U.S. patent application number 13/773785 was filed with the patent office on 2013-09-05 for anti-bacterial activity of 9-hydroxy derivatives of 6,11-bicyclolides.
This patent application is currently assigned to Enanta Pharmaceuticals, Inc.. The applicant listed for this patent is ENANTA PHARMACEUTICALS, INC.. Invention is credited to Rajesh Iyengar, Yat Sun Or, Ly Tam Phan, Yanchun Wang.
Application Number | 20130231298 13/773785 |
Document ID | / |
Family ID | 41265425 |
Filed Date | 2013-09-05 |
United States Patent
Application |
20130231298 |
Kind Code |
A1 |
Iyengar; Rajesh ; et
al. |
September 5, 2013 |
ANTI-BACTERIAL ACTIVITY OF 9-HYDROXY DERIVATIVES OF
6,11-BICYCLOLIDES
Abstract
The present invention discloses compounds of formula (I) or
pharmaceutically acceptable salts, esters, or prodrugs thereof:
##STR00001## which exhibit superior antibacterial properties,
particularly against Haemophilus influenzae. The present invention
further relates to pharmaceutical compositions comprising the
aforementioned compounds for administration to a subject in need of
antibiotic treatment. The invention also relates to methods of
treating a bacterial infection in a subject by administering a
pharmaceutical composition comprising the compounds of the present
invention. The invention further includes process by which to make
the compounds of the present invention.
Inventors: |
Iyengar; Rajesh; (West
Newton, MA) ; Wang; Yanchun; (Newton, MA) ;
Phan; Ly Tam; (Milton, MA) ; Or; Yat Sun;
(Watertown, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ENANTA PHARMACEUTICALS, INC. |
Watertown |
MA |
US |
|
|
Assignee: |
Enanta Pharmaceuticals,
Inc.
Watertown
MA
|
Family ID: |
41265425 |
Appl. No.: |
13/773785 |
Filed: |
February 22, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12437616 |
May 8, 2009 |
8383785 |
|
|
13773785 |
|
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|
61051991 |
May 9, 2008 |
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Current U.S.
Class: |
514/29 ;
536/7.1 |
Current CPC
Class: |
C07H 17/08 20130101;
A61P 31/04 20180101; A61P 29/00 20180101; A61K 31/7056 20130101;
A61K 31/706 20130101 |
Class at
Publication: |
514/29 ;
536/7.1 |
International
Class: |
A61K 31/706 20060101
A61K031/706; A61K 31/7056 20060101 A61K031/7056; C07H 17/08
20060101 C07H017/08 |
Claims
1. Compounds represented by formula (I): ##STR00082## or a
racemate, enantiomer, diastereomer, geometric isomer, tautomer,
solvate, pharmaceutically acceptable salt, ester and prodrug
thereof, wherein V is selected from the group consisting of: (a)
--R.sub.1--, where R.sub.1 is substituted or unsubstituted
--C.sub.1-C.sub.8 alkylene-, --C.sub.2-C.sub.8 alkenylene- or
--C.sub.2-C.sub.8 alkynylene- each containing 0, 1, 2, or 3
heteroatoms selected from O, S or N; (b)
--R.sub.1--(C.dbd.O)--R.sub.2--, where R.sub.2 is independently
selected from R.sub.1; (c)
--R.sub.1--(C.dbd.N-E-R.sub.3)--R.sub.2--, where E is absent, O,
NH, NH(C.dbd.O), NH(C.dbd.O)NH or NHSO.sub.2; where R.sub.3 is
independently selected from the group consisting of: (i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) --R.sub.4, where R.sub.4 is substituted or unsubstituted
--C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl or
--C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms
selected from O, S or N; and (iv) --R.sub.5, where R.sub.5 is
substituted and unsubstituted --C.sub.3-C.sub.12 cycloalkyl each
containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; (d)
--R.sub.1--(C.dbd.CH-J-R.sub.6)--R.sub.2--; where J is absent, O,
CO, SO.sub.2, NH, NH(C.dbd.O), NH(C.dbd.O)NH or NHSO.sub.2; and
wherein R.sub.6 is independently selected from halogen and R.sub.3;
(e) --R.sub.1--[C(OR.sub.7)(OR.sub.8)]--R.sub.2--, where R.sub.7
and R.sub.8 are selected from the group consisting of
C.sub.1-C.sub.12 alkyl, aryl or substituted aryl; or R.sub.7 and
R.sub.8 taken together is --(CR.sub.aR.sub.b).sub.r--, where r is 2
or 3; R.sub.a and R.sub.b are independently selected from hydrogen,
aryl, and R.sub.4; or (f)
--R.sub.1--[C(SR.sub.7)(SR.sub.8)]--R.sub.2--; R is selected from
the group consisting of: (a) --R.sub.3; (b) --C(O)R.sub.3; (c)
--C(O)OR.sub.3; (d) --S(O).sub.2R.sub.3; (e) hydroxy prodrug group;
(f) hydroxy protecting group; and (g) --C(O)N(R.sub.9R.sub.10);
where R.sub.9 and R.sub.10 are each independently selected from
R.sub.3; alternatively, R.sub.9 and R.sub.10 taken together with
the nitrogen atom to which they are connected form a substituted or
unsubstituted 3- to 10-membered ring which may optionally contain
one or more heterofunctions selected from the group consisting of:
--O--, --N(R.sub.3)--, --S(O).sub.n--, wherein n=0, 1 or 2; W is
selected from: (a) hydrogen; (b) hydroxy prodrug group; (c)
--R.sub.4; (d) --C(O)R.sub.3; (e) --C(O)O--R.sub.3; and (f)
--C(O)N(R.sub.9R.sub.10); one of A and B is R.sub.u and the other
is OR.sub.11, wherein R.sub.11 is independently selected from: (a)
hydrogen; (b) --R.sub.4; (c) --C(O)R.sub.3; (d) --C(O)NHR.sub.3;
(e) --S(O).sub.2R.sub.3; (f) monosaccharide; and (g) -disaccharide;
alternatively, A and B taken together with the carbon atom to which
they are attached to form: (a) C.dbd.O; or (b) C.dbd.CH-J-R.sub.6;
L is independently selected from R.sub.4; Q is: (a) --R.sub.3; (b)
--(C.dbd.O)R.sub.3; (c) --(C.dbd.O)NHR.sub.3; (d)
--(C.dbd.O)OR.sub.3; (e) --(SO).sub.2R.sub.3; (f) monosaccharide;
(g) disaccharide; or (h) trisaccharide; Z is: (a) hydrogen; (b)
--N.sub.3; (c) --CN; (d) --NO.sub.2; (e) --CONH.sub.2; (f) --COOH;
(g) --CHO; (h) --R.sub.4; (i) --COOR.sub.4; (j) --(C.dbd.O)R.sub.4;
or (k) --(C.dbd.O)NR.sub.9R.sub.10; and each of X and Y is
independently: a) hydrogen; b) hydroxy; c) halogen; or d)
--R.sub.4.
2. A compound according to claim 1 represented by formula (II):
##STR00083## or a pharmaceutically acceptable salt, ester or salt
thereof, where Z.sub.1 and Z.sub.2 are independently selected from:
(a) hydrogen; (b) deuterium; (c) halogen; (d) --R.sub.3, where
R.sub.3 is independently selected from the group consisting of: (i)
hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted
heteroaryl; and (iii) --R.sub.4, where R.sub.4 is substituted or
unsubstituted --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
or --C.sub.2-C.sub.6 alkynyl each containing 0, 1, 2, or 3
heteroatoms selected from O, S or N; and (iv) --R.sub.5, where
R.sub.5 is substituted and unsubstituted --C.sub.3-C.sub.12
cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from
O, S or N; (e) --C(O)-J.sub.1-R.sub.3, wherein J.sub.1 is absent,
O, or S and R.sub.3 is as previously defined; (f) --OR.sub.3; (g)
--O(C.dbd.O)R.sub.3; (h) --O(C.dbd.O)OR.sub.3; (i)
--O(C.dbd.O)NHR.sub.3; (j) --NH(C.dbd.O)R.sub.3; (k)
--NH(C.dbd.O)NHR.sub.3; (l) --NH(C.dbd.O)OR.sub.3;
(m)--NH(SO.sub.2)R.sub.3; (n) --NH(SO.sub.2)NHR.sub.3; (o)
--NR.sub.9R.sub.10, where R.sub.9 and R.sub.10 are each
independently selected from R.sub.3; alternatively, R.sub.9 and
R.sub.10 taken together with the nitrogen atom to which they are
connected form a 3- to 10-membered ring which may optionally
contain one or more heterofunctions selected from the group
consisting of: --O--, --N(R.sub.3)--, --S(O).sub.n--, wherein n=0,
1 or 2; and (p) --C(O)--NR.sub.9R.sub.10; alternatively, Z.sub.1
and Z.sub.2 taken together with the carbon atom to which they are
attached are: (a) C.dbd.O; (b) C(OR.sub.7)(OR.sub.8), where R.sub.7
and R.sub.8 are selected from the group consisting of
C.sub.1-C.sub.12 alkyl, aryl or substituted aryl; or R.sub.7 and
R.sub.8 taken together is --(CR.sub.aR.sub.b).sub.r--, where r is 2
or 3; R.sub.a and R.sub.b are independently selected from hydrogen,
aryl, and R.sub.4; (c) C(SR.sub.7)(SR.sub.8); (d) C.dbd.CHR.sub.3,
where R.sub.3 is as previously defined; or (e) C.dbd.N-E-R.sub.3,
where E is absent, O, NH, NH(C.dbd.O), NH(C.dbd.O)NH or NHSO.sub.2;
R.sub.p is hydrogen, hydroxy protecting group, ester or hydroxy
prodrug group; and A, B, R, W, Y, R.sub.9, and R.sub.10 are as
previously defined in claim 1.
3. A compound according to claim 2 represented by formula (III):
##STR00084## or a pharmaceutically acceptable salt, ester or
prodrug thereof where R, W, Z.sub.1, Z.sub.2, Rp, R.sub.9 and
R.sub.10 are as previously defined in claim 2.
4. A compound according to claim 2 represented by formula (IV):
##STR00085## or a pharmaceutically acceptable salt, ester or salt
thereof, where R, W, Y, Z.sub.1, Z.sub.2, Rp, R.sub.9 and R.sub.10
are as previously defined in claim 2.
5. A compound according to claim 1 represented by formula (V):
##STR00086## or a pharmaceutically acceptable salt, ester or
prodrug thereof where W, R, Y, Rp, R.sub.3, R.sub.9 and R.sub.10
are as previously defined in claim 1.
6. A compound according to claim 1 represented by formula (VI):
##STR00087## or a pharmaceutically acceptable salt, ester or
prodrug thereof where W, R, Y, Rp, R.sub.6, R.sub.9 and R.sub.10
are as previously defined in claim 1.
7. A compound of claim 1 having the Formula A, selected from
compounds 1-28 of Table 1: ##STR00088## wherein Y and R.sub.3 is
delineated for each example in Table 1: TABLE-US-00003 TABLE 1
Compound No. Y --R.sub.3 (1) H ##STR00089## (2) H ##STR00090## (3)
H ##STR00091## (4) H ##STR00092## (5) H ##STR00093## (6) H
##STR00094## (7) H ##STR00095## (8) H ##STR00096## (9) H
##STR00097## (10) F ##STR00098## (11) F ##STR00099## (12) F
##STR00100## (13) F ##STR00101## (14) F ##STR00102## (15) F
##STR00103## (16) F ##STR00104## (17) F ##STR00105## (18) F
##STR00106## (19) H ##STR00107## (20) H ##STR00108## (21) F
##STR00109## (22) F ##STR00110## (23) F ##STR00111## (24) F
##STR00112## (25) F ##STR00113## (26) H ##STR00114## (27) H
##STR00115## (28) H ##STR00116##
8. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 or a pharmaceutically
acceptable salt, ester or prodrug thereof, in combination with a
pharmaceutically acceptable carrier.
9. A method for treating a bacterial infection in a subject,
comprising administering to said subject a therapeutically
effective amount of a pharmaceutical composition according to claim
8.
10. A method of treating cystic fibrosis in subject, comprising
administering to said subject, a therapeutically effective amount
of a pharmaceutical composition of claim 8.
11. A method of treating inflammation in a subject comprising
administering to said subject, therapeutically effective amount of
a pharmaceutical composition of claim 8.
