 3, 4, 5, 6 or 7 membered
ring; Wherein when R.sub.22 is hydrogen, R.sub.23 is other than
--C(O)CH.sub.3. In a more preferred embodiment, R.sub.5 is selected
from:
##STR00007## Wherein w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R.sub.100 is hydrogen, halogen, --NR.sub.20R.sub.21, OR.sub.20,
SR.sub.20, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3,
--C(O)OR.sub.20, --C(O)R.sub.20, --C(O)NR.sub.20R.sub.21,
--S(O)R.sub.20, --S(O)NR.sub.20, --S(O).sub.2R.sub.20, alkyl,
substituted alkyl, aryl, substituted aryl, heterocyclic or
substituted heterocyclic; Each R.sub.101 and R.sub.102 is
independently selected from hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, heterocyclic or substituted
heterocyclic.
In a preferred embodiment, the invention relates to a compound
selected from Table A:
TABLE-US-00001 TABLE A IC.sub.90 No Structure (.mu.M) 1
##STR00008## I 2 ##STR00009## II 3 ##STR00010## I 4 ##STR00011## I
5 ##STR00012## I 6 ##STR00013## I 7 ##STR00014## II 8 ##STR00015##
I 9 ##STR00016## III 10 ##STR00017## II 11 ##STR00018## III 12
##STR00019## II 13 ##STR00020## I 14 ##STR00021## IV 15
##STR00022## II 16 ##STR00023## IV 17 ##STR00024## NA 18
##STR00025## II 19 ##STR00026## IV 20 ##STR00027## I 21
##STR00028## II 22 ##STR00029## IV 23 ##STR00030## IV 24
##STR00031## IV 25 ##STR00032## III 26 ##STR00033## IV 27
##STR00034## II 28 ##STR00035## II 29 ##STR00036## II 30
##STR00037## II 31 ##STR00038## NA 32 ##STR00039## IV 33
##STR00040## I 34 ##STR00041## I 35 ##STR00042## I 36 ##STR00043##
II 37 ##STR00044## III 38 ##STR00045## NA 39 ##STR00046## II 40
##STR00047## NA 41 ##STR00048## I 42 ##STR00049## III 43
##STR00050## NA 44 ##STR00051## NA 45 ##STR00052## IV 46
##STR00053## NA 47 ##STR00054## IV 48 ##STR00055## III 49
##STR00056## III 50 ##STR00057## IV.
The antitubercular activity of Compounds 1-50 was evaluated against
Mtb strain H37Rv. The inhibitory activity (IC.sub.90) of the
compounds is reported in Table A. The inhibitory activity is
characterized based on the following scale: I=0.001 .mu.M-10 .mu.M
II=10 .mu.M-50 .mu.M III=50 .mu.M-100 .mu.M IV=>100 .mu.M NA=No
Activity
The invention further relates to the use of a compound of Formula I
for the treatment of a mycobacterial infection. The compounds of
the invention can be used for anti-mycobacterial activity against
mycobacterium infection, in particular against infection caused by
resistant strains of mycobacterium tuberculosis. Compounds of
Formula I are useful for the treatment of mycobacterial diseases,
particularly those caused by pathogenic mycobacteria.
The invention further relates to the use of a compound of Formula I
in the manufacture of a medicament. The invention further relates
to combination therapy using compounds of Formula I with
antibacterial agents, in particular anti-mycobacterial agents. The
compounds of Formula I can be combined with antibacterial agents
such as rifampicin, rifampin, isoniazid, pyrazinamide, amikacin,
ethionamide, moxifloxacin, ethambutol, streptomycin,
para-aminosalicylic acid, cycloserine, capreomycin, kanamycin,
thiacetazone, PA-824, quinolones/fluoroquinolones such as for
example ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as
for example clarithromycin, clofazimine, amoxycillin with
clavulanic acid, rifamycins, rifabutin, rifapentine.
The following schemes represent general protocols for synthesis of
compounds of Formula I:
##STR00058## ##STR00059##
##STR00060## ##STR00061##
##STR00062##
##STR00063##
##STR00064## ##STR00065##
##STR00066##
##STR00067##
##STR00068##
ABBREVIATIONS
Abbreviations which may appear in the synthetic schemes and
examples are:
Ac for acetyl;
Alloc for allyloxycarbonyl;
Boc for tert-butoxycarbonyl;
DCC for N,N'-dicyclohexylcarbodiimide;
DCM for dichloromethane;
DMAP for 4-(dimethylamino)pyridine;
DMF for dimethyl formamide;
DMSO for dimethyl sulfoxide;
Dppf for 1,1'-bis)diphenylphosphino)ferrocene;
EtOAc for ethyl acetate;
EtOH for ethanol;
iPr for isopropyl;
IPA for isopropyl alcohol;
MeOH for methanol;
TBME for tert-butyl methyl ether;
TEA for triethylamine;
TFA for trifluoroaetic acid; and
THF for tetrahydrofuran.
Definitions
Listed below are definitions of various terms used to describe this
invention. These definitions apply to the terms as they are used
throughout this specification and claims, unless otherwise limited
in specific instances, either individually or as part of a larger
group.
The term "aliphatic group" or "aliphatic" refers to a non-aromatic
moiety that may be saturated (e.g. single bond) or contain one or
more units of unsaturation, e.g., double and/or triple bonds. An
aliphatic group may be straight chained, branched or cyclic,
contain carbon, hydrogen or, optionally, one or more heteroatoms
and may be substituted or unsubstituted. In addition to aliphatic
hydrocarbon groups, aliphatic groups include, for example,
polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and
polyimines, for example. Such aliphatic groups may be further
substituted. It is understood that aliphatic groups may include
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, and substituted or unsubstituted cycloalkyl
groups as described herein.
The term "acyl" refers to a carbonyl substituted with hydrogen,
alkyl, partially saturated or fully saturated cycloalkyl, partially
saturated or fully saturated heterocycle, aryl, or heteroaryl. For
example, acyl includes groups such as (C.sub.1-C.sub.6) alkanoyl
(e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl,
t-butylacetyl, etc.), (C.sub.3-C.sub.6)cycloalkylcarbonyl (e.g.,
cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,
cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g.,
pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl,
piperidinylcarbonyl, piperazinylcarbonyl,
tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and
heteroaroyl (e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl,
furanyl-2-carbonyl, furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl,
1H-pyrroyl-3-carbonyl, benzo[b]thiophenyl-2-carbonyl, etc.). In
addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl
portion of the acyl group may be any one of the groups described in
the respective definitions. When indicated as being "optionally
substituted", the acyl group may be unsubstituted or optionally
substituted with one or more substituents (typically, one to three
substituents) independently selected from the group of substituents
listed below in the definition for "substituted" or the alkyl,
cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl
group may be substituted as described above in the preferred and
more preferred list of substituents, respectively.
The term "alkyl" is intended to include both branched and straight
chain, substituted or unsubstituted saturated aliphatic hydrocarbon
radicals/groups having the specified number of carbons. Preferred
alkyl groups comprise about 1 to about 24 carbon atoms
("C.sub.1-C.sub.24"). Other preferred alkyl groups comprise at
about 1 to about 8 carbon atoms ("C.sub.1-C.sub.8") such as about 1
to about 6 carbon atoms ("C.sub.1-C.sub.6"), or such as about 1 to
about 3 carbon atoms ("C.sub.1-C.sub.3"). Examples of
C.sub.1-C.sub.6 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,
neopentyl and n-hexyl radicals.