12. A process for preparing a compound of formula I, comprising the
step of: (a) reacting a compound represented by the formula
##STR00117## wherein R, A, B, X, Y and PG are as defined in claim
1, with alkylating agent of formula ##STR00118## where R.sub.50 is
--C.sub.1-C.sub.12 alkyl, --C.sub.1-C.sub.12 alkenyl, or
--C.sub.1-C.sub.12 alkynyl, in the presence of a palladium
catalyst; (b) oxidizing the double bond to the corresponding
ketone; (c) reacting the compound from step (b) with
R.sub.3ONH.sub.2, where R.sub.3 is defined in claim 1, in the
presence of an acid or a base; and (d) optionally deprotecting the
compound from step (c).
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 12/437,616, filed May 8, 2009, which claims the benefit of U.S.
Provisional Application No. 61/051,991, filed on May 9, 2008. The
entire teachings of the above applications are incorporated herein
by reference.
TECHNICAL FIELD
[0002] The present invention relates to novel semisynthetic
macrolides having antibacterial activity that are useful in the
treatment and prevention of bacterial infections. More
particularly, the invention relates to sp.sup.3 C9 oxygenated
compounds, compositions containing such compounds and methods for
using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
[0003] The spectrum of activity of macrolides, including
erythromycin, covers most relevant bacterial species responsible
for upper and lower respiratory tract infections. 14-membered ring
macrolides are well known for their overall efficacy, safety and
lack of serious side effects. Erythromycin, however, is quickly
degraded into inactive products in the acidic medium of the stomach
resulting in low bioavailability and gastrointestinal side effects.
Improvement of erythromycin pharmacokinetics has been achieved
through the synthesis of more acid-stable derivatives, for example,
roxithromycin, clarithromycin, and the 15-membered ring macrolide
azithromycin. However, all of these drugs, including 16-membered
ring macrolides, present several drawbacks. They are inactive
against MLS.sub.B-resistant streptococci
(MLS.sub.B=Macrolides-Lincosamides-type B Streptogramines) and with
the exception of azithromycin, weakly active against Haemophilus
influenzae. Furthermore, the resistance of Streptococcus pneumoniae
to erythromycin has increased significantly in recent years (5% to
above 40%). There is high percentage of cross-resistance to
penicillin among these isolates, with a worldwide epidemic spread
of 10-40% in some areas.
[0004] Kashimura et al. have disclosed 6-O-methylerythromycin
derivatives having a tricyclic basic nuclear structure in European
Application 559896, published in Nov. 11, 1991. Also, Asaka et al.
have disclosed 5-O-desoaminylerythronolide derivatives containing a
tricyclic carbamate structure in PCT Application WO 93/21200,
published Apr. 22, 1992.
[0005] Erythromycin derivatives containing a variety of
substituents at the 6-O position have been disclosed in U.S. Pat.
Nos. 5,866,549 and 6,075,011 as well as PCT Application WO
00/78773. Furthermore, Ma et al. have described erythromycin
derivatives with aryl groups tethered to the C-6 position (Ma et
al., J. Med. Chem., 44, pp 4137-4156 (2001)). PCT application WO
97/10251, published Mar. 20, 1997, discloses intermediates useful
for preparation of 6-O-methyl 3-descladinose erythromycin
derivatives. U.S. Pat. Nos. 5,866,549, 6,075,011, 6,878,691,
7,064,100 and PCT application WO 00/78773, published Dec. 28, 2000,
also disclose certain 6-O-substituted erythromycin derivatives.
SUMMARY OF THE INVENTION
[0006] The present invention provides a novel class of sp.sup.3 C-9
oxygenated compounds that possess superior antibacterial activity,
particularly against Haemophilus influenzae. The present invention
further provides a new synthetic route that would allow
incorporation of an sp.sup.3 oxygenated C-9 on a 6,11 bridged
system.
[0007] The compounds of the present invention are represented by
formula (I) as illustrated below:
##STR00002##
or a racemate, enantiomer, diastereomer, geometric isomer,
tautomer, solvate, pharmaceutically acceptable salt, ester and
prodrug thereof, wherein V is selected from the group consisting
of: [0008] (a) --R.sub.1--, where R.sub.1 is substituted or
unsubstituted --C.sub.1-C.sub.8 alkylene-, --C.sub.2-C.sub.8
alkenylene- or --C.sub.2-C.sub.8 alkynylene- each containing 0, 1,
2, or 3 heteroatoms selected from O, S or N; [0009] (b)
--R.sub.1--(C.dbd.O)--R.sub.2--, where R.sub.2 is independently
selected from R.sub.1; [0010] (c)
--R.sub.1--(C.dbd.N-E-R.sub.3)--R.sub.2--, where E is absent, O,
NH, NH(C.dbd.O), NH(C.dbd.O)NH or NHSO.sub.2; where R.sub.3 is
independently selected from the group consisting of: [0011] (i)
hydrogen; [0012] (ii) aryl; substituted aryl; heteroaryl;
substituted heteroaryl; [0013] (iii) --R.sub.4, where R.sub.4 is
substituted or unsubstituted --C.sub.1-C.sub.8 alkyl,
--C.sub.2-C.sub.8 alkenyl or --C.sub.2-C.sub.8 alkynyl each
containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and
[0014] (iv) --R.sub.5, where R.sub.5 is substituted or
unsubstituted --C.sub.3-C.sub.12 cycloalkyl each containing 0, 1,
2, or 3 heteroatoms selected from O, S or N; [0015] (d)
--R.sub.1--(C.dbd.CH-J-R.sub.6)--R.sub.2--; where J is absent, O,
CO, SO.sub.2, NH, NH(C.dbd.O), NH(C.dbd.O)NH or NHSO.sub.2; and
wherein R.sub.6 is independently selected from halogen and R.sub.3;
[0016] (e) --R.sub.1--[C(OR.sub.7)(OR.sub.8)]--R.sub.2--, where
R.sub.7 and R.sub.8 are selected from the group consisting of
C.sub.1-C.sub.12 alkyl, aryl or substituted aryl; or R.sub.7 and
R.sub.8 taken together are --(CR.sub.aR.sub.b).sub.r--, where r is
2 or 3; and each R.sub.a and R.sub.b is independently selected from
hydrogen, aryl, and R.sub.4; or [0017] (f)
--R.sub.1--[C(SR.sub.7)(SR.sub.8)]--R.sub.2--; R is selected from
the group consisting of: [0018] (a) --R.sub.3; [0019] (b)
--C(O)R.sub.3; [0020] (c) --C(O)OR.sub.3; [0021] (d)
--S(O).sub.2R.sub.3; [0022] (e) hydroxy prodrug group; [0023] (f)
hydroxy protecting group; and [0024] (g) --C(O)N(R.sub.9R.sub.10);
where R.sub.9 and R.sub.10 are each independently selected from
R.sub.3; alternatively, R.sub.9 and R.sub.10 taken together with
the nitrogen atom to which they are connected form a substituted or
unsubstituted 3- to 10-membered ring which may optionally contain
one or more heterofunctions selected from the group consisting of:
--O--, --N(R.sub.3)--, --S(O).sub.n--, wherein n=0, 1 or 2; W is
selected from: [0025] (a) hydrogen; [0026] (b) hydroxy prodrug
group; [0027] (c) --R.sub.4; [0028] (d) --C(O)R.sub.3; [0029] (e)
--C(O)O--R.sub.3; and [0030] (f) --C(O)N(R.sub.9R.sub.10); one of A
and B is R.sub.11 and the other is OR.sub.11, wherein R.sub.11 is
independently selected from: [0031] (a) hydrogen; [0032] (b)
--R.sub.4; [0033] (c) --C(O)R.sub.3; [0034] (d) --C(O)NHR.sub.3;
[0035] (e) --S(O).sub.2R.sub.3; [0036] (f) -monosaccharide; and
[0037] (g) -disaccharide; alternatively, A and B are taken together
with the carbon atom to which they are attached to form: [0038] (a)
C.dbd.O; or [0039] (b) C.dbd.CH-J-R.sub.6; L is independently
selected from R.sub.4;
Q is:
[0039] [0040] (a) --R.sub.3; [0041] (b) --(C.dbd.O)R.sub.3; [0042]
(c) --(C.dbd.O)NHR.sub.3; [0043] (d) --(C.dbd.O)OR.sub.3; [0044]
(e) --S(O).sub.2R.sub.3; [0045] (f) monosaccharide; [0046] (g)
disaccharide; or [0047] (h) trisaccharide;
Z is:
[0047] [0048] (a) hydrogen; [0049] (b) --N.sub.3; [0050] (c) --CN;
[0051] (d) --NO.sub.2; [0052] (e) --CONH.sub.2; [0053] (f) --COOH;
[0054] (g) --CHO; [0055] (h) --R.sub.4; [0056] (i) --COOR.sub.4;
[0057] (j) --(C.dbd.O)R.sub.4; or
[0058] (k) --(C.dbd.O)NR.sub.9R.sub.10; and
each of X and Y is independently: [0059] a) hydrogen; [0060] b)
hydroxy; [0061] c) halogen; or [0062] d) --R.sub.4.
[0063] In another embodiment of the present invention there are
disclosed pharmaceutical compositions comprising a therapeutically
effective amount of a compound of the invention in combination with
a pharmaceutically acceptable carrier or excipient. In yet another
embodiment of the invention are methods of treating bacterial
infections in a subject in need of such treatment with said
pharmaceutical compositions. Suitable carriers and formulations of
the compounds of the present invention are disclosed.
DETAILED DESCRIPTION OF THE INVENTION
[0064] In a first embodiment of the compounds of the present
invention are compounds represented by formula I as illustrated
above, or a pharmaceutically acceptable salt, ester or prodrug
thereof.
[0065] In one embodiment of the compounds of the present invention
are compounds represented by formula II as illustrated below, or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00003##
where Z.sub.1 and Z.sub.2 are independently selected from: [0066]
(a) hydrogen; [0067] (b) deuterium; [0068] (c) halogen; [0069] (d)
--R.sub.3, where R.sub.3 is independently selected from the group
consisting of: [0070] (i) hydrogen; [0071] (ii) aryl; substituted
aryl; heteroaryl; substituted heteroaryl; [0072] (iii)-R.sub.4,
where R.sub.4 is substituted or unsubstituted --C.sub.1-C.sub.6
alkyl, --C.sub.2-C.sub.6 alkenyl, or --C.sub.2-C.sub.6 alkynyl each
containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and
[0073] (iv) --R.sub.5, where R.sub.5 is substituted and
unsubstituted --C.sub.3-C.sub.12 cycloalkyl each containing 0, 1,
2, or 3 heteroatoms selected from O, S or N; [0074] (e)
--C(O)-J.sub.1-R.sub.3, wherein J.sub.1 is absent, O, or S and
R.sub.3 is as previously defined; [0075] (f) --OR.sub.3; [0076] (g)
--O(C.dbd.O)R.sub.3; [0077] (h) --O(C.dbd.O)OR.sub.3; [0078] (i)
--O(C.dbd.O)NHR.sub.3; [0079] (j) --NH(C.dbd.O)R.sub.3; [0080] (k)
--NH(C.dbd.O)NHR.sub.3; [0081] (l) --NH(C.dbd.O)OR.sub.3; [0082]
(m) --NH(SO.sub.2)R.sub.3; [0083] (n) --NH(SO.sub.2)NHR.sub.3;
[0084] (o) --NR.sub.9R.sub.10, where R.sub.9 and R.sub.10 are each
independently selected from R.sub.3; [0085] alternatively, R.sub.9
and R.sub.10 taken together with the nitrogen atom to which they
are connected form a 3- to 10-membered ring which may optionally
contain one or more heterofunctions selected from the group
consisting of: --O--, --N(R.sub.3)--, --S(O).sub.n--, wherein n=0,
1 or 2; and [0086] (p) --C(O)--NR.sub.9R.sub.10; alternatively,
Z.sub.1 and Z.sub.2 taken together with the carbon atom to which
they are attached are: [0087] (a) C.dbd.O; [0088] (b)
C(OR.sub.7)(OR.sub.8), where R.sub.7 and R.sub.8 are selected from
the group consisting of C.sub.1-C.sub.12 alkyl, aryl or substituted
aryl; or R.sub.7 and R.sub.8 taken together is
--(CR.sub.aR.sub.b).sub.r--, where r is 2 or 3; R.sub.a and R.sub.b
are independently selected from hydrogen, aryl, and R.sub.4; [0089]
(c) C(SR.sub.7)(SR.sub.8); [0090] (d) C.dbd.CHR.sub.3, where
R.sub.3 is as previously defined; or [0091] (e) C.dbd.N-E-R.sub.3,
where E is absent, O, NH, NH(C.dbd.O), NH(C.dbd.O)NH or NHSO.sub.2;
R.sub.p is hydrogen, hydroxy protecting group, ester or hydroxy
prodrug group; A, B, R, W, Y, R.sub.9, and R.sub.10 are as
previously defined.
[0092] In one embodiment of the compounds of the present invention
are compounds represented by formula III as illustrated below, or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00004##
[0093] where R, W, Z.sub.1, Z.sub.2, R.sub.p, R.sub.9 and R.sub.10
are as previously defined.
[0094] In one embodiment of the compounds of the present invention
are compounds represented by formula IV as illustrated below, or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00005##
[0095] where R, W, Y, Z.sub.1, Z.sub.2, R.sub.p, R.sub.9 and
R.sub.10 are as previously defined.
[0096] In one embodiment of the compounds of the present invention
are compounds represented by formula V as illustrated below, or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00006##
[0097] where W, R, Y, R.sub.p, R.sub.3, R.sub.9 and R.sub.10 are as
previously defined.
[0098] In one embodiment of the compounds of the present invention
are compounds represented by formula VI as illustrated below, or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00007##
[0099] where W, R, Y, R.sub.p, R.sub.6, R.sub.9 and R.sub.10 are as
previously defined.
[0100] Representative compounds according to the invention are
those selected from the group consisting of compounds (1)-(28) of
the formula A:
##STR00008##
where for each compound R.sub.3 and Y are set forth in Table 1.
TABLE-US-00001 TABLE 1 Compound No. Y --R.sub.3 (1) H ##STR00009##
(2) H ##STR00010## (3) H ##STR00011## (4) H ##STR00012## (5) H
##STR00013## (6) H ##STR00014## (7) H ##STR00015## (8) H
##STR00016## (9) H ##STR00017## (10) F ##STR00018## (11) F
##STR00019## (12) F ##STR00020## (13) F ##STR00021## (14) F
##STR00022## (15) F ##STR00023## (16) F ##STR00024## (17) F
##STR00025## (18) F ##STR00026## (19) H ##STR00027## (20) H
##STR00028## (21) F ##STR00029## (22) F ##STR00030## (23) F
##STR00031## (24) F ##STR00032## (25) F ##STR00033## (26) H
##STR00034## (27) H ##STR00035## (28) H ##STR00036##
[0101] A further embodiment of the present invention includes
pharmaceutical compositions comprising any single compound
delineated herein, or a pharmaceutically acceptable salt, ester, or
prodrug thereof, with a pharmaceutically acceptable carrier or
excipient.
[0102] Yet another embodiment of the present invention is a
pharmaceutical composition comprising a combination of two or more
compounds delineated herein, or a pharmaceutically acceptable salt,
ester, or prodrug thereof, with a pharmaceutically acceptable
carrier or excipient.
[0103] Yet a further embodiment of the present invention is a
pharmaceutical composition comprising any single compound
delineated herein in combination with one or more antibiotics known
in the art (such as penicillin, amoxicillin, azithromycin,
erythromycin, ciprofloxacin, telithromycin, cethromycin, and the
like), or a pharmaceutically acceptable salt, ester, or prodrug
thereof, with a pharmaceutically acceptable carrier or
excipient.
[0104] In addition, the present invention contemplates processes of
making any compound delineated herein via any synthetic method
delineated herein.
DEFINITIONS
[0105] 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.
[0106] The term "aryl," as used herein, refers to a mono- or
polycyclic carbocyclic ring system including, but not limited to,
phenyl, naphthyl, tetrahydronaphthyl, indanyl and idenyl.
[0107] The term "heteroaryl," as used herein, refers to a mono- or
polycyclic aromatic radical having one or more ring atom selected
from S, O and N; and the remaining ring atoms are carbon, wherein
any N or S contained within the ring may be optionally oxidized.
Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl,
pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,
isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,
quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl and
quinoxalinyl.
[0108] In accordance with the invention, any of the aryls,
substituted aryls, heteroaryls and substituted heteroaryls
described herein, can be any aromatic group. Aromatic groups can be
substituted or unsubstituted.
[0109] The terms "C.sub.1-C.sub.6 alkyl,", "C.sub.1-C.sub.8 alkyl,"
or "C.sub.1-C.sub.12 alkyl," as used herein, refer to saturated,
straight- or branched-chain hydrocarbon radicals containing from
one to six, one to eight, or one to twelve carbon atoms,
respectively. Examples of C.sub.1-C.sub.8 alkyl radicals include,
but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,
tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals; and
examples of C.sub.1-C.sub.12 alkyl radicals include, but are not
limited to, ethyl, propyl, isopropyl, n-hexyl, octyl, decyl,
dodecyl radicals.
[0110] The terms "C.sub.2-C.sub.6 alkenyl" or "C.sub.2-C.sub.8
alkenyl," as used herein, refer to straight- or branched-chain
hydrocarbon radicals containing from two to six or from two to
eight carbon atoms, respectively, having at least one carbon-carbon
double bond by the removal of a single hydrogen atom. Alkenyl
groups include, but are not limited to, for example, ethenyl,
propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and
the like.
[0111] The terms "C.sub.2-C.sub.6 alkynyl" or "C.sub.2-C.sub.8
alkynyl," as used herein, refer to straight- or branched-chain
hydrocarbon radicals containing from two to six or from two to
eight carbon atoms, respectively, having at least one carbon-carbon
triple bond by the removal of a single hydrogen atom.
Representative alkynyl groups include, but are not limited to, for
example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the
like.
[0112] The term "C.sub.3-C.sub.8-cycloalkyl", or
"C.sub.3-C.sub.12-cycloalkyl," as used herein, refers to a
monocyclic or polycyclic saturated carbocyclic ring compound.
Examples of C.sub.3-C.sub.8-cycloalkyl include, but not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and
cyclooctyl; and examples of C.sub.3-C.sub.12-cycloalkyl include,
but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
[0113] The term "C.sub.3-C.sub.8 cycloalkenyl", or
"C.sub.3-C.sub.12 cycloalkenyl" as used herein, refers to
monocyclic or polycyclic carbocyclic ring compound having at least
one carbon-carbon double bond. Examples of C.sub.3-C.sub.8
cycloalkenyl include, but not limited to, cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl, and the like; and examples of C.sub.3-C.sub.12
cycloalkenyl include, but not limited to, cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl, and the like.
[0114] It is understood that any alkyl, alkenyl, alkynyl and
cycloalkyl moiety described herein can also be an aliphatic group,
an alicyclic group or a heterocyclic group. An "aliphatic" group is
a non-aromatic moiety that may contain any combination of carbon
atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other
atoms, and optionally contain one or more units of unsaturation,
e.g., double and/or triple bonds. An aliphatic group may be
straight chained, branched or cyclic and preferably contains
between about 1 and about 24 carbon atoms, more typically between
about 1 and about 12 carbon atoms. 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.
[0115] The term "alicyclic," as used herein, denotes a group
derived from a monocyclic or bicyclic saturated carbocyclic ring
compound. Examples include, but not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and
bicyclo[2.2.2]octyl. Such alicyclic groups may be further
substituted.
[0116] The terms "heterocyclic" or "heterocycloalkyl" can be used
interchangeably and referred to a non-aromatic ring or a bi- or
tri-cyclic group fused system, where (i) each ring system contains
at least one heteroatom independently selected from oxygen, sulfur
and nitrogen, (ii) each ring system can be saturated or unsaturated
(iii) the nitrogen and sulfur heteroatoms may optionally be
oxidized, (iv) the nitrogen heteroatom may optionally be
quaternized, (v) any of the above rings may be fused to an aromatic
ring, and (vi) the remaining ring atoms are carbon atoms which may
be optionally oxo-substituted. Representative heterocyclic groups
include, but are not limited to, 1,3-dioxolane, pyrrolidinyl,
pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,
morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,
pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be
further substituted.
[0117] The term "substituted" refers to substitution by independent
replacement of one, two, or three or more of the hydrogen atoms
thereon with substituents including, but not limited to, --F, --Cl,
--Br, --I, --OH, protected hydroxy, --NO.sub.2, --CN, --NH.sub.2,
protected amino, oxo, thioxo, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.8-alkenyl, --NH--C.sub.2-C.sub.8-alkynyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.8-alkenyl, --O--C.sub.2-C.sub.8-alkynyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-alkyl,
--C(O)--C.sub.2-C.sub.8-alkenyl, --C(O)--C.sub.2-C.sub.8-alkynyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.8-alkenyl,
--CONH--C.sub.2-C.sub.8-alkynyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.8-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.8-alkenyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.11-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.8-alkenyl, --OCONH--C.sub.2-C.sub.8-alkynyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-- heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.8-alkenyl,
--NHC(O)--C.sub.2-C.sub.8-alkynyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.8-alkenyl,
--NHCO.sub.2--C.sub.2-C.sub.8-alkynyl,
--NHCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-- heterocycloalkyl,
--NHC(O)NH.sub.2, --NHC(O)NH--C.sub.1-C.sub.12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.8-alkenyl,
--NHC(O)NH--C.sub.2-C.sub.8-alkynyl,
--NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)NH-aryl,
--NHC(O)NH-heteroaryl, --NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
--NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.8-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.8-alkynyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, --NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.8-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.8-alkynyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
--NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.8-alkenyl,
--NHC(NH)--C.sub.2-C.sub.8-alkynyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.8-alkenyl,
--C(NH)NH--C.sub.2-C.sub.8-alkenyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.8-alkenyl,
--S(O)--C.sub.2-C.sub.8-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl --SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.8-alkenyl,
--SO.sub.2NH--C.sub.2-C.sub.8-alkynyl,
--SO.sub.2NH--C.sub.3-C.sub.12-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.8-alkenyl,
--NHSO.sub.2--C.sub.2-C.sub.8-alkynyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycloalkyl, polyalkoxyalkyl, polyalkoxy,
-methoxymethoxy, -methoxyethoxy, --SH, --S--C.sub.1-C.sub.12-alkyl,
--S--C.sub.2-C.sub.8-alkenyl, --S--C.sub.2-C.sub.8-alkynyl,
--S--C.sub.3-C.sub.12-cycloalkyl, --S-aryl, --S-heteroaryl,
--S-heterocycloalkyl, or methylthiomethyl. It is understood that
the aryls, heteroaryls, alkyls, and the like can be further
substituted.
[0118] The term "monosaccharide" embraces radicals of cladinose,
allose, altrose, arabinose, erythrose, erythrulose, fructose,
D-fucitol, L-fucitol, fucosamine, fucose, galactosamine,
D-galactosaminitol, galactose, glucosamine, glucosaminitol,
glucose, glyceraldehyde, glycerol, glycerone, gulose, idose,
lyxose, mannosamine, annose, psicose, quinovose, quinovosamine,
rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sorbose,
tagatose, tartaric acid, threose, xylose and xylulose. The
monosaccharide may further be a deoxy sugar (alcoholic hydroxy
group replaced by hydrogen), amino sugar (alcoholic hydroxy group
replaced by amino group), a thio sugar (alcoholic hydroxy group
replaced by thiol, or C.dbd.O replaced by C.dbd.S, or a ring oxygen
of cyclic form replaced by sulfur), a seleno sugar, a telluro
sugar, an aza sugar (ring carbon replaced by nitrogen), an imino
sugar (ring oxygen replaced by nitrogen), a phosphano sugar (ring
oxygen replaced with phosphorus), a phospha sugar (ring carbon
replaced with phosphorus), a C-substituted monosaccharide (hydrogen
at a non-terminal carbon atom replaced with carbon), an unsaturated
monosaccharide, an alditol (carbonyl group replaced with CHOH
group), aldonic acid (aldehydic group replaced by carboxy group), a
ketoaldonic acid, a uronic acid, an aldaric acid, and so forth.
Amino sugars include amino monosaccharides, preferably
galactosamine, glucosamine, mannosamine, fucosamine, quinovosamine,
neuraminic acid, muramic acid, lactosediamine, acosamine,
bacillosamine, daunosamine, desosamine, forosamine, garosamine,
kanosamine, kansosamine, mycaminose, mycosamine, perosamine,
pneumosamine, purpurosamine, rhodosamine. It is understood that the
monosaccharide and the like can be further substituted.