The term "alkenyl" refers to linear or branched radicals having at
least one carbon-carbon double bond. Such radicals preferably
contain from about two to about twenty-four carbon atoms
("C.sub.2-C.sub.24"). Other preferred alkenyl radicals are "lower
alkenyl" radicals having two to about ten carbon atoms
("C.sub.2-C.sub.10") such as ethenyl, allyl, propenyl, butenyl and
4-methylbutenyl. Preferred lower alkenyl radicals include 2 to
about 6 carbon atoms ("C.sub.2-C.sub.6"). The terms "alkenyl", and
"lower alkenyl", embrace radicals having "cis" and "trans"
orientations, or alternatively, "E" and "Z" orientations.
The term "alkynyl" refers to linear or branched radicals having at
least one carbon-carbon triple bond. Such radicals preferably
contain from about two to about twenty-four car- bon atoms
("C.sub.2-C.sub.24"). Other preferred alkynyl radicals are "lower
alkynyl" radicals having two to about ten carbon atoms such as
propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and
1-pentynyl. Preferred lower alkynyl radicals include 2 to about 6
carbon atoms ("C.sub.2-C.sub.6").
The term "cycloalkyl" refers to saturated carbocyclic radicals
having three to about twelve carbon atoms ("C.sub.3-C.sub.12"). The
term "cycloalkyl" embraces saturated carbocyclic radicals having
three to about twelve carbon atoms. Examples of such radicals
include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloalkenyl" refers to partially unsaturated carbocyclic
radicals having three to twelve carbon atoms. Cycloalkenyl radicals
that are partially unsaturated carbocyclic radicals that contain
two double bonds (that may or may not be conjugated) can be called
"cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower
cycloalkenyl" radicals having four to about eight carbon atoms.
Examples of such radicals include cyclobutenyl, cyclopentenyl and
cyclohexenyl.
The term "alkylene," as used herein, refers to a divalent group
derived from a straight chain or branched saturated hydrocarbon
chain having the specified number of carbons atoms. Examples of
alkylene groups include, but are not limited to, ethylene,
propylene, butylene, 3-methyl-pentylene, and 5-ethyl-hexylene.
The term "alkenylene," as used herein, denotes a divalent group
derived from a straight chain or branched hydrocarbon moiety
containing the specified number of carbon atoms having at least one
carbon-carbon double bond. Alkenylene groups include, but are not
limited to, for example, ethenylene, 2-propenylene, 2-butenylene,
1-methyl-2-buten-1-ylene, and the like.
The term "alkynylene," as used herein, denotes a divalent group
derived from a straight chain or branched hydrocarbon moiety
containing the specified number of carbon atoms having at least one
carbon-carbon triple bond. Representative alkynylene groups
include, but are not limited to, for example, propynylene,
1-butynylene, 2-methyl-3-hexynylene, and the like.
The term "alkoxy" refers to linear or branched oxy-containing
radicals each having alkyl portions of one to about twenty-four
carbon atoms or, preferably, one to about twelve carbon atoms. More
preferred alkoxy radicals are "lower alkoxy" radicals having one to
about ten carbon atoms and more preferably having one to about
eight carbon atoms. Examples of such radicals include methoxy,
ethoxy, propoxy, butoxy and tert-butoxy.
The term "alkoxyalkyl" refers to alkyl radicals having one or more
alkoxy radicals attached to the alkyl radical, that is, to form
monoalkoxyalkyl and dialkoxyalkyl radicals.
The term "aryl", alone or in combination, means an aromatic system
containing one, two or three rings wherein such rings may be
attached together in a pendent manner or may be fused. The term
"aryl" embraces aromatic radicals such as phenyl, naphthyl,
tetrahydronaphthyl, indane furanyl, quinazolinyl, pyridyl and
biphenyl.
The terms "heterocyclyl", "heterocycle" "heterocyclic" or
"heterocyclo" refer to saturated, partially unsaturated and
unsaturated heteroatom-containing ring-shaped radicals, which can
also be called "heterocyclyl", "heterocycloalkenyl" and
"heteroaryl" correspondingly, where the heteroatoms may be selected
from nitrogen, sulfur and oxygen. Examples of saturated
heterocyclyl radicals include saturated 3 to 6-membered
heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.
pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.);
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2
oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.);
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.).
Examples of partially unsaturated heterocyclyl radicals include
dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
Heterocyclyl radicals may include a pentavalent nitrogen, such as
in tetrazolium and pyridinium radicals. The term "heterocycle" also
embraces radicals where heterocyclyl radicals are fused with aryl
or cycloalkyl radicals. Examples of such fused bicyclic radicals
include benzofuran, benzothiophene, and the like.
The term "heteroaryl" refers to unsaturated aromatic heterocyclyl
radicals. Examples of heteroaryl radicals include unsaturated 3 to
6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.)
tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.),
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to
6-membered heteromonocyclic group containing a sulfur atom, for
example, thienyl, etc.; unsaturated 3- to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.) etc.; unsaturated condensed heterocyclyl group containing 1
to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl,
benzoxadiazolyl, etc.); unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.)
etc.; unsaturated condensed heterocyclyl group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl,
benzothiadiazolyl, etc.) and the like.
The term "heterocycloalkyl" refers to heterocyclo-substituted alkyl
radicals. More preferred heterocycloalkyl radicals are "lower
heterocycloalkyl" radicals having one to six carbon atoms in the
heterocyclo radical.
The term "alkylthio" refers to radicals containing a linear or
branched alkyl radical, of one to about ten carbon atoms attached
to a divalent sulfur atom. Preferred alkylthio radicals have alkyl
radicals of one to about twenty-four carbon atoms or, preferably,
one to about twelve carbon atoms. More preferred alkylthio radicals
have alkyl radicals which are "lower alkylthio" radicals having one
to about ten carbon atoms. Most preferred are alkylthio radicals
having lower alkyl radicals of one to about eight carbon atoms.
Examples of such lower alkylthio radicals include methylthio,
ethylthio, propylthio, butylthio and hexylthio.
The terms "aralkyl" or "arylalkyl" refer to aryl-substituted alkyl
radicals such as benzyl, diphenylmethyl, triphenylmethyl,
phenylethyl, and diphenylethyl.
The term "aryloxy" refers to aryl radicals attached through an
oxygen atom to other radicals.
The terms "aralkoxy" or "arylalkoxy" refer to aralkyl radicals
attached through an oxygen atom to other radicals.
The term "aminoalkyl" refers to alkyl radicals substituted with
amino radicals. Preferred aminoalkyl radicals have alkyl radicals
having about one to about twenty-four carbon atoms or, preferably,
one to about twelve carbon atoms. More preferred aminoalkyl
radicals are "lower aminoalkyl" that have alkyl radicals having one
to about ten carbon atoms. Most preferred are aminoalkyl radicals
having lower alkyl radicals having one to eight carbon atoms.
Examples of such radicals include aminomethyl, aminoethyl, and the
like.
The term "alkylamino" denotes amino groups which are substituted
with one or two alkyl radicals. Preferred alkylamino radicals have
alkyl radicals having about one to about twenty carbon atoms or,
preferably, one to about twelve carbon atoms. More preferred
alkylamino radicals are "lower alkylamino" that have alkyl radicals
having one to about ten carbon atoms. Most preferred are alkylamino
radicals having lower alkyl radicals having one to about eight
carbon atoms. Suitable lower alkylamino may be monosubstituted
N-alkylamino or disubstituted N,N-alkylamino, such as
N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or
the like.
The term "substituted" refers to the replacement of one or more
hydrogen radicals in a given structure with the radical of a
specified substituent including, but not limited to: halo, alkyl,
alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio,
alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl,
arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,
aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro,
alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl,
aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,
carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,
heteroaryl, heterocyclic, and aliphatic. It is understood that the
substituent may be further substituted.
For simplicity, chemical moieties that are defined and referred to
throughout can be univalent chemical moieties (e.g., alkyl, aryl,
etc.) or multivalent moieties under the appropriate structural
circumstances clear to those skilled in the art. For example, an
"alkyl" moiety can be referred to a monovalent radical (e.g.
CH.sub.3--CH.sub.2--), or in other instances, a bivalent linking
moiety can be "alkyl," in which case those skilled in the art will
understand the alkyl to be a divalent radical (e.g.,
--CH.sub.2--CH.sub.2--), which is equivalent to the term
"alkylene." Similarly, in circumstances in which divalent moieties
are required and are stated as being "alkoxy", "alkylamino",
"aryloxy", "alkylthio", "aryl", "heteroaryl", "heterocyclic",
"alkyl" "alkenyl", "alkynyl", "aliphatic", or "cycloalkyl", those
skilled in the art will understand that the terms "alkoxy",
"alkylamino", "aryloxy", "alkylthio", "aryl", "heteroaryl",
"heterocyclic", "alkyl", "alkenyl", "alkynyl", "aliphatic", or
"cycloalkyl" refer to the corresponding divalent moiety.
The terms "halogen" or "halo" as used herein, refers to an atom
selected from fluorine, chlorine, bromine and iodine.
The terms "compound" "drug", and "prodrug" as used herein all
include pharmaceutically acceptable salts, co-crystals, solvates,
hydrates, polymorphs, enantiomers, diastereoisomers, racemates and
the like of the compounds, drugs and prodrugs having the formulas
as set forth herein.
Substituents indicated as attached through variable points of
attachments can be attached to any available position on the ring
structure.
As used herein, the term "effective amount of the subject
compounds," with respect to the subject method of treatment, refers
to an amount of the subject compound which, when delivered as part
of desired dose regimen, brings about management of the disease or
disorder to clinically acceptable standards.
"Treatment" or "treating" refers to an approach for obtaining
beneficial or desired clinical results in a patient. For purposes
of this invention, beneficial or desired clinical results include,
but are not limited to, one or more of the following: alleviation
of symptoms, diminishment of extent of a disease, stabilization
(i.e., not worsening) of a state of disease, preventing spread of
disease, preventing occurrence or recurrence of disease, delay or
slowing of disease progression, amelioration of the disease state,
and remission (whether partial or total).
Pharmaceutical Compositions
The pharmaceutical compositions of the present invention comprise a
therapeutically effective amount of a compound of the present
invention formulated together with one or more pharmaceutically
acceptable carriers or excipients.
As used herein, the term "pharmaceutically acceptable carrier or
excipient" means a non-toxic, inert solid, semi-solid, gel or
liquid filler, diluent, encapsulating material or formulation
auxiliary of any type. Some examples of materials which can serve
as pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; cyclodextrins such as alpha-(.alpha.),
beta-(.beta.) and gamma-(.gamma.) cyclodextrins; starches such as
corn starch and potato starch; cellulose and its derivatives such
as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; powdered tragacanth; malt; gelatin; talc; excipients such
as cocoa butter and suppository waxes; oils such as peanut oil,
cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and
soybean oil; glycols such as propylene glycol; esters such as ethyl
oleate and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of
the formulator.
The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. In a preferred embodiment, administration is parenteral
administration by injection.
The pharmaceutical compositions of this invention may contain any
conventional non-toxic pharmaceutically-acceptable carriers,
adjuvants or vehicles. In some cases, the pH of the formulation may
be adjusted with pharmaceutically acceptable acids, bases or
buffers to enhance the stability of the formulated compound or its
delivery form. The term parenteral as used herein includes
subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions, may be formulated according to the known
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable suspension or emulsion, such as INTRALIPID.RTM.,
LIPOSYN.RTM. or OMEGA-VEN.RTM., or solution, in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. INTRALIPID.RTM. is an intravenous fat
emulsion containing 10-30% soybean oil, 1-10% egg yolk
phospholipids, 1-10% glycerin and water. LIPOSYN.RTM. is also an
intravenous fat emulsion containing 2-15% safflower oil, 2-15%
soybean oil, 0.5-5% egg phosphatides 1-10% glycerin and water.
OMEGAVEN.RTM. is an emulsion for infusion containing about 5-25%
fish oil, 0.5-10% egg phosphatides, 1-10% glycerin and water. Among
the acceptable vehicles and solvents that may be employed are
water, Ringer's solution, USP and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any
bland fixed oil can be employed including synthetic mono- or
diglycerides. In addition, fatty acid such as oleic acid are used
in the preparation of injectables.
The injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this
invention with suitable non-irritating excipients or carriers such
as cocoa butter, polyethylene glycol or a suppository wax which are
solid at ambient temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity and release the
active compound.
Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical
formulating art. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to
an active compound of this invention, excipients such as animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
For pulmonary delivery, a therapeutic composition of the invention
is formulated and administered to the patient in solid or liquid
particulate form by direct administration e.g., inhalation into the
respiratory system. Solid or liquid particulate forms of the active
compound prepared for practicing the present invention include
particles of respirable size: that is, particles of a size
sufficiently small to pass through the mouth and larynx upon
inhalation and into the bronchi and alveoli of the lungs. Delivery
of aerosolized therapeutics is known in the art (see, for example
U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.
5,508,269 to Smith et al., and WO 98/43650 by Montgomery).
EXAMPLES
Example 1
5,7-Dimethyl-6-(4-(morpholinomethyl)phenyl)-4-phenyl-2H-chromen-2-one
##STR00069##
4-Bromo-3,5-dimethylphenyl 3-phenylpropiolate (1-1)
##STR00070##
To a stirring mixture of 3-phenylpropiolic (6579 mg, 45.00 mmol),
4-bromo-3,5-dimethylphenol (6032 mg, 30.0 mmol) and
4-(dimethylamino)pyridine (370 mg, 3.0 mmol) in dichloromethane (50
mL) was added a solution of DCC (7442 mg, 36.00 mmol) in
dichloromethane (30 mL) under ice-cooling. The mixture was stirred
under ice-cooling and slowly warmed up to room temperature. After
stirred for 9 h, the mixture was filtered through a pad of Celite
and the filtrate was evaporated to dryness. The residue was
chromatographed on a silica gel (chloroform:hexanes=3:2) to give
the title compound 1-1 (9849 mg, 100% yield) as a pale yellow
oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.70-7.56 (m, 1H),
7.54-7.45 (m, 1H), 7.45-7.34 (m, 1H), 6.93 (s, 1H), 2.43 (s,
3H).
6-Bromo-5,7-dimethyl-4-phenyl-2H-chromen-2-one (1-2)
##STR00071##
To a stirring solution of 4-bromo-3,5-dimethyl-phenyl
3-phenylpropiolate (1-1) (9839 mg, 30.00 mmol) in dichloromethane
(15 mL) and trifluoroacetic acid (45 mL) was added palladium
acetate (350 mg, 1.60 mmol) under ice-cooling. After stirred for 2
h under ice-cooling, the mixture was diluted with
1,2-dichloroethane and evaporated to dryness. The residue was
chromatographed on a silica gel (chloroform:hexanes=1:1-3:2) to
give the title compound 1-2 (7581 mg, 77% yield) as a dark yellow
solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.54-7.39 (m, 3H),
7.35-7.24 (m, 2H), 7.19 (s, 1H), 6.26 (s, 1H), 2.51 (s, 3H), 1.95
(s, 3H).