[0119] The terms "disaccharide", "trisaccharide" and
"polysaccharide" embrace radicals of abequose, amicetose, amylose,
apiose, arcanose, ascarylose, ascorbic acid, boivinose, cellobiose,
cellotriose, chacotriose, chalcose, colitose, cymarose,
2-deoxyribose, 2-deoxyglucose, diginose, digitalose, digitoxose,
evalose, evemitrose, gentianose, gentiobiose, hamamelose, inulin,
isolevoglucosenone, isomaltose, isomaltotriose, isopanose,
kojibiose, lactose, lactosamine, lactosediamine, laminarabiose,
levoglucosan, levoglucosenone, .beta.-maltose, manninotriose,
melezitose, melibiose, muramic acid, mycarose, mycinose, neuraminic
acid, nigerose, nojirimycin, noviose, oleandrose, panose, paratose,
planteose, primeverose, raffinose, rhodinose, rutinose, sarmentose,
sedoheptulose, sedoheptulosan, solatriose, sophorose, stachyose,
streptose, sucrose, .alpha.,.alpha.-trehalose, trehalosamine,
turanose, tyvelose, umbelliferose and the like. Further, it is
understood that the "disaccharide", "trisaccharide" and
"polysaccharide" and the like can be further substituted.
Disaccharide also includes amino sugars and their derivatives,
particularly, a mycaminose derivatized at the C-4' position or a 4
deoxy-3-amino-glucose derivatized at the C-6' position.
[0120] The term "trisaccharide" includes amino sugars and halo
sugars, where halo sugars is saccharide group having at least one
halogen substituent.
[0121] The term "halogen," as used herein, refers to an atom
selected from fluorine, chlorine, bromine and iodine.
[0122] The term "hydroxy activating group", as used herein, refers
to a labile chemical moiety which is known in the art to activate a
hydroxyl group so that it will depart during synthetic procedures
such as in a substitution or an elimination reaction. Examples of
hydroxyl activating group include, but not limited to, mesylate,
tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
[0123] The term "activated hydroxy", as used herein, refers to a
hydroxy group activated with a hydroxyl activating group, as
defined above, including mesylate, tosylate, triflate,
p-nitrobenzoate, phosphonate groups, for example.
[0124] The term "hydroxy protecting group," as used herein, refers
to a labile chemical moiety which is known in the art to protect a
hydroxyl group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the hydroxy
protecting group as described herein may be selectively removed.
Hydroxy protecting groups as known in the art are described
generally in T. H. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, 3rd edition, John Wiley & Sons, New York
(1999). Examples of hydroxyl protecting groups include
benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl,
diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl,
allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl,
methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,
2,2,2-trichloroethyl, 2-trimethylsilyl ethyl,
1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl,
para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl),
tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl,
2,2,2-triehloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,
methanesulfonyl, para-toluenesulfonyl, trimethylsilyl,
triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxyl
protecting groups for the present invention are acetyl (Ac or
--C(O)CH.sub.3), benzoyl (Bz or --C(O)C.sub.6H.sub.5), and
trimethylsilyl (TMS or --Si(CH.sub.3).sub.3).
[0125] The term "protected hydroxy," as used herein, refers to a
hydroxy group protected with a hydroxy protecting group, as defined
above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl,
methoxymethyl groups, for example.
[0126] The term "hydroxy prodrug group", as used herein, refers to
a promoiety group which is known in the art to change the
physicochemical, and hence the biological properties of a parent
drug in a transient manner by covering or masking the hydroxy
group. After said synthetic procedure(s), the hydroxy prodrug group
as described herein must be capable of reverting back to hydroxy
group in vivo. Hydroxy prodrug groups as known in the art are
described generally in Kenneth B. Sloan, Prodrugs, Topical and
Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences;
Volume 53), Marcel Dekker, Inc., New York (1992).
[0127] The term "amino protecting group," as used herein, refers to
a labile chemical moiety which is known in the art to protect an
amino group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the amino protecting
group as described herein may be selectively removed. Amino
protecting groups as known in the art are described generally in T.
H. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
Examples of amino protecting groups include, but are not limited
to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl,
benzyloxycarbonyl, and the like.
[0128] The term "leaving group" means a functional group or atom
which can be displaced by another functional group or atom in a
substitution reaction, such as a nucleophilic substitution
reaction. By way of example, representative leaving groups include
chloro, bromo and iodo groups; sulfonic ester groups, such as
mesylate, tosylate, brosylate, nosylate and the like; and acyloxy
groups, such as acetoxy, trifluoroacetoxy and the like.
[0129] The term "protected amino," as used herein, refers to an
amino group protected with an amino protecting group as defined
above.
[0130] The term "aprotic solvent," as used herein, refers to a
solvent that is relatively inert to proton activity, i.e., not
acting as a proton-donor. Examples include, but are not limited to,
hydrocarbons, such as hexane and toluene, for example, halogenated
hydrocarbons, such as, for example, methylene chloride, ethylene
chloride, chloroform, and the like, heterocyclic compounds, such
as, for example, tetrahydrofuran and N-methylpyrrolidinone, and
ethers such as diethyl ether, bis-methoxymethyl ether. Such
compounds are well known to those skilled in the art, and it will
be obvious to those skilled in the art that individual solvents or
mixtures thereof may be preferred for specific compounds and
reaction conditions, depending upon such factors as the solubility
of reagents, reactivity of reagents and preferred temperature
ranges, for example. Further discussions of aprotic solvents may be
found in organic chemistry textbooks or in specialized monographs,
for example: Organic Solvents Physical Properties and Methods of
Purification, 4th ed., edited by John A. Riddick et al., Vol. II,
in the Techniques of Chemistry Series, John Wiley & Sons, NY,
1986.
[0131] The term "protic solvent" as used herein, refers to a
solvent that tends to provide protons, such as an alcohol, for
example, methanol, ethanol, propanol, isopropanol, butanol,
t-butanol, and the like. Such solvents are well known to those
skilled in the art, and it will be obvious to those skilled in the
art that individual solvents or mixtures thereof may be preferred
for specific compounds and reaction conditions, depending upon such
factors as the solubility of reagents, reactivity of reagents and
preferred temperature ranges, for example. Further discussions of
protogenic solvents may be found in organic chemistry textbooks or
in specialized monographs, for example: Organic Solvents Physical
Properties and Methods of Purification, 4th ed., edited by John A.
Riddick et al., Vol. II, in the Techniques of Chemistry Series,
John Wiley & Sons, NY, 1986.
[0132] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds. The term "stable", as used herein, refers to
compounds which possess stability sufficient to allow manufacture
and which maintains the integrity of the compound for a sufficient
period of time to be useful for the purposes detailed herein (e.g.,
therapeutic or prophylactic administration to a subject).
[0133] The synthesized compounds can be separated from a reaction
mixture and further purified by a method such as column
chromatography, high pressure liquid chromatography, or
recrystallization. As can be appreciated by the skilled artisan,
further methods of synthesizing the compounds of the formulae
herein will be evident to those of ordinary skill in the art.
Additionally, the various synthetic steps may be performed in an
alternate sequence or order to give the desired compounds.
Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the compounds described herein are known in the art and include,
for example, those such as described in R. Larock, Comprehensive
Organic Transformations, VCH Publishers (1989); T. W. Greene and P.
G. M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John
Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's
Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995), and subsequent editions thereof.
[0134] The term "subject" as used herein refers to an animal.
Preferably the animal is a mammal. More preferably the mammal is a
human. A subject also refers to, for example, dogs, cats, horses,
cows, pigs, guinea pigs, fish, birds and the like.
[0135] The compounds of this invention may be modified by appending
appropriate functionalities to enhance selective biological
properties. Such modifications are known in the art and may include
those which increase biological penetration into a given biological
system (e.g., blood, lymphatic system, central nervous system),
increase oral availability, increase solubility to allow
administration by injection, alter metabolism and alter rate of
excretion.
[0136] The compounds described herein contain one or more
asymmetric centers and thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that may be defined,
in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)-
or (L)- for amino acids. The present invention is meant to include
all such possible isomers, as well as their racemic and optically
pure forms. Optical isomers may be prepared from their respective
optically active precursors by the procedures described above, or
by resolving the racemic mixtures. The resolution can be carried
out in the presence of a resolving agent, by chromatography or by
repeated crystallization or by some combination of these techniques
which are known to those skilled in the art. Further details
regarding resolutions can be found in Jacques, et al., Enantiomers,
Racemates, and Resolutions (John Wiley & Sons, 1981). When the
compounds described herein contain olefinic double bonds, other
unsaturation, or other centers of geometric asymmetry, and unless
specified otherwise, it is intended that the compounds include both
E and Z geometric isomers or cis- and trans- isomers. Likewise, all
tautomeric forms are also intended to be included. The
configuration of any carbon-carbon double bond appearing herein is
selected for convenience only and is not intended to designate a
particular configuration unless the text so states; thus a
carbon-carbon double bond or carbon-heteroatom double bond depicted
arbitrarily herein as trans may be cis, trans, or a mixture of the
two in any proportion.
[0137] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et al. describes
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66: 1-19 (1977). The salts can be prepared in situ during
the final isolation and purification of the compounds of the
invention, or separately by reacting the free base function with a
suitable organic acid. Examples of pharmaceutically acceptable
include, but are not limited to, nontoxic acid addition salts are
salts of an amino group formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid
and perchloric acid or with organic acids such as acetic acid,
maleic acid, tartaric acid, citric acid, succinic acid or malonic
acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include, but are
not limited to, adipate, alginate, ascorbate, aspartate,
benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,
sulfonate and aryl sulfonate.
[0138] As used herein, the term "pharmaceutically acceptable ester"
refers to esters which hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters include, but are not limited to, formates,
acetates, propionates, butyrates, acrylates and
ethylsuccinates.
[0139] The term "pharmaceutically acceptable prodrugs" as used
herein refers to those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals with undue toxicity, irritation, allergic response, and the
like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the present invention.
"Prodrug", as used herein means a compound which is convertible in
vivo by metabolic means (e.g. by hydrolysis) to a compound of
Formula I. Various forms of prodrugs are known in the art, for
example, as discussed in Bundgaard, (ed.), Design of Prodrugs,
Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol.
4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design
and Application of Prodrugs, Textbook of Drug Design and
Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal
of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of
Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella
(eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical
Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis
In Drug And Prodrug Metabolism: Chemistry, Biochemistry And
Enzymology," John Wiley and Sons, Ltd. (2002).
[0140] The present invention also relates to solvates of the
compounds of the invention, for example hydrates.
[0141] This invention also encompasses pharmaceutical compositions
containing, and methods of treating bacterial infections through
administering, pharmaceutically acceptable prodrugs of compounds of
the invention. For example, compounds of the invention having free
amino, amido, hydroxy or carboxylic groups can be converted into
prodrugs. Prodrugs include compounds wherein an amino acid residue,
or a polypeptide chain of two or more (e.g., two, three or four)
amino acid residues is covalently joined through an amide or ester
bond to a free amino, hydroxy or carboxylic acid group of compounds
of the invention. The amino acid residues include but are not
limited to the 20 naturally occurring amino acids commonly
designated by three letter symbols and also includes
4-hydroxyproline, hydroxyysine, demosine, isodemosine,
3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,
citrulline, homocysteine, homoserine, ornithine and methionine
sulfone. Additional types of prodrugs are also encompassed. For
instance, free carboxyl groups can be derivatized as amides or
alkyl esters. Free hydroxy groups may be derivatized using groups
including but not limited to hemisuccinates, phosphate esters,
dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
Carbamate prodrugs of hydroxy and amino groups are also included,
as are carbonate prodrugs, sulfonate esters and sulfate esters of
hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl
and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl
ester, optionally substituted with groups including but not limited
to ether, amine and carboxylic acid functionalities, or where the
acyl group is an amino acid ester as described above, are also
encompassed. Prodrugs of this type are described in J. Med. Chem.
1996, 39, 10. Free amines can also be derivatized as amides,
sulfonamides or phosphonamides. All of these prodrug moieties may
incorporate groups including but not limited to ether, amine and
carboxylic acid functionalities.