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 160.00, 156.21, 153.78,
142.84, 139.72, 137.02, 129.24, 129.09, 127.30, 125.93, 117.59,
117.03, 25.02, 24.93.
5,7-Dimethyl-6-(4-(morpholinomethyl)phenyl)-4-phenyl-2H-chromen-2-one
(example 1)
A mixture of 6-bromo-5,7-dimethyl-4-phenyl-2H-chromen-2-one (1-2)
(99 mg, 0.30 mmol), 4-(bromomethyl)phenylboronic acid (97 mg, 0.45
mmol), morpholine (39 .mu.L, 0.45 mmol), potassium carbonate (70
mg, 0.51 mmol) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (25 mg, 0.030
mmol) in a mixture of 1,4-dioxane and water (9:1, 3 mL) was stirred
at 130.degree. C. for 30 min under microwave irradiation. After
cooled to room temperature, the mixture was diluted with ethyl
acetate, filtered through a pad of Celite. The filtrate was washed
with water and brine and dried over sodium sulfate. Evaporation of
the solvents give a residue, which was chromatographed on silica
gel (EtOAc:hexanes=1:1-2:1) to give the title compound 1 (114 mg,
89% yield) as a light brown solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45-7.27 (m, 7H), 7.21
(s, 1H), 7.00 (d, J=8.0, 2H), 6.24 (s, 1H), 3.78-3.64 (m, 4H), 3.52
(s, 2H), 2.51-2.38 (m, 4H), 2.07 (s, 3H), 1.48 (s, 3H).
Example 2
5,7-Dimethyl-4-phenyl-6-(4-(piperidine-1-ylmethyl)phenyl)-2H-chromen-2-one
##STR00072##
A mixture of 6-bromo-5,7-dimethyl-4-phenyl-2H-chromen-2-one (1-2)
(99 mg, 0.30 mmol), 4-(bromomethyl)phenylboronic acid (97 mg, 0.45
mmol), piperidine (45 .mu.L, 0.46 mmol), potassium carbonate (124
mg, 0.90 mmol) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (22 mg, 0.03
mmol) in a mixture of 1,4-dioxane and water (9:1, 3 mL) was stirred
at 100.degree. C. for 4 h. After cooled to room temperature, the
mixture was partitioned between ethyl acetate and water. Organic
phase was separated and dried over magnesium sulfate. Evaporation
of the solvents give a residue, which was chromatographed on silica
gel (EtOAc:hexanes=1:2-1:1) to give the title compound 2 (103 mg,
81% yield) as a yellow solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45-7.36 (m, 3H),
7.36-7.27 (m, 4H), 7.21 (s, 1H), 6.98 (d, J=8.0, 2H), 6.24 (s, 1H),
3.48 (s, 2H), 2.38 (s, 4H), 2.08 (s, 3H), 1.66-1.52 (m, 4H), 1.49
(s, 3H), 1.47-1.37 (m, 2H).
MS (ESI) m/z 424 (M+H).sup.+.
Example 3
6-(4-((Cyclohexylamino)methyl)phenyl)-5,7-dimethyl-4-phenyl-2H-chromen-2-o-
ne
##STR00073##
A mixture of 6-bromo-5,7-dimethyl-4-phenyl-2H-chromen-2-one (1-2)
(99 mg, 0.30 mmol), 4-(bromomethyl)phenylboronic acid (97 mg, 0.45
mmol), cyclohexylamine (52 .mu.L, 0.45 mmol), potassium carbonate
(70 mg, 0.51 mmol) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (25 mg,
0.030 mmol) in a mixture of 1,4-dioxane and water (9:1, 3 mL) was
stirred at 130.degree. C. for 30 min under microwave irradiation.
After cooled to room temperature, the mixture was diluted with
ethyl acetate, filtered through a pad of Celite. The filtrate was
washed with water and brine and dried over sodium sulfate.
Evaporation of the solvents give a residue, which was
chromatographed on silica gel (EtOAc:hexanes=1:1-2:1-1:0) to give
the title compound 3 (79 mg, 60% yield) as a brown gum.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.46-7.27 (m, 7H), 7.21
(s, 1H), 7.00 (d, J=7.9, 2H), 6.24 (s, 1H), 3.83 (s, 2H), 2.60-2.41
(m, 1H), 2.07 (s, 3H), 2.00-1.86 (m, 2H), 1.84-1.66 (m, 2H),
1.67-1.55 (m, 2H), 1.49 (s, 5H), 1.36-0.99 (m, 7H).
Example 4
6-(4-((Hexylamino)methyl)phenyl)-5,7-dimethyl-4-phenyl-2H-chromen-2-one
##STR00074##
A mixture of 6-bromo-5,7-dimethyl-4-phenyl-2H-chromen-2-one (1-2)
(99 mg, 0.30 mmol), 4-(bromomethyl)phenylboronic acid (97 mg, 0.45
mmol), 1-hexylamine (60 .mu.L, 0.45 mmol), potassium carbonate (70
mg, 0.51 mmol) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (25 mg, 0.03
mmol) in a mixture of 1,4-dioxane and water (9:1, 3 mL) was stirred
at 130.degree. C. for 30 min under microwave irradiation. After
cooled to room temperature, the mixture was diluted with ethyl
acetate, filtered through a pad of Celite. The filtrate was washed
with water and brine and dried over sodium sulfate. Evaporation of
the solvents give a residue, which was chromatographed on silica
gel (ethyl acetate:hexanes=1:1.about.2:1.about.1:0) to give the
title compound 4 (44 mg, 33% yield) as a brown caramel.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.47-7.27 (m, 7H), 7.21
(s, 1H), 7.00 (d, J=8.0, 2H), 6.24 (s, 1H), 3.81 (s, 2H), 2.72-2.58
(m, 2H), 2.07 (s, 3H), 1.50 (m, 5H), 1.41-1.09 (m, 8H), 0.87 (t,
J=6.8, 3H).
Example 5
5,7-Dimethyl-6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-phenyl-2H-chro-
men-2-one
##STR00075##
A mixture of 6-bromo-5,7-dimethyl-4-phenyl-2H-chromen-2-one (1-2)
(99 mg, 0.30 mmol), 4-(bromomethyl)phenylboronic acid (97 mg, 0.45
mmol), 1-methyl-piperidine (50 .mu.L, 0.45 mmol), potassium
carbonate (70 mg, 0.51 mmol) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2
(25 mg, 0.03 mmol) in a mixture of 1,4-dioxane and water (9:1, 3
mL) was stirred at 130.degree. C. for 30 min under microwave
irradiation. After cooled to room temperature, the mixture was
diluted with ethyl acetate, filtered through a pad of Celite. The
filtrate was washed with water and brine and dried over sodium
sulfate. Evaporation of the solvents give a residue, which was
chromatographed on silica gel (0-5% methanol in chloroform) to give
the title compound 5 (27 mg, 20% yield) as a brown gum.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.47-7.37 (m, 3H),
7.38-7.27 (m, 4H), 7.21 (s, 1H), 6.99 (d, J=8.0, 2H), 6.24 (s, 1H),
3.51 (s, 2H), 2.41 (brs, 8H), 2.29 (s, 3H), 2.04 (s, 3H), 1.49 (s,
3H).
Example 6
4-(3-Aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen-2-
-one hydrochloride
##STR00076##
4-Bromo-3,5-dimethylphenyl propiolate (6-1)
##STR00077##
To a stirred solution of 4-bromo-3,5-dimethylphenol (40.87 g, 203.3
mmol) and propiolic acid (20.91 g, 298.5 mmol) in CH.sub.2Cl.sub.2
(400 mL) was added DCC (50.78 g, 246.1 mmol) in CH.sub.2Cl.sub.2
(100 mL) and DMAP (0.82 g, 6.7 mmol) at 0.degree. C. The mixture
was stirred at room temperature for 3 h and filtered. The filtrate
was concentrated and purified by silica gel column chromatography
(hexanes:EtOAc:CH.sub.2Cl.sub.2=20:1:10). The fractions containing
the desired compound were concentrated. To the concentrate added
hexane and the precipitated solid was collected by filtration. The
solid was washed with hexane and dried to give the title compound
6-1 (26.12 g, 51% yield) as a white solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.89 (s, 2H), 3.08 (s,
1H), 2.42 (s, 6H).
4-Bromo-3,5-dimethylphenyl 3-(3-nitrophenyl)propiolate (6-2)
##STR00078##
1-Iodo-3-nitrobenzene (41.05 g, 164.3 mmol) in THF (100 mL) was
degassed under reduced pressure at -78.degree. C., and then
nitrogen gas was introduced. To the solution was added
K.sub.2CO.sub.3 (41.27 g, 298.6 mmol), CuI (2.27 g, 11.9 mmol) and
PdCl.sub.2(Ph.sub.3P).sub.2 (1.11 g, 1.57 mmol), and the mixture
was stirred at 65.degree. C. 4-bromo-3,5-dimethylphenyl propiolate
(6-1) (37.79 g, 149.3 mmol) in THF (68 mL) was added by syringe
pump over a period of 5.4 hr, and the mixture was stirred an
additional 1 h after addition was complete. After being cooled to
room temperature, the mixture was filtered. The filtrate was
concentrated and purified by silica gel column chromatography. The
fractions containing the desired compound were concentrated. To the
concentrate added hexane and the precipitated solid was collected
by filtration. The solid was washed with hexane and dried to give
the title compound 6-2 (15.96 g, 29% yield) as a brown solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.49 (s, 1H), 8.35 (d,
J=7.8, 1H), 7.94 (d, J=7.8, 1H), 7.64 (t, J=7.8, 1H), 6.94 (s, 2H),
2.44 (s, 6H).
6-Bromo-5,7-dimethyl-4-(3-nitrophenyl)-2H-chromen-2-one (6-3)
##STR00079##
To a stirred solution of 4-bromo-3,5-dimethylphenyl
3-(3-nitrophenyl)propiolate (6-2) (15.96 g, 42.65 mmol) in
CH.sub.2Cl.sub.2 (100 mL) was added TFA (10 mL) and Pd(OAc).sub.2
(480 mg, 2.14 mmol) at 0.degree. C. The mixture was warmed to room
temperature and stirred for 4.5 h. To the mixture was added
1,2-dichloroethane and concentrated. Then toluene was added and
concentrated. To the concentrate added toluene, dichloromethane and
hexane, and the precipitated solid was collected by filtration. The
solid was washed with hexane and dried to give the title compound
6-3 (15.51 g, 97% yield) as a brown solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.35 (d, J=7.7, 1H), 8.19
(s, 1H), 7.70 (t, J=7.7, 1H), 7.65 (d, J=7.7, 1H), 7.24 (s, 1H),
6.31 (s, 1H), 2.54 (s, 3H), 1.95 (s, 3H).
MS (ESI) m/z 374 (M+H).sup.+.
4-(3-Aminophenyl)-6-bromo-5,7-dimethyl-2H-chromen-2-one (6-4)
##STR00080##
To a stirred solution of
6-bromo-5,7-dimethyl-4-(3-nitrophenyl)-2H-chromen-2-one (6-3)
(15.41 g, 41.18 mmol) in EtOH (100 mL) and acetic acid (40 mL) was
added iron (11.50 g, 205.9 mmol) at room temperature. The mixture
was heated at 110.degree. C. for 2 h. The reaction mixture was
cooled at room temperature and filtrated. To the filtrate was added
EtOAc and Na.sub.2CO.sub.3 (37 g, 0.35 mol) in water (200 mL).
After being stirred at room temperature, the mixture was filtrated.
Then the filtrated was diluted with EtOAc and extracted with EtOAc.
The organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated. To the concentrate added
CH.sub.2Cl.sub.2-MeOH (1:9), and the precipitated solid was
collected by filtration. The solid was washed with
CH.sub.2Cl.sub.2-MeOH (1:9) and purified by silica gel column
chromatography (hexanes:EtOAc=2:1.about.1:1) to give the title
compound 6-4 (2.44 g, 17% yield) as a yellow solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.22 (t, J=7.9, 1H), 7.20
(s, 1H), 6.75 (d, J=7.9, 1H), 6.64 (d, J=7.9, 1H), 6.58 (s, 1H),
6.27 (s, 1H), 3.80 (s, 2H), 2.52 (s, 3H), 2.05 (s, 3H).
MS (ESI) m/z 344 (M+H).sup.+.
4-(3-Aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen-2-
-one (6-5)
##STR00081##
A mixture of
4-(3-aminophenyl)-6-bromo-5,7-dimethyl-2H-chromen-2-one (6-4) (25
mg, 0.073 mmol), 4-(bromomethyl)phenylboronic acid (24 mg, 0.11
mmol), morpholine (30 .mu.L, 0.35 mmol), K.sub.2CO.sub.3 (18 mg,
0.13 mmol),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)-dichlo-
romethane adduct (6 mg, 0.007 mmol), water (0.3 mL) and 1,4-dioxane
(2.7 mL) was heated in a sealed vial in a microwave reactor at
130.degree. C. for 30 min. To the mixture was added EtOAc and
water, and extracted with EtOAc. The organic layers were washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by silica gel column chromatography (hexanes:
EtOAc=1:1.about.0:1) to afford the title compound 6-5 (24 mg, 75%
yield) as a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35 (d, J=8.0, 2H), 7.19
(s, 1H), 7.16 (d, J=7.7, 1H), 7.00 (d, J=8.0, 2H), 6.71-6.63 (m,
2H), 6.60 (s, 1H), 6.24 (s, 1H), 3.77-3.69 (m, 6H), 3.52 (s, 2H),
2.48-2.42 (m, 4H), 2.07 (s, 3H), 1.59 (s, 3H).
MS (ESI) m/z 441 (M+H).sup.+.
4-(3-Aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen-2-
-one hydrochloride (example 6)
To a stirred solution of
4-(3-aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen--
2-one (6-5) (290 mg, 0.658 mmol) in TBME (4 mL) was added
hydrochloric acid (110 .mu.L) in EtOH (0.1 mL) and TBME (3 mL) at
50.degree. C. After being heated at 50.degree. C. for 0.5 h, the
mixture was stirred at room temperature for 1 h. Then the
precipitated solid was collected by filtration and washed with TBME
to give the title compound 6 (311 mg, 59% yield) as a yellow
solid.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.66-7.56 (m, 3H),
7.44-7.37 (m, 2H), 7.35-7.25 (m, 4H), 6.27 (s, 1H), 4.42 (s, 2H),
4.10-4.01 (m, 2H), 3.82-3.70 (m, 2H), 3.44-3.37 (m, 2H), 3.26-3.20
(m, 2H), 2.08 (s, 3H), 1.54 (s, 3H).