[0142] As used herein, unless otherwise indicated, the term
"bacterial infection(s)" or "protozoa infections"; includes, but is
not limited to, bacterial infections and protozoa infections that
occur in mammals, fish and birds as well as disorders related to
bacterial infections and protozoa infections that may be treated or
prevented by administering antibiotics such as the compounds of the
present invention. Such bacterial infections and protozoa
infections and disorders related to such infections include, but
are not limited to, the following: pneumonia, otitis media,
meningitis, sinusitus, bronchitis, tonsillitis, cystic fibrosis
(CF) and mastoiditis related to infection by Streptococcus
pneumoniae, Haemophilus influenzae, Moraxella catarrhalis,
Staphylococcus aureus, Peptostreptococcus spp, or Pseudomonas spp.;
pharynigitis, rheumatic fever, and glomerulonephritis related to
infection by Streptococcus pyogenes, Groups C and G streptococci,
Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory
tract infections related to infection by Mycoplasma pneumoniae,
Legionella pneumophila, Streptococcus pneumoniae, Haemophilus
influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft
tissue infections, abscesses and osteomyelitis, and puerperal fever
related to infection by Staphylococcus aureus, coagulase-positive
staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), S.
pyogenes, S. agalactiae, Streptococcal groups C-F (minute-colony
streptococci), viridans streptococci, Corynebacterium spp.,
Clostridium spp., or Bartonella henselae; uncomplicated acute
urinary tract infections related to infection by S. saprophyticus
or Enterococcus spp.; urethritis and cervicitis; and sexually
transmitted diseases related to infection by Chlamydia trachomatis,
Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or
Nesseria gonorrheae; toxin diseases related to infection by S.
aureus (food poisoning and Toxic shock syndrome), or Groups A, S,
and C streptococci; ulcers related to infection by Helicobacter
pylori; systemic febrile syndromes related to infection by Borrelia
recurrentis; Lyme disease related to infection by Borrelia
burgdorferi; conjunctivitis, keratitis, and dacrocystitis related
to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.
pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.;
disseminated Mycobacterium avium complex (MAC) disease related to
infection by Mycobacterium avium, or Mycobacterium intracellulare;
gastroenteritis related to infection by Campylobacter jejuni;
intestinal protozoa related to infection by Cryptosporidium spp.
odontogenic infection related to infection by viridans
streptococci; persistent cough related to infection by Bordetella
pertussis; gas gangrene related to infection by Clostridium
perfringens or Bacteroides spp.; Skin infection by S. aureus,
Propionibacterium acne; atherosclerosis related to infection by
Helicobacter pylori or Chlamydia pneumoniae; or the like.
[0143] Bacterial infections and protozoa infections and disorders
related to such infections that may be treated or prevented in
animals include, but are not limited to, the following: bovine
respiratory disease related to infection by P. haemolytica, P.
multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric
disease related to infection by E. coli or protozoa (i.e.,
coccidia, cryptosporidia, etc.), dairy cow mastitis related to
infection by S. aureus, S. uberis, S. agalactiae, S. dysgalactiae,
Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine
respiratory disease related to infection by A. pleuropneumoniae, P.
multocida, or Mycoplasma spp.; swine enteric disease related to
infection by E. coli, Lawsonia intracellularis, Salmonella spp., or
Serpulina hyodyisinteriae; cow footrot related to infection by
Fusobacterium spp.; cow metritis related to infection by E. coli;
cow hairy warts related to Infection by Fusobacterium necrophorum
or Bacteroides nodosus; cow pink-eye related to infection by
Moraxella bovis, cow premature abortion related to infection by
protozoa (i.e. neosporium); urinary tract infection in dogs and
cats related to infection by E. coli; skin and soft tissue
infections in dogs and cats related to infection by S. epidermidis,
S. intermedius, coagulase neg. Staphylococcus or P. multocida; and
dental or mouth infections in dogs and oats related to infection by
Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter
spp., Eubacterium spp., Peptostreptococcus spp., Porphfyromonas
spp., Campylobacter spp., Actinomyces spp., Erysipelothrix spp.,
Rhodococcus spp., Trypanosoma spp., Plasmodium spp., Babesia spp.,
Toxoplasma spp., Pneumocystis spp., Leishmania spp., and
Trichomonas spp. or Prevotella spp. Other bacterial infections and
protozoa infections and disorders related to such infections that
may be treated or prevented in accord with the method of the
present invention are referred to in J. P. Sanford at al.,"The
Sanford Guide To Antimicrobial Therapy," 26th Edition,
(Antimicrobial Therapy, Inc., 1996).
Antibacterial Activity
[0144] Susceptibility tests can be used to quantitatively measure
the in vitro activity of an antimicrobial agent against a given
bacterial isolate. Compounds are tested for in vitro antibacterial
activity by a micro-dilution method. Minimal Inhibitory
Concentration (MIC) is determined in 96 well microtiter plates
utilizing the appropriate broth medium for the observed bacterial
isolates. Antimicrobial agents are serially diluted (2-fold) in
DMSO to produce a concentration range from about 64 .mu.g/ml to
about 0.03 .mu.g/ml. The diluted compounds (2 .mu.l/well) are then
transferred into sterile, uninoculated medium (0.2 mL) by use of a
96 fixed tip-pipetting station. The inoculum for each bacterial
strain is standardized to approximately 5.times.10.sup.5 CFU/mL by
optical comparison to a 0.5 McFarland turbidity standard. The
plates are inoculated with 10 .mu.l/well of adjusted bacterial
inoculum. The 96 well plates are covered and incubated at
35+/-2.degree. C. for 24 hours in ambient air environment.
Following incubation, plate wells are visually examined by Optical
Density measurement for the presence of growth (turbidity). The
lowest concentration of an antimicrobial agent at which no visible
growth occurs is defined as the MIC. The compounds of the invention
generally demonstrated an MIC in the range from about 64 .mu.g/ml
to about 0.03 .mu.g/ml.
[0145] All in vitro testing follows the guidelines described in the
Approved Standards M7-A7 protocol, published by the Clinical
Laboratory Standards Institute (CLSI).
[0146] The invention further provides compositions and methods of
treating patients suffering from an inflammatory condition
comprising administering to a patient in need thereof, a
therapeutically effective amount of at least one compound of the
invention. Specific examples of inflammatory conditions treatable
according to the invention include, but are not limited to,
scleritis; epi-scleritis; allergic conjunctivitis; pulmonary
inflammatory diseases, particularly cystic fibrosis (CF), asthma,
chronic obstructive pulmonary disease (COPD), allergic
bronchopulmonary aspergillosis (ABPA), and sarcoidosis;
procto-sigmoiditis; allergic rhinitis; arthritis; tendonitis;
apthous stomatitis; and inflammatory bowel disease.
[0147] The invention further provides compositions and methods for
i) prophylactic treatment of those patients susceptible to the
symptoms CF including pulmonary infection and inflammation
associated with CF, ii) treatment at the initial onset of symptoms
of pulmonary infection and inflammation associated with CF, and
iii) treatment of ongoing or relapsing symptoms of infection and
inflammation associated with CF. In accordance with the invention a
compound according to any one of compounds of the invention, is
administered to a patient in need of treatment for CF, in amount
sufficient to prevent, diminish or eradicate symptoms of CF
including chronic pulmonary inflammation and infection.
Pharmaceutical Compositions
[0148] 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.
[0149] As used herein, the term "pharmaceutically acceptable
carrier or excipient" means a non-toxic, inert solid, semi-solid 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; 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 aluminun 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.
[0150] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir, preferably by oral administration or 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.
[0151] 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.
[0152] 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 solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
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 acids such as
oleic acid are used in the preparation of injectables.
[0153] 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.
[0154] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution, which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the drug
in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the drug in liposomes
or microemulsions that are compatible with body tissues.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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, particularly aerosolized antibiotics,
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, all of which are incorporated herein by
reference). A discussion of pulmonary delivery of antibiotics is
also found in U.S. Pat. No. 6,014,969, incorporated herein by
reference.
[0164] According to the methods of treatment of the present
invention, bacterial infections, cystic fibrosis and inflammatory
conditions are treated or prevented in a patient such as a human or
another animal by administering to the patient a therapeutically
effective amount of a compound of the invention, in such amounts
and for such time as is necessary to achieve the desired
result.
[0165] By a "therapeutically effective amount" of a compound of the
invention is meant an amount of the compound which confers a
therapeutic effect on the treated subject, at a reasonable
benefit/risk ratio applicable to any medical treatment. The
therapeutic effect may be objective (i.e., measurable by some test
or marker) or subjective (i.e., subject gives an indication of or
feels an effect). An effective amount of the compound described
above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably
from about 1 to about 50 mg/Kg. Effective doses will also vary
depending on route of administration, as well as the possibility of
co-usage with other agents. It will be understood, however, that
the total daily usage of the compounds and compositions of the
present invention will be decided by the attending physician within
the scope of sound medical judgment. The specific therapeutically
effective dose level for any particular patient will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; the activity of the specific compound
employed; the specific composition employed; the age, body weight,
general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment;
drugs used in combination or contemporaneously with the specific
compound employed; and like factors well known in the medical
arts.
[0166] The total daily dose of the compounds of this invention
administered to a human or other animal in single or in divided
doses can be in amounts, for example, from 0.01 to 50 mg/kg body
weight or more usually from 0.1 to 25 mg/kg body weight. Single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose. In general, treatment regimens according
to the present invention comprise administration to a patient in
need of such treatment from about 10 mg to about 1000 mg of the
compound(s) of this invention per day in single or multiple
doses.
[0167] The compounds of the formulae described herein can, for
example, be administered by injection, intravenously,
intraarterially, subdermally, intraperitoneally, intramuscularly,
or subcutaneously; or orally, buccally, nasally, transmucosally,
topically, in an ophthalmic preparation, or by inhalation, with a
dosage ranging from about 0.1 to about 500 mg/kg of body weight,
alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120
hours, or according to the requirements of the particular drug. The
methods herein contemplate administration of an effective amount of
compound or compound composition to achieve the desired or stated
effect. Typically, the pharmaceutical compositions of this
invention will be administered from about 1 to about 6 times per
day or alternatively, as a continuous infusion. Such administration
can be used as a chronic or acute therapy. The amount of active
ingredient that may be combined with pharmaceutically exipients or
carriers to produce a single dosage form will vary depending upon
the host treated and the particular mode of administration. A
typical preparation will contain from about 5% to about 95% active
compound (w/w). Alternatively, such preparations may contain from
about 20% to about 80% active compound.
[0168] Lower or higher doses than those recited above may be
required. Specific dosage and treatment regimens for any particular
patient will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body weight,
general health status, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
disease, condition or symptoms, the patient's disposition to the
disease, condition or symptoms, and the judgment of the treating
physician.
[0169] Upon improvement of a patient's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level. Patients may, however, require intermittent treatment on a
long-term basis upon any recurrence of disease symptoms.
[0170] When the compositions of this invention comprise a
combination of a compound of the formulae described herein and one
or more additional therapeutic or prophylactic agents, both the
compound and the additional agent should be present at dosage
levels of between about 1 to 100%, and more preferably between
about 5 to 95% of the dosage normally administered in a monotherapy
regimen. The additional agents may be administered separately, as
part of a multiple dose regimen, from the compounds of this
invention. Alternatively, those agents may be part of a single
dosage form, mixed together with the compounds of this invention in
a single composition.
[0171] Unless otherwise defined, all technical and scientific terms
used herein are accorded the meaning commonly known to one of
ordinary skill in the art. All publications, patents, published
patent applications, and other references mentioned herein are
hereby incorporated by reference in their entirety.