Example 7
4-(4-Aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen-2-
-one
##STR00082##
4-Bromo-3,5-dimethylphenyl 3-(4-nitrophenyl)propiolate (7-1)
##STR00083##
1-Iodo-4-nitrobenzene (550 mg, 2.17 mmol) in THF (4 mL) was
degassed under reduced pressure at -78.degree. C., and then
nitrogen gas was introduced. To the solution was added
K.sub.2CO.sub.3 (552 mg, 298.6 mmol), CuI (30 mg, 0.16 mmol) and
PdCl.sub.2(Ph.sub.3P).sub.2 (14 mg, 0.020 mmol), and the mixture
was stirred at 65.degree. C. 4-bromo-3,5-dimethylphenyl propiolate
(6-1) (506 mg, 2.03 mmol) in THF (2.5 mL) was added by syringe pump
over a period of 6 h. After being cooled to room temperature, the
mixture was filtered and washed with EtOAc. The filtrate was
concentrated and purified by silica gel column chromatography to
give the title compound 7-1 (551 mg, 74% yield) as a brown
solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.29 (d, J=8.7, 2H), 7.81
(d, J=8.7, 2H), 6.94 (s, 2H), 2.44 (s, 6H).
6-Bromo-5,7-dimethyl-4-(4-nitrophenyl)-2H-chromen-2-one (7-2)
4-(4-Aminophenyl)-6-bromo-5,7-dimethyl-2H-chromen-2-one (7-3)
##STR00084##
To a stirred solution of 4-bromo-3,5-dimethylphenyl
3-(4-nitrophenyl)propiolate (7-1) (524 mg, 1.40 mmol) in
CH.sub.2Cl.sub.2 (8 mL) was added TFA (0.8 mL) and Pd(OAc).sub.2
(16 mg, 0.071 mmol) at 0.degree. C. The mixture was warmed to room
temperature and stirred for 3.5 h. To the mixture was added
1,2-dichloroethane and concentrated. Then to the concentrate were
added CHCl.sub.3, DMSO and EtOH, and filtrated. The filtrate was
concentrated and purified by silica gel column chromatography to
afford the crude material (22 mg) containing compound 7-2.
To a stirred solution of the crude material (22 mg) containing
6-bromo-5,7-dimethyl-4-(4-nitrophenyl)-2H-chromen-2-one (7-2) in
EtOH (0.75 mL) and acetic acid (0.15 mL) was added iron (16 mg,
0.29 mmol) at room temperature. The mixture was heated at
110.degree. C. for 2.5 h. The reaction mixture was then cooled at
room temperature and filtrated. To the filtrate was added EtOAc and
saturated NaHCO.sub.3 solution, and extracted with EtOAc. The
organic layers were washed with brine, dried over Na.sub.2SO.sub.4
and concentrated. The residues was purified by silica gel column
chromatography (hexane:EtOAc=5:1.about.2:1) to give the title
compound 7-3 (4.0 mg, 0.8% yield, 2 steps) as an orange solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.19 (s, 1H), 7.08 (d,
J=8.4, 2H), 6.74 (d, J=8.4, 2H), 6.24 (s, 1H), 3.89 (s, 2H), 2.52
(s, 3H), 2.06 (s, 3H).
MS (ESI) m/z 344 (M+H).sup.+.
4-(4-Aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen-2-
-one (example 7)
A mixture of
4-(4-aminophenyl)-6-bromo-5,7-dimethyl-2H-chromen-2-one (7-3) (4
mg, 0.01 mmol), 4-(bromomethyl)phenylboronic acid (4 mg, 0.02
mmol), morpholine (4.7 .mu.L, 0.054 mmol), potassium carbonate (3
mg, 0.02 mmol),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)-dichlorometha-
ne adduct (1 mg, 0.001 mmol), water (0.2 mL) and 1,4-dioxane (1.8
mL) was heated in a sealed vial in a microwave reactor at
130.degree. C. for 30 min. To the mixture was added EtOAc and
water, and extracted with EtOAc. The organic layers were combined,
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated.
The residue was purified by silica gel column chromatography
(hexanes:EtOAc=5:5.about.0:1), and then purified by preparative TLC
to afford the title compound 7 (2.3 mg, 43% yield) as a yellow
oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.36 (d, J=8.0, 2H), 7.18
(s, 1H), 7.08 (d, J=8.5, 2H), 7.02 (d, J=8.0, 2H), 6.70 (d, J=8.5,
2H), 6.22 (s, 1H), 3.81 (s, 2H), 3.75-3.70 (m, 4H), 3.53 (s, 2H),
2.49-2.43 (m, 4H), 2.07 (s, 3H).
MS (ESI) m/z 441 (M+H).sup.+.
Example 8
5,7-Dimethyl-6-(4-(morpholinomethyl)phenyl)-4-(3-nitrophenyl)-2H-chromen-2-
-one
##STR00085##
A mixture of
6-bromo-5,7-dimethyl-4-(3-nitrophenyl)-2H-chromen-2-one (6-3) (27
mg, 0.073 mmol), 4-(bromomethyl)phenylboronic acid (24 mg, 0.11
mmol), morpholine (10 .mu.L, 0.12 mmol), potassium carbonate (18
mg, 0.13 mmol),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)-dichlo-
romethane adduct (6 mg, 0.007 mmol), water (0.3 mL) and 1,4-dioxane
(2.7 mL) was heated in a sealed vial in a microwave reactor at
130.degree. C. for 30 min. To the mixture was added EtOAc and
water, and extracted with EtOAc. The organic layers were combined,
washed with brine, dried over MgSO.sub.4 and concentrated. The
residue was purified by silica gel column chromatography
(hexanes:EtOAc=2:1.about.1:1.about.0:1) to afford the title
compound 8 (15 mg, 44% yield) as a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.31-8.26 (m, 1H),
8.22-8.21 (m, 1H), 7.71-7.64 (m, 2H), 7.36 (d, J=7.2, 2H), 7.25 (s,
1H), 7.04-6.96 (m, 2H), 6.26 (s, 1H), 3.73-3.69 (m, 4H), 3.52 (s,
2H), 2.48-2.42 (m, 4H), 2.09 (s, 3H), 1.47 (s, 3H).
MS (ESI) m/z 471 (M+H).sup.+.
Example 9
Methyl
3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-chromen-4-y-
l)benzoate
##STR00086##
Methyl 3-(3-(tert-butoxy)-3-oxoprop-1-yn-1-yl)benzoate (9-1)
##STR00087##
To the mixture of methyl 3-iodobenzoate (157 mg, 0.60 mmol),
potassium carbonate (166 mg, 1.20 mmol), cupper(I) iodide (14 mg,
0.07 mmol) and PdCl.sub.2(Ph.sub.3P).sub.2 (21 mg, 0.03 mmol) in
tetrahydrofuran (2 mL) was added tert-butyl propiolate (330 .mu.L,
2.40 mmol) at room temperature. After stirred for 20 h at
60.degree. C., the mixture was evaporated to dryness. The residue
was chromatographed on a silica gel (EtOAc:hexanes=0:1.about.1:10)
to give the title compound 9-1 (155 mg, 99% yield) as a light brown
oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.25 (t, J=1.4, 1H),
8.16-8.05 (m, 1H), 7.80-7.68 (m, 1H), 7.46 (t, J=7.8, 1H), 3.93 (s,
3H), 1.55 (s, 9H).