Abbreviations
[0172] Abbreviations which may appear in the following synthetic
schemes and examples are:
[0173] Ac for acetyl;
[0174] AcOH for acetic acid;
[0175] AIBN for azobisisobutyronitrile;
[0176] BSA for N,O-bis(trimethysilyl)acetamide;
[0177] BINAP for 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;
[0178] Boc.sub.2O for di-tert-butyl-dicarbonate;
[0179] Boc for t-butoxycarbonyl;
[0180] Bpoc for 1-methyl-1-(4-biphenylyl)ethyl carbonyl;
[0181] Bz for benzoyl;
[0182] Bn for benzyl;
[0183] BocNHOH for tert-butyl N-hydroxycarbamate;
[0184] t-BuOK for potassium tert-butoxide;
[0185] Bu.sub.3SnH for tributyltin hydride;
[0186] BOP for (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
Hexafluorophosphate;
[0187] Brine for sodium chloride solution in water;
[0188] CDI for carbonyldiimidazole;
[0189] CH.sub.2Cl.sub.2 for dichloromethane;
[0190] CH.sub.3 for methyl;
[0191] CH.sub.3CN for acetonitrile;
[0192] Cs.sub.2CO.sub.3 for cesium carbonate;
[0193] CuCl for copper(I) chloride;
[0194] CuI for copper(I) iodide;
[0195] dba for dibenzylidene acetone;
[0196] dppb for diphenylphosphino butane;
[0197] DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;
[0198] DCC for N,N'-dicyclohexylcarbodiimide;
[0199] DEAD for diethylazodicarboxylate;
[0200] DIAD for diisopropyl azodicarboxylate;
[0201] DIPEA or (i-Pr).sub.2EtN for N,N,-diisopropylethyl
amine;
[0202] Dess-Martin periodinane for
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one;
[0203] DMAP for 4-dimethylaminopyridine;
[0204] DME for 1,2-dimethoxyethane;
[0205] DMF for N,N-dimethylformamide;
[0206] DMSO for dimethyl sulfoxide;
[0207] DPPA for diphenylphosphoryl azide;
[0208] EDC for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide;
[0209] EDC HCl for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride;
[0210] EtOAc for ethyl acetate;
[0211] EtOH for ethanol;
[0212] Et.sub.2O for diethyl ether;
[0213] HATU for
O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium
Hexafluorophosphate;
[0214] HCl for hydrogen chloride;
[0215] HOBT for 1-hydroxybenzotriazole;
[0216] K.sub.2CO.sub.3 for potassium carbonate;
[0217] n-BuLi for n-butyl lithium;
[0218] i-BuLi for i-butyl lithium;
[0219] t-BuLi for t-butyl lithium;
[0220] PhLi for phenyl lithium;
[0221] LDA for lithium diisopropylamide;
[0222] TMEDA for N,N,N',N'-tetramethylethylenediamine;
[0223] LiTMP for lithium 2,2,6,6-tetramethylpiperidinate;
[0224] MeOH for methanol;
[0225] Mg for magnesium;
[0226] MOM for methoxymethyl;
[0227] Ms for mesyl or --SO.sub.2--CH.sub.3;
[0228] Ms.sub.2O for methanesulfonic anhydride or
mesyl-anhydride;
[0229] NaN(TMS).sub.2 for sodium bis(trimethylsilyl)amide;
[0230] NaCl for sodium chloride;
[0231] NaH for sodium hydride;
[0232] NaHCO.sub.3 for sodium bicarbonate or sodium hydrogen
carbonate;
[0233] Na.sub.2CO.sub.3 sodium carbonate;
[0234] NaOH for sodium hydroxide;
[0235] Na.sub.2SO.sub.4 for sodium sulfate;
[0236] NaHSO.sub.3 for sodium bisulfite or sodium hydrogen
sulfite;
[0237] Na.sub.2S.sub.2O.sub.3 for sodium thiosulfate;
[0238] NH.sub.2NH.sub.2 for hydrazine;
[0239] NH.sub.4HCO.sub.3 for ammonium bicarbonate;
[0240] NH.sub.4Cl for ammonium chloride;
[0241] NMMO for N-methylmorpholine N-oxide;
[0242] NaIO.sub.4 for sodium periodate;
[0243] Ni for nickel;
[0244] OH for hydroxyl;
[0245] OsO.sub.4 for osmium tetroxide;
[0246] TIPS for triisopropylsilyl;
[0247] TEA or Et.sub.3N for triethylamine;
[0248] TFA for trifluoroacetic acid;
[0249] THF for tetrahydrofuran;
[0250] TMS for trimethylsilyl;
[0251] TPP or PPh.sub.3 for triphenylphosphine;
[0252] Troc for 2,2,2-trichloroethyl carbonyl;
[0253] Ts for tosyl or --SO.sub.2--C.sub.6H.sub.4CH.sub.3;
[0254] Ts.sub.2O for tolylsulfonic anhydride or
tosyl-anhydride;
[0255] TsOH for p-tolylsulfonic acid;
[0256] Pd for palladium;
[0257] Ph for phenyl;
[0258] POPd for dihydrogen
dichlorobis(di-tert-butylphosphinito-.kappa.P)palladate(II);
[0259] Pd.sub.2(dba).sub.3 for
tris(dibenzylideneacetone)dipalladium(0);
[0260] Pd(PPh.sub.3).sub.4 for
tetrakis(triphenylphosphine)palladium(0);
[0261] PdCl.sub.2(Ph.sub.3P).sub.2 for
trans-dichlorobis(triphenylphosphine)palladium(II);
[0262] Pt for platinum;
[0263] Rh for rhodium;
[0264] Ru for ruthenium;
[0265] TBS for tert-butyl dimethylsilyl; or
[0266] TMS for trimethylsilyl;
[0267] TMSCl for trimethylsilyl chloride.
Synthetic Methods
[0268] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes that illustrate the methods by which the compounds of the
invention may be prepared, which are intended as an illustration
only and not to limit the scope of the invention. Various changes
and modifications to the disclosed embodiments will be apparent to
those skilled in the art and such changes and modifications
including, without limitation, those relating to the chemical
structures, substituents, derivatives, and/or methods of the
invention may be made without departing from the spirit of the
invention and the scope of the appended claims. The intermediates
of the present invention can be prepared by methods which are known
in the art such as processes described by U.S. Pat. Nos. 5,892,008,
6,878,691 and 6,753,318, each of which is incorporated herein by
reference in its entirety.
[0269] Surprisingly, when the 6,11 bridge system is already
incorporated into the species and intermediates disclosed in U.S.
Pat. Nos. 6,878,691 and 6,753,318, reduction of the ketone to the
corresponding hydroxy moiety cannot be achieved by any known
methods. While not bound by theory, it is believed that the 6,11
bridge system has changed the conformation and/or blocked the C9
position of the molecule thereby preventing reduction at that
position. The present invention provides a new synthetic route that
would allow incorporation of an sp.sup.a oxygenated C-9 and a
6,11-bridged system thereby providing compounds with superior
antibiotic activity, particularly against Haemophilus
influenzae.
##STR00037##
[0270] Scheme 1 describes one method of preparing intermediates
1-6, which are key intermediates for preparing compounds of the
invention. Commercially available erythromycin A can be converted
to intermediate (1-1) by the methods disclosed in U.S. Pat. No.
5,892,008. Formation of the 6,11-bridge can be achieved by reacting
with a compound of formula (1-1) with a suitable alkylating agent
of the formula (1-1a):
##STR00038##
[0271] wherein R.sub.50 is --C.sub.1-C.sub.12 alkyl,
--C.sub.2-C.sub.12 alkenyl, or --C.sub.2-C.sub.12 alkynyl
optionally substituted with one or more substitutents selected from
halogen, aryl, substituted aryl, heteroaryl, or substituted
heteroaryl; --C.sub.3-C.sub.12 cycloalkyl.
[0272] Most palladium(0) catalysts are expected to work in this
process. Some palladium(II) catalysts, such as
palladium(II)acetate, which is converted into a palladium(0)
species in-situ by the actions of a phosphine, will work as well.
See, for example, Beller et al. Angew. Chem. Int. Ed. Engl., 1995,
34 (17), 1848. The palladium catalyst can be selected from, but not
limited to, palladium(II)acetate,
tetrakis(triphenylphospine)palladium(0),
tris(dibenzylideneacetone)dipalladium,
tetradibenzylideneacetone)dipalladium and the like. Palladium on
carbon and palladium (II) halide catalysts are less preferred than
other palladium catalysts for this process. Phosphines suitable for
this process include, but are not limited to triphenylphosphine,
bis(diphenylphosphino)methane, bis(diphenylphosphino)ethane,
bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,
bis(diphenylphosphino)pentane, and tri-o-tolyl-phosphine, and the
like. The reaction is carried out in an aprotic solvent, preferably
at elevated temperature, preferably at or above 50.degree. C.
Suitable aprotic solvents include, but are not limited to,
tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide,
N-methyl-2-pyrrolidone, toluene, hexamethylphosphoric triamide,
1,2-dimethoxyethane, methyl-tert-butyl ether, heptane,
acetonitrile, isopropyl acetate and ethyl acetate. Generally, the
alkylating agents have the formula (1-1a) as previously described.
The preferred alkylating agents are those wherein R.sub.50 is
tert-butyl, isopropyl or isobutyl. The alkylating reagents are
prepared by reaction of a diol with a wide variety of compounds for
incorporating the di-carbonate moiety. These compounds include, but
are not limited to, tert-butyl chloroformate, di-tert-butyl
dicarbonate, and 1-(tert-butoxycarbonyl)imidazole and the reaction
is carried out in the presence of an organic or an inorganic
base.
[0273] Removal of the cladinose moiety of the macrolide (1-2)
either by mild acid hydrolysis or by enzymatic hydrolysis to afford
compound (1-3). Representative acids include, but are not limited
to, dilute hydrochloric acid, sulfuric acid, perchloric acid,
chloroacetic acid, dichloroacetic acid or trifluoroacetic acid.
Suitable solvents for the reaction include, but are not limited to,
methanol, ethanol, isopropanol, butanol, water and mixtures there
of.
[0274] Conversion of compounds of formula (1-3) to compounds of
formula (1-4) can be accomplished by oxidation of the 3-hydroxy
group to a 3-oxo group using Dess-Martin periodinane (for further
details concerning the Dess-Martin oxidation see D. B. Dess, J. C.
Martin, J. Org. Chem. 48, 4155 (1983)), a Corey-Kim reaction with
N-chlorosuccinimide-dimethylsulfide (for further details concerning
the Corey-Kim oxidation reaction see E. J. Corey, C. U. Kim, J. Am.
Chem. Soc. 94, 7586 (1972), or a Moffat oxidation with a
carbodiimide-DMSO complex in the presence of pyridinium
trifluoroacetate, TPAP, PDC, and the like (for further details
concerning the Moffat oxidation see J. G. Moffatt,
"Sulfoxide-Carbodiimide and Related Oxidations" in Oxidation vol.
2, R. L. Augustine, D. J. Trecker, Eds. (Dekker, New York, 1971) pp
1-64; T. T. Tidwell, Org. React. 39, 297-572 passim (1990); and T.
V. Lee, Comp. Org. Syn. 7, 291-303 passim (1991).
[0275] Selective deprotection of the C-9 hydroxy moiety of (1-4) to
form compounds of formula (1-5) can be achieved by procedures known
in the art such as described in T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and
Sons (1999).
[0276] The transformation of (1-5) to (1-7) can be achieved by
treatment with a fluorinating agent. Fluorinating reagents include,
but are not limited to N-fluorobenzenesulfonamide in presence of
base, 10% F.sub.2 in formic acid, 3,5-dichloro-1-fluoropyridinium
triflate, (CF.sub.3SO.sub.2).sub.2NF,
N-fluoro-N-methyl-p-toluenesulfonamide in presence of base,
N-Fluoropyridinium triflate, and N-fluoroperfluoropiperidine in
presence of base.
[0277] Suitable bases for the fluorinating reaction are alkali
metal hydride bases, such as NaH and KH, or amine bases, such as
LDA or triethylamine. The choice of base is dependent on the
fluorinating agent but this is well known within the art.
[0278] Conversion of alkenes (1-5) or (1-7) into ketones (1-6) or
(1-8) respectively, can be accomplished by ozonolysis followed by
decomposition of the ozonide with the appropriate reducing agents.
The reaction is typically carried out in an inert solvent such as,
but not limited to, methanol, ethanol, ethyl acetate, glacial
acetic acid, chloroform, methylene chloride or hexane or mixtures
thereof, preferably methanol, preferably at -78.degree. C. to
-20.degree. C. Representative reducing agents are, for example,
triphenylphosphine, trimethylphosphite, thiourea, and dimethyl
sulfide, preferably triphenylphosphine. A more thorough discussion
of ozonolysis and conditions therefor may be found in J. March,
Advanced Organic Chemistry, 4.sup.th ed., Wiley & Son, Inc,
1992. Alternatively, compounds of formula (1-6) can be prepared
from compounds of formula (1-5) by dihydroxydation with OsO.sub.4
followed by NaIO.sub.4 cleavage.
##STR00039##
[0279] Scheme 2 outlines formation of oxime derivatives from key
intermediate (2-1) followed by 2'-deprotection of Rp to yield
compounds of the invention. Oxime formation can be carried out
under mild acidic conditions, such as but not limited to, dilute
hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic
acid, dichloroacetic acid or trifluoroacetic acid with commercially
available hydroxylamines or hydroxylamines known in the art such as
ones disclosed in U.S. Pat. No. 6,878,691 or hydroxylamines
specifically prepared to improve antibacterial activity.
Deprotection of the 2'-Rp protecting group can be carried achieved
according to procedures known in the art such as described in T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd. Ed., John Wiley and Sons (1999).
##STR00040##
[0280] Compounds according to the invention of the formula (3-0)
can be further functionalized in a variety of ways. Scheme 3
details a procedure for the conversion of the ketone of formula
(3-0) into an oxime of formula (3-1). Oxime formation can be
accomplished using the appropriate substituted hydroxylamine under
either acidic or basic conditions in a variety of solvents.
Representative acids include, but are not limited to, hydrochloric,
phosphoric, sulfuric, p-toluenesulfonic, and pyridinium p-toluene
sulfonate. Likewise, representative bases include, but are not
limited to, triethylamine, pyridine, diisopropylethyl amine,
2,6-lutidine, and the like. Appropriate solvents include, but are
not limited to, methanol, ethanol, water, tetrahydrofuran,
1,2-dimethoxyethane, and ethyl acetate or combination thereof.
Preferably the reaction is carried out in ethanol with acids such
as hydrochloric acid, methanesulfonic acid, perchloric acid and the
like.
[0281] It will be appreciated by one skilled in the art that
ketones of formula (3-0) can be transformed into alkenes of formula
(3-2) and (3-7) via Wittig reaction with the appropriate
phosphonium salt in the presence of a base, see (a) Burke,
Tetrahedron Lett., 1987, 4143-4146, (b) Rathke and Nowak, J. Org.
Chem., 1985, 2624-2626, (c) Maryanoff and Reitz, Chem. Rev., 1989,
863-927. Furthermore, vinyl halides of formula (3-7) can be
functionalized by Sonogashira coupling with alkynes in the presence
of a palladium catalyst, a copper halide and an amine base to give
compounds of formula (3-8) (see (a) Sonogashira, Comprehensive
Organic Synthesis, Volume 3, Chapters 2,4; (b) Sonogashira,
Synthesis 1977, 777). In a similar manner, alkenes of formula (3-2)
can be obtained from vinyl halides (3-7) via Suzuki cross coupling
with organoboron reagents in the presence of a palladium catalyst
and a base, or via Stille cross coupling with organostananes in the
presence of a palladium catalyst (see (a) Suzuki, J. Organomet.
Chem. 1999, 576,147-168, (b) Stille, Angew. Chem. Int. Ed. Engl.,
1986, 508-524 (c) Farina, J. Am. Chem. Soc., 1991, 9585-9595).
[0282] Furthermore, alcohols of type (3-3) can be prepared by
reduction of the corresponding ketone of formula (3-0) under a
variety of conditions (see Hudlicky, M. Reductions in Organic
Chemistry, Ellis Horwood Limited: Chichester, 1984). The alcohols
thus derived can be further modified to give compounds of formula
(3-4). A process to generate compounds of formula (3-4) includes,
but is not limited to, alkylation of the alcohol with an
electrophile or conversion of the alcohol into a leaving group,
such as a triflate, tosylate, phosphonate, halide, or the like,
followed by displacement with a heteroatom nucleophile (e.g. an
amine, alkoxide, sulfide or the like).
[0283] Yet another means by which to functionalize ketones of
formula (3-0) is via addition of Grignard reagents to form alcohols
of formula (3-5). The requisite Grignard reagents are readily
available via the reaction of a variety of alkyl or aryl halides
with magnesium under standard conditions (see B. S. Furniss, A. J.
Hannaford, P. W. G. Smith, A. R. Tatchell, Vogel's Textbook of
Practical Organic Chemistry, 5.sup.th ed., Longman, 1989). The
addition is performed in an inert solvent, generally at low
temperatures. Suitable solvents include, but are not limited to,
tetrahydrofuran, diethylether, 1,4-dioxane, 1,2-dimethoxyethane,
and hexanes. Preferably the solvent is tetrahydrofuran or
diethylether. Preferably the reaction is run at -78.degree. C. to
0.degree. C.
[0284] In a similar way, reaction with other organometallic
reagents gives rise to alcohols of formula (3-5). Examples of
useful organometallic reagents include, but are not limited to,
organo-aluminum, organo-lithium, organo-cerium, organo-zinc,
organo-thallium, and organo-boron reagents. A more thorough
discussion of organometallic reagents can be found in B. S.
Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell, Vogel's
Textbook of Practical Organic Chemistry, 5.sup.th ed., Longman,
1989.
[0285] Ketone of formula (3-0) can be further utilized by
conversion into amine of formula (3-6) via a reductive amination.
Reductive amination is achieved by treating the ketone with an
amine in the presence of a reducing agent to obtain the product
amine (3-6). The reaction can be carried out either with or without
added acid. Examples of acids that are commonly used include, but
are not limited to, hydrochloric, phosphoric, sulfuric, acetic, and
the like. Reducing agents that effect reductive amination include,
but are not limited to, hydrogen and a catalyst, zinc and
hydrochloric acid, sodium cyanoborohydride, sodium borohydride,
iron pentacarbonyl, and alcoholic potassium hydroxide. Generally
alcoholic solvents are used. The preferred conditions use sodium
cyanoborohydride in methanol with added acetic acid.
[0286] It will be appreciated by one skilled in the art, that the
unsaturated compounds represented by compounds (3-2) and (3-8) can
be reduced to form the corresponding saturated compound (see
Hudlicky, M., Reductions in Organic Chemistry, Ellis Horwood
Limited: Chichester, 1984).
##STR00041##
[0287] Compounds of the invention according to formula (4-1) are
also capable of further functionalization to generate compounds of
the present invention. Alkene (4-1) can be treated with an aryl
halide or aryl triflate in the presence of a palladium catalyst
[Pd(0) or Pd(II)] to provide compound (4-3): (See (a) Heck,
Palladium Reagents in Organic Synthesis, Academic Press: New York,
1985, Chapter 1; (b) Sonogashira, Comprehensive Organic Synthesis,
Volume 3, Chapters 2,4; (c) Sonogashira, Synthesis 1977, 777).
Under the Heck coupling conditions, regioisomers and stereoisomers
of the double bond are possible. Alternatively, compound (4-1) can
undergo a cross metathesis reaction with vinylaromatic derivatives
using ruthenium catalysts to give compounds of formula (4-2) (see
(a) J. Org. Chem. 2000, 65, 2204-2207; (b) Reviews: Synlett. 1999,
2, 267; (c) Reviews: Ivin, K. J.; Mol, J. C., Olefin Metathesis and
Metathesis Polymerization, 2.sup.nd ed., Academic Press: New York,
1997; (d) J. Org. Chem. 1999, 64, 4798-4816; (e) Angew. Chem., Int.
Ed. Engl. 1997, 36, 2036-2056; (f) Tetrahedron 1998, 54,
4413-4450).
##STR00042##
[0288] It will be appreciated that compounds of the present
invention include modification of the 3' N of compounds of the
formula (5-1). Compounds of formula (5-2) can be made via the
methods known in the art, such as in U.S. Pat. Nos. 6,034,069 and
6,387,885.
[0289] All references cited herein, whether in print, electronic,
computer readable storage media or other form, are expressly
incorporated by reference in their entirety, including but not
limited to, abstracts, articles, journals, publications, texts,
treatises, internet web sites, databases, patents, and patent
publications.
EXAMPLES
[0290] The compounds and processes of the present invention will be
better understood in connection with the following examples, which
are intended as an illustration only and not limiting of the scope
of the invention. Various changes and modifications to the
disclosed embodiments will be apparent to those skilled in the art
and such changes and modifications including, without limitation,
those relating to the chemical structures, substituents,
derivatives, formulations and/or methods of the invention may be
made without departing from the spirit of the invention and the
scope of the appended claims.
Example 1
Compound of Formula A, Wherein R.sub.3 is
##STR00043##
[0291] and Y=H (Compound 1)
Step 1a:
[0292] Compound 1-1, where PG1 is TIPS and PG is TMS, (24 g, 23.1
mmol) was placed with 1-1a, where R.sub.50 is t-butyl, (14 g, 48.6
mmol), 1,4-bis(diphenylphosphino) butane (1.5 g, 3.5 mmol) and
tris(dibenzylidine acetone)dipalladium (2.11 g, 2.3 mmol) in THF
(125 mL) and heated at reflux for 1 h. The reaction was cooled,
quenched with water, extracted with ethyl acetate, dried
(MgSO.sub.4) and concentrated to a dark foam that was used in the
next step. MS: (ESI) m/z (M+H): 1088.66.
Step 1b:
[0293] Compound from step 1a was placed with ethyl alcohol (100 mL)
and 2M aqueous HCl (35 mL) and heated at 90.degree. C. for 30 min.
The reaction was cooled, quenched with 3N aqueous NaOH, extracted
with ethyl acetate, dried (MgSO.sub.4) and concentrated to a dark
foam that was used in the next step. MS: (ESI) m/z (M+H):
786.66.
Step 1c:
[0294] Acetic anhydride (3.3 mL, 35 mmol) was added to a room
temperature solution of Compound from step 1b in DCM (115 mL) and
stirred for 2 h. Dess Martin Periodinane (20 g, 47 mmol) was added
to this reaction mixture and stirred for 4 h. The reaction was
quenched with sodium thiosulfate and saturated sodium bicarbonate,
extracted with DCM, dried (MgSO.sub.4) and concentrated to a dark
foam that was used in the next step. MS: (ESI) m/z (M+H):
826.64.
Step 1d:
[0295] Concentrated HCl (215 mL) was added dropwise to a solution
of compound from step 1c in THF (150 mL) at 0.degree. C. The
reaction was warmed to rt over 2 h, quenched with 3N aqueous
NaOH/ice, extracted with ethyl acetate, dried (MgSO.sub.4),
concentrated and purified by flash chromatography to obtain the
title compound as a yellow foam. MS: (ESI) m/z (M+H): 670.46.
.sup.13C NMR (CDCl.sub.3): .delta. 205.16, 169.81, 168.46, 143.41,
122.12, 101.48, 82.63, 80.28, 79.09, 77.70, 76.71, 74.82, 71.77,
71.21, 69.28, 65.01, 63.55, 51.54, 48.14, 42.00, 40.81, 37.65,
31.07, 30.70, 23.76, 21.51, 21.17, 20.93, 20.64, 17.28, 15.82,
14.08, 12.43.
Step 1e:
[0296] Ozone gas was bubbled through a solution of compound from
step 1d (11.2 mmol) and camphor sulfonic acid (2.85 g, 12.3 mmol)
in DCM (50 mL) and MeOH (30 mL) maintained at -78.degree. C. till
the reaction was complete by MS. Dimethyl sulfide (7.8 mL, 112
mmol) was added to the reaction mixture and warmed to room
temperature over 4 h. The reaction was quenched with saturated,
aqueous NaHCO.sub.3, extracted with ethyl acetate, dried
(MgSO.sub.4) and concentrated to a yellow foam that was used in the
oxime forming step. MS: (ESI) m/z (M+H): 672.39.
Step 1f:
[0297] A solution of Compound from step 1e (0.035 g, 0.05 mmol) in
THF was added to a slurry of
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine (0.050 g, 0.26
mmol) in 2N HCl maintained at 0.degree. C., followed by the
addition of water to effect a clear solution. The reaction was
warmed to room temperature over 30 min, quenched with saturated
aqueous NaHCO.sub.3, extracted with ethyl acetate, dried
(MgSO.sub.4), concentrated and suspended in MeOH overnight. The
solvents were removed in vacuo and the residue purified on RP-HPLC
to afford the titled compound and its corresponding Z-isomer. Data
for E isomer: MS: (ESI) m/z (M+H): 802.32. .sup.13C NMR
(CDCl.sub.3): .delta. 204.9, 168.84, 155.84, 151.56, 148.47,
142.34, 139.58, 130.96, 127.35, 112.34, 108.05, 103.77, 82.33,
81.93, 81.27, 78.9, 76.88, 76.72, 76.01, 73.49, 70.46, 69.31,
66.56, 63.76, 63.0, 51.94, 48.82, 40.64, 29.99, 23.75, 21.56,
21.32, 20.97, 17.25, 16.47, 14.53, 12.34.