3-(3-(Methoxycarbonyl)phenyl)propiolic acid (9-2)
##STR00088##
The mixture of methyl
3-(3-(tert-butoxy)-3-oxoprop-1-yn-1-yl)benzoate (9-1) (139 mg, 0.53
mmol) in a mixture of trifluoroacetic acid and dichloromethane
(v:v=95:5, 1.5 mL) was stirred at room temperature for 2 h. The
mixture was diluted with 1,2-dichloroethane and the whole was
evaporated to dryness. The residue was triturated with hexane and
the solid was collected by decantation and dried under vacuum to
give the title compound 9-2 (102 mg, 94% yield) as a light brown
solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.16-8.02 (m, 2H), 7.91
(dt, J=7.7, 1.3, 1H), 7.64 (t, J=7.7, 1H), 3.88 (s, 3H).
.sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 165.12, 154.00, 136.87,
132.86, 131.21, 130.44, 129.79, 119.62, 82.87, 82.31, 52.51.
Methyl
3-(3-(4-bromo-3,5-dimethylphenoxy)-3-oxoprop-1-yn-1-yl)benzoate
(9-3)
##STR00089##
To a stirring solution of 3-(3-methoxycarbonylphenyl)propiolic acid
(9-2) (102 mg, 0.50 mmol), 4-bromo-3,5-dimethylphenol (103 mg, 0.51
mmol) and 4-(dimethylamino)pyridine (12 mg, 0.10 mmol) in
dichloromethane (2 mL) was added a solution of DCC (114 mg, 0.55
mmol) in dichloromethane (1 mL) under ice-cooling. The mixture was
stirred under ice-cooling for 30 min then stirred at room
temperature for 18 h. The mixture was diluted with dichloromethane
filtered through a pad of Celite. The filtrate was evaporated to
dryness, which was chromatographed on a silica gel
(dichloromethane:hexanes=2:3) to give title compound 9-3 (95 mg,
49% yield) as a white solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.31 (t, J=1.4, 1H),
8.22-8.07 (m, 1H), 7.87-7.71 (m, 1H), 7.51 (t, J=7.8, 1H), 6.94 (s,
2H), 3.95 (s, 3H), 2.43 (s, 6H).
Methyl 3-(6-bromo-5,7-dimethyl-2-oxo-2H-chromen-4-yl)benzoate
(9-4)
##STR00090##
To a stirring solution of methyl
3-(3-(4-bromo-3,5-dimethylphenoxy)-3-oxoprop-1-yn-1-yl)benzoate
(9-3) (95 mg, 0.25 mmol) in dichloromethane (1 mL) and
trifluoroacetic acid (2 mL) was added palladium acetate (5 mg, 0.02
mmol) under ice-cooling. After stirred for 3 h under ice-cooling,
the mixture was diluted with 1,2-dichloromethane and evaporated to
dryness. Chromatography of the residue on a silica gel
(chloroform:hexanes=1:1-1:0) gave title compound 9-4 (69 mg, 73%
yield) as a light brown gum.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.15 (dt, J=7.7, 1.4,
1H), 7.99 (t, J=1.7, 1H), 7.57 (t, J=7.7, 1H), 7.49 (dt, J=7.7,
1.5, 1H), 7.23 (s, 1H), 6.28 (s, 1H), 3.95 (s, 3H), 2.53 (s, 3H),
1.94 (s, 3H).
Methyl
3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-chromen-4-y-
l)benzoate (example 9)
A mixture of methyl
3-(6-bromo-5,7-dimethyl-2-oxo-2H-chromen-4-yl)benzoate (9-4) (63
mg, 0.16 mmol), 4-(bromomethyl)phenylboronic acid (51 mg, 0.24
mmol), morpholine (21 .mu.L, 0.24 mmol), potassium carbonate (37
mg, 0.27 mmol),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)-dichlorometha-
ne adduct (13 mg, 0.016 mmol), water (0.3 mL) and 1,4-dioxane (2.7
mL) was heated in a sealed vial in a microwave reactor at
130.degree. C. for 30 min. To the mixture was added EtOAc and
water, and extracted with EtOAc. The organic layers were combined,
washed with saturated NaHCO.sub.3 solution and brine, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
silica gel column chromatography (hexanes:
EtOAc=4:1.fwdarw.3:2.fwdarw.1:1) to afford the title compound 9 (41
mg, 53% yield) as a foam.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.08 (s, 1H), 8.01 (s,
1H), 7.51 (s, 2H), 7.35 (d, J=7.8, 2H), 7.23 (s, 1H), 7.05-6.96 (m,
2H), 6.24 (s, 1H), 3.93 (s, 3H), 3.72 (s, 4H), 3.52 (s, 2H), 2.45
(s, 4H), 2.08 (s, 3H), 1.46 (s, 3H).
MS (ESI) m/z 484 (M+H).sup.+.
Example 10
N-(3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-chromen-4-yl)ph-
enyl)acetamide
##STR00091##
To a stirred solution of
4-(3-aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen--
2-one (6-5) (14 mg, 0.03 mmol) and Et.sub.3N (21 .mu.L, 0.15 mmol)
in CH.sub.2Cl.sub.2 (1.5 mL) was added acetyl chloride (3 .mu.L) at
room temperature. After being stirred at room temperature for 2 h,
to the mixture was added acetyl chloride (2 .mu.L). Then the
mixture was stirred at room temperature for 0.5 h. The mixture was
diluted with EtOAc and brine, and then extracted with EtOAc. The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by silica gel column
chromatography (EtOAc:MeOH=10:0.about.9:1.about.8:2) to afford the
title compound 10 (15 mg, quantitative yield) as a colorless
oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.58 (s, 1H), 7.44 (d,
J=7.2, 1H), 7.38-7.32 (m, 4H), 7.23-7.19 (m, 2H), 7.06-6.98 (m,
3H), 6.23 (s, 1H), 3.73-3.69 (m, 4H), 3.52 (s, 2H), 2.47-2.43 (m,
4H), 2.19 (s, 3H), 2.07 (s, 3H), 1.55 (s, 3H).
MS (ESI) m/z 483 (M+H).sup.+.
Example 11
N-(3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-chromen-4-yl)ph-
enyl)methanesulfonamide
##STR00092##
To a stirred solution of
4-(3-aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen--
2-one (6-5) (10 mg, 0.023 mmol) and pyridine (18 .mu.L) in
CH.sub.2Cl.sub.2 (1.0 mL) was added methanesulfonyl chloride (3
.mu.L) at room temperature. After being stirred at room temperature
for 1 h, to the mixture was added additional methanesulfonyl
chloride (6 .mu.L). Then the mixture was stirred at room
temperature for 2.7 h. The mixture was diluted with brine, and
extracted with CH.sub.2Cl.sub.2. The combined organic layers were
concentrated. The residue was purified by silica gel column
chromatography
(hexanes:EtOAc:MeOH=5:5:0.fwdarw.0:10:0.fwdarw.0:9:1.fwdarw.0:8:2)
to afford the title compound 11 (6 mg, 50% yield) as a yellow
oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45-7.34 (m, 3H),
7.22-7.12 (m, 3H), 7.05-6.98 (m, 2H), 6.55 (s, 1H), 6.24 (s, 1H),
3.78-3.70 (m, 4H), 3.55 (s, 2H), 3.04 (s, 3H), 2.54-2.44 (m, 4H),
2.08 (s, 3H), 1.54 (s, 3H).