Example 2
Compound of Formula A, Wherein R.sub.3 is
##STR00044##
[0298] and Y=H (Compound 2)
[0299] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
0-[5-(3-Amino-[1,2,4]thiadiazol-5-yl)-pyridin-2-ylmethyl]-hydroxylamine
for O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 835.13. .sup.13C NMR (CDCl.sub.3):
.delta. 204.77, 184.38, 170.0, 168.61, 161.3, 156.25, 147.3,
134.65, 125.47, 121.85, 103.87, 81.99, 81.72, 80.55, 78.51, 76.43,
76.26, 76.15, 70.3, 69.47, 65.79, 63.44, 62.4, 51.62, 48.60, 40.19,
30.72, 29.63, 28.18, 23.45, 21.23, 21.09, 20.81, 17.08, 16.2, 14.2,
12.00.
Example 3
Compound of Formula A, Wherein R.sub.3 is
##STR00045##
[0300] and Y=H (Compound 3)
[0301] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[5-(4-Amino-thiazol-2-yl)-pyridin-2-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 834.43. .sup.13C NMR (CDCl.sub.3):
.delta. 204.85, 168.84, 162.52, 159.12, 157.53, 156.15, 146.74,
133.85, 128.76, 121.97, 103.42, 91.24, 82.15, 81.97, 81.02, 78.83,
76.68, 76.63, 76.27, 70.23, 68.93, 66.49, 63.79, 62.75, 51.88,
48.68, 40.59, 29.9, 23.68, 21.49, 21.15, 21.02, 17.28, 16.48,
14.52, 12.2.
Example 4
Compound of Formula A, Wherein R.sub.3 is
##STR00046##
[0302] and Y=H (Compound 4)
[0303] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-(6-Isoxazol-5-yl-pyridin-3-ylmethyl)-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 803.45. .sup.13C NMR (CDCl.sub.3):
.delta. 204.88, 168.84, 168.67, 155.96, 151.23, 150.12, 145.99,
137.32, 134.28, 120.76, 104.16, 101.66, 82.24, 81.60, 80.95, 78.68,
76.67, 75.76, 73.30, 69.73, 65.98, 63.53, 62.75, 51.79, 48.89,
40.41, 28.33, 23.62, 21.43, 21.33, 20.73, 17.07, 16.37, 14.34,
12.28.
Example 5
Compound of Formula A, Wherein R.sub.3 is
##STR00047##
[0304] AND Y=H (Compound 5)
[0305] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[5-(3-Amino-pyrazol-1-yl)-pyridin-2-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 817.59. .sup.13C NMR (CDCl.sub.3):
.delta. 204.94, 168.88, 156.57, 156.12, 154.25, 138.71, 135.77,
128.03, 125.62, 122.62, 104.13, 97.29, 82.31, 82.03, 81.08, 78.77,
76.60, 76.25, 70.54, 69.68, 66.03, 63.79, 62.76, 51.87, 48.81,
40.39, 28.47, 23.66, 21.53, 21.34, 21.11, 17.24, 16.42, 14.46,
12.18.
Example 6
Compound of Formula A, Wherein R.sub.3 is
##STR00048##
[0306] and Y=H (Compound 6)
[0307] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-(6'-Amino-[2,2']bipyridinyl-6-ylmethyl)-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 828.68.
Example 7
Compound of Formula A, Wherein R.sub.3 is
##STR00049##
[0308] and Y=H (Compound 7)
[0309] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[6-(3-Amino-pyrazol-1-yl)-pyridin-3-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 817.51.
Example 8
Compound of Formula A, Wherein R.sub.3 is
##STR00050##
[0310] and Y=H (Compound 8)
[0311] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[5-(6-Amino-pyridin-2-yl)-thiazol-2-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: Data for E isomer: MS: (ESI) m/z (M+H): 834.46.
Example 9
Compound of Formula A, Wherein R.sub.3 is
##STR00051##
[0312] and Y=H (Compound 9)
[0313] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[2-(6-Amino-pyridin-2-yl)-thiazol-4-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 834.51. .sup.13C NMR (CDCl.sub.3):
.delta. C13(CDCl.sub.3, Selected) 205.1, 169.8, 168.8, 158.3,
155.6, 154.3, 149.7, 138.3, 119.2, 110.5, 110.0, 104.2, 82.3, 81.9,
81.2, 78.8, 76.7, 76.0, 72.3, 70.6, 69.8, 66.1, 63.7, 62.9, 51.9,
48.9, 41.9, 40.5, 38.7, 30.6, 28.5, 23.7, 21.6, 21.4, 20.9, 17.2,
16.6, 14.5, 12.3, 11.7.
Example 10
Compound of Formula A, Wherein R.sub.3 is
##STR00052##
[0314] and Y=F (Compound 10)
Step 10a:
[0315] To a solution of compound from step 1d in DMF and t-BuOH at
-10.degree. C. was added KO.sup.tBu and stirred for 1 hour followed
by the addition of N-fluorbenzenesulfonimide and continued to
stirred at -10.degree. C. for 30 minutes. The reaction was quenched
by the addition of ethyl vinyl ether, warmed to room temperture,
quenched by the addition of saturated sodium bicarbonate, extracted
with ethyl acetate, dried (MgSO.sub.4), concentrated and purified
by flash chromatography to afford a white foam.
Step 10b:
[0316] Ozonolysis on this substrate was carried out in a similar
manner as described for Example 1, Step 1e substituting Compound
from Step 10a for Compound for Step 1d. This product from Step 10b
was used in the oxime forming step.
Step 10c:
[0317] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[5-(4-Amino-thiazol-2-yl)-pyridin-2-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 852.67.
Example 11
Compound of Formula A, Wherein R.sub.3 is
##STR00053##
[0318] and Y=F (Compound 11)
[0319] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[5-(6-Amino-pyridin-2-yl)-thiazol-2-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 852.34.
Example 12
Compound of Formula A, Wherein R.sub.3 is
##STR00054##
[0320] and Y=F (Compound 12)
[0321] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[2-(6-Amino-pyridin-2-yl)-thiazol-5-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 852.17.
Example 13
Compound of Formula A, Wherein R.sub.3 is
##STR00055##
[0322] and Y=F (Compound 13)
[0323] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-(6-Isoxazol-5-yl-pyridin-3-ylmethyl)-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 821.57. .sup.13C NMR (CDCl.sub.3):
.delta. C13(CDCl.sub.3, Selected) 205.1, 204.9, 168.9, 165.9,
165.7, 155.4, 151.3, 150.1, 146.1, 137.3, 134.4, 120.8, 104.4,
101.7, 99.3, 97.6, 82.6, 81.8, 81.2, 79.7, 76.8, 75.3, 73.4, 70.6,
69.9, 66.0, 63.4, 61.9, 43.6, 40.8, 40.5, 29.7, 28.4, 25.5, 25.3,
23.3, 21.4, 20.0, 17.0, 15.5, 12.3, 10.5.
Example 14
Compound of Formula A, Wherein R.sub.3 is
##STR00056##
[0324] and Y=F (Compound 14)
[0325] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[2-(6-Amino-pyridin-2-yl)-oxazol-4-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 836.36.
Example 15
Compound of Formula A, Wherein R.sub.3 is
##STR00057##
[0326] and Y=F (Compound 15)
[0327] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[4-(4-Amino-thiazol-2-yl)-benzyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 851.34.
Example 16
Compound of Formula A, Wherein R.sub.3 is
##STR00058##
[0328] and Y=F (Compound 16)
[0329] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-(5-Thiazol-2-yl-pyridin-2-ylmethyl)-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 837.31. .sup.13C NMR (CDCl.sub.3):
.delta. C13(CDCl.sub.3, Selected) 205.0, 204.8, 166.0, 165.8,
165.2, 159.7, 155.7, 147.4, 144.3, 134.5, 128.7, 122.0, 119.7,
104.3, 99.3, 97.6, 82.6, 82.0, 81.5, 79.7, 76.7, 75.6, 70.6, 69.8,
66.1, 63.6, 61.9, 40.7, 40.5, 30.2, 28.5, 25.5, 25.4, 23.3, 21.4,
20.2, 17.1, 15.5, 12.4.
Example 17
Compound of Formula A, Wherein R.sub.3 is
##STR00059##
[0330] and Y=F (Compound 17)
[0331] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f substituting
O-[2-(6-Amino-pyridin-2-yl)-thiazol-4-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 852.47.
Example 18
Compound of Formula A, Wherein R.sub.3 is
##STR00060##
[0332] and Y=F (Compound 18)
[0333] The E and Z isomers of the titled compound were prepared
using the procedure of Example 1, step 1f, substituting
O-[6-(4-Amino-thiazol-2-yl)-pyridin-3-ylmethyl]-hydroxylamine for
O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Data for E
isomer: MS: (ESI) m/z (M+H): 852.17.
[0334] The hydroxylamines were prepared according to literature
procedures and procedures disclosed in U.S. Pat. No. 6,878,691 and
US Published Application No. 2009/0118506.
Representative Compounds with Improved Antibacterial
Activities:
[0335] Susceptibility tests can be used to quantitatively measure
the in vitro activity of an antimicrobial agent against a given
bacterial isolate. Compounds are tested for in vitro antibacterial
activity by a micro-dilution method. Minimal Inhibitory
Concentration (MIC) is determined in 96 well microtiter plates
utilizing the appropriate broth medium for the observed bacterial
isolates. Antimicrobial agents are serially diluted (2-fold) in
DMSO to produce a concentration range from about 64 .mu.g/ml to
about 0.03 .mu.g/ml. The diluted compounds (2 .mu.l/well) are then
transferred into sterile, uninoculated medium (0.2 mL) by use of a
96 fixed tip-pipetting station. The inoculum for each bacterial
strain is standardized to approximately 5.times.10.sup.5 CFU/mL by
optical comparison to a 0.5 McFarland turbidity standard. The
plates are inoculated with 10 .mu.l/well of adjusted bacterial
inoculum. The 96 well plates are covered and incubated at 35+/-2'C
for 24 hours in ambient air environment. Following incubation,
plate wells are visually examined by Optical Density measurement
for the presence of growth (turbidity). The lowest concentration of
an antimicrobial agent at which no visible growth occurs is defined
as the MIC. The compounds of the invention generally demonstrated
an MIC in the range from about 64 .mu.g/ml to about 0.03
.mu.g/ml.
[0336] All in vitro testing follows the guidelines described in the
Approved Standards M7-A7 protocol, published by the Clinical
Laboratory Standards Institute (CLSI).
[0337] Table II below provides MIC data for compounds of the
invention and related species from U.S. Pat. No. 6,878,691 and US
Published Application No. 2009/0118506, each of which is
incorporated herein by reference. The values in the table are
minimum inhibition concentration (MIC) and are expressed as
ug/mL.
TABLE-US-00002 TABLE II ##STR00061## ##STR00062## H. influenzae H.
influenzae MIC (.mu.g/mL) MIC (.mu.g/mL) strain strain strain
strain Compound # R = Sidechain Y 33929 49247 Z3 33929 49247 1
##STR00063## H 4 2 Me 4 8 2 ##STR00064## H 1 1 Me 4 4 3
##STR00065## H 4 2 Me 4 4 4 ##STR00066## H 1 1 Me 4 4 5
##STR00067## H 2 2 Me 8 8 6 ##STR00068## H 1 1 Me 8 4 7
##STR00069## H 1 1 Me 8 8 8 ##STR00070## H 2 1 Et 4 4 9
##STR00071## H 1 1 Me -- -- 10 ##STR00072## F 4 1 Me 4 2 11
##STR00073## F 1 1 Me 4 4 12 ##STR00074## F 2 1 Me 2 2 13
##STR00075## F 2 1 Me -- -- 14 ##STR00076## F 2 1 Me 2 2 15
##STR00077## F 4 4 Et 8 8 16 ##STR00078## F 2 -- Et 4 4 17
##STR00079## F 1 1 Me 4 -- 18 ##STR00080## F 2 1 Et 8 8
##STR00081##
[0338] 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.
[0339] Although the invention has been described with respect to
various preferred embodiments, it is not intended to be limited
thereto, but rather those skilled in the art will recognize that
variations and modifications may be made therein which are within
the spirit of the invention and the scope of the appended
claims.
[0340] 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.
* * * * *