MS (ESI) m/z 519 (M+H).sup.+.
Example 12
Ethyl
(3-(5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2-oxo-2H-chromen-4-y-
l)phenyl)carbamate
##STR00093##
To a stirred solution of
4-(3-aminophenyl)-5,7-dimethyl-6-(4-(morpholinomethyl)phenyl)-2H-chromen--
2-one (6-5) (10 mg, 0.023 mmol) and pyridine (18 .mu.L) in
CH.sub.2Cl.sub.2 (1.0 mL) was added ethyl chloroformate (3 .mu.L)
at room temperature. After being stirred at room temperature for 1
h, the mixture was diluted with brine, and then extracted with
CH.sub.2Cl.sub.2. The combined organic layers were concentrated.
The residue was purified by silica gel column chromatography
(hexanes:EtOAc=5:5.fwdarw.0:10) to afford the title compound 12 (9
mg, 76% yield) as a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45 (s, 1H), 7.37-7.32
(m, 4H), 7.20 (s, 1H), 7.05-6.98 (m, 3H), 6.63 (s, 1H), 6.24 (s,
1H), 4.22 (d, J=7.2, 2H), 3.74-3.69 (m, 4H), 3.52 (s, 2H),
2.48-2.43 (m, 4H), 2.07 (s, 3H), 1.54 (s, 3H), 1.30 (d, J=7.2,
3H).
MS (ESI) m/z 513 (M+H).sup.+.
Example 13
5,7-Dimethyl-6-(4-(morpholinomethyl)phenyl)-4-(pyridin-3-yl)-2H-chromen-2--
one
##STR00094##
4-Bromo-3,5-dimethylphenyl 3-(pyridin-3-yl)propiolate (13-1)
##STR00095##
3-Iodopyridine (226 mg, 1.10 mmol) in THF (2 mL) was degassed under
reduced pressure at -78.degree. C., and then nitrogen gas was
introduced. To the solution was added K.sub.2CO.sub.3 (276 mg, 2.00
mmol), CuI (15 mg, 0.079 mmol) and PdCl.sub.2(Ph.sub.3P).sub.2 (7
mg, 0.01 mmol), and the mixture was stirred at 65.degree. C.
4-bromo-3,5-dimethylphenyl propiolate (6-1) (253 mg, 1.00 mmol) in
THF (2 mL) was added by syringe pump over a period of 5 h, and the
mixture was stirred an additional 1 h after addition was complete.
After being cooled to room temperature, the mixture was filtered.
The filtrate was concentrated and purified by silica gel column
chromatography to give the title compound 13-1 (88 mg, 27% yield)
as a black oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.86 (s, 1H), 8.71 (dd,
J=1.4, 4.9, 1H), 7.93 (dt, J=1.4, 7.9, 1H), 7.38 (ddd, J=0.8, 4.9,
7.9, 1H), 6.94 (s, 2H), 2.44 (s, 6H).
MS (ESI) m/z 331 (M+H).sup.+.
6-Bromo-5,7-dimethyl-4-(pyridin-3-yl)-2H-chromen-2-one (13-2)
5,7-Dimethyl-6-(4-(morpholinomethyl)phenyl)-4-(pyridin-3-yl)-2H-chromen-2--
one (example 13)
##STR00096##
To a stirred solution of 4-bromo-3,5-dimethylphenyl
3-(pyridin-3-yl)propiolate (13-1) (87 mg, 0.26 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was added TFA (0.1 mL) and Pd(OAc).sub.2 (3
mg, 0.01 mmol) at 0.degree. C. The mixture was warmed to room
temperature and stirred for 1.3 h. To the mixture was added TFA
(0.9 mL) and Pd(OAc).sub.2 (30 mg, 0.13 mmol), and stirred for 2 h.
To the mixture was added 1,2-dichloroethane and concentrated. Then
to the concentrate was added EtOAc and saturated NaHCO.sub.3
solution, and the precipitated solid was collected by
filtration.
The solid was washed with EtOAc and the filtrate was extracted with
EtOAc. The organic layers were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was combined with
the solid to afford the crude material containing compound
13-2.
A mixture of the crude material containing
6-bromo-5,7-dimethyl-4-(pyridin-3-yl)-2H-chromen-2-one (13-2),
4-(bromomethyl)phenylboronic acid (84 mg, 0.39 mmol), morpholine
(101 .mu.L, 1.17 mmol), K.sub.2CO.sub.3 (65 mg, 0.47 mmol),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)-dichlorometha-
ne adduct (21 mg, 0.026 mmol), water (0.2 mL) and 1,4-dioxane (1.8
mL) was heated in a sealed vial in a microwave reactor at
130.degree. C. for 30 min. To the mixture was added EtOAc and
water, and extracted with EtOAc. The organic layers were combined,
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated.
The residue was purified by silica gel column chromatography
(hexanes:EtOAc=5:5.fwdarw.0:1). The fractions containing the
desired compound were pooled and concentrated. To the concentrate
was added aqueous 1N HCl, TBME and PhMe, and extracted with aqueous
1N HCl. The aqueous layers were added water, brine and
CH.sub.2Cl.sub.2, and extracted with CH.sub.2Cl.sub.2 and EtOAc.
The organic layers were concentrated and then purified by
preparative TLC to afford the title compound 13 (1.4 mg, 1.3%
yield, 2 steps) as a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (d, J=4.0, 1H), 8.60
(s, 1H), 7.66 (d, J=7.8, 1H), 7.41-7.33 (m, 3H), 7.24 (s, 1H), 7.00
(d, J=6.7, 2H), 6.26 (s, 1H), 3.77-3.68 (m, 4H), 3.53 (s, 2H),
2.50-2.41 (m, 4H), 2.09 (s, 3H), 1.51 (s, 3H).
MS (ESI) m/z 427 (M+H).sup.+.
Example 14
The antitubercular activity was evaluated against Mtb strain H37Rv.
The inhibitory activity (IC.sub.90) of the compounds is reported in
Table A.
IC.sub.90 was determined using an OD600 based assay. Bacteria were
grown to mid-log phase and plated in 96 well plates at OD600=0.025
in the presence of small molecule inhibitors. Bacteria were
incubated in sealed Tupperware containers for 7 days, and growth
was assessed by reading OD600. The IC.sub.90 was defined as the
concentration of inhibitor which resulted in 90% inhibition of
growth of the control. For IC.sub.99 determinations, cultures were
set up as described above, however plates were incubated for a
total of 14 days at which time cultures were harvested and plated
on agar plates for enumeration of CFU. The IC.sub.99 was determined
as the concentration of inhibitor that resulted in 99% inhibition
of growth relative to the DMSO control.
The patent and scientific literature referred to herein establishes
the knowledge that is available to those with skill in the art. All
United States patents and published or unpublished United States
patent applications cited herein are incorporated by reference. All
published foreign patents and patent applications cited herein are
hereby incorporated by reference. All other published references,
documents, manuscripts and scientific literature cited herein are
hereby incorporated by reference.
While this invention has been particularly shown and described with
references to preferred embodiments thereof, it will be understood
by those skilled in the art that various changes in form and
details may be made therein without departing from the scope of the
invention encompassed by the appended claims.
* * * * *
References