U.S. patent application number 11/810336 was filed with the patent office on 2008-01-17 for amino-methyl substituted tetracycline compounds.
This patent application is currently assigned to Paratek Pharmaceuticals, Inc.. Invention is credited to Paul Abato, Victor Amoo, Haregewein Assefa, Joel Berniac, Beena Bhatia, Todd Bowser, Jackson Chen, Roger Frechette, Laura Honeyman, Mohamed Y. Ismail, Oak Kim, Rachid Mechiche, Mark L. Nelson, Kwasi Ohemeng, N. Laxma Reddy, Atul K. Verma, Peter Viski, Tadeusz Warchol, Ivan Yanachkov.
Application Number | 20080015169 11/810336 |
Document ID | / |
Family ID | 27807973 |
Filed Date | 2008-01-17 |
United States Patent
Application |
20080015169 |
Kind Code |
A1 |
Nelson; Mark L. ; et
al. |
January 17, 2008 |
Amino-methyl substituted tetracycline compounds
Abstract
Aminomethyl substituted tetracycline compounds, pharmaceutical
compositions, and methods of use thereof are discussed.
Inventors: |
Nelson; Mark L.; (Norfolk,
MA) ; Ohemeng; Kwasi; (Sakumono, GH) ;
Frechette; Roger; (Reading, MA) ; Abato; Paul;
(Providence, RI) ; Amoo; Victor; (Daphne, AL)
; Assefa; Haregewein; (Braintree, MA) ; Berniac;
Joel; (Stoneham, MA) ; Bhatia; Beena;
(Mansfield, MA) ; Bowser; Todd; (Charlton, MA)
; Chen; Jackson; (East Amherst, NY) ; Honeyman;
Laura; (Roslindale, MA) ; Ismail; Mohamed Y.;
(Bedford, MA) ; Kim; Oak; (Cambridge, MA) ;
Mechiche; Rachid; (South Boston, MA) ; Reddy; N.
Laxma; (Solon, OH) ; Verma; Atul K.;
(Mansfield, MA) ; Viski; Peter; (Asharoken,
NY) ; Warchol; Tadeusz; (Northborough, MA) ;
Yanachkov; Ivan; (Shrewsbury, MA) |
Correspondence
Address: |
LAHIVE & COCKFIELD, LLP
ONE POST OFFICE SQUARE
BOSTON
MA
02109-2127
US
|
Assignee: |
Paratek Pharmaceuticals,
Inc.
Boston
MA
|
Family ID: |
27807973 |
Appl. No.: |
11/810336 |
Filed: |
June 5, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10737361 |
Dec 15, 2003 |
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11810336 |
Jun 5, 2007 |
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10384855 |
Mar 10, 2003 |
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10737361 |
Dec 15, 2003 |
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60362654 |
Mar 8, 2002 |
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60395495 |
Jul 12, 2002 |
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Current U.S.
Class: |
514/152 ;
514/319; 514/370; 514/425; 546/195; 548/193; 548/546; 552/203 |
Current CPC
Class: |
C07C 335/12 20130101;
C07D 207/20 20130101; C07D 211/58 20130101; A61P 29/00 20180101;
A61P 31/04 20180101; C07C 2601/08 20170501; A61P 21/00 20180101;
A61P 25/04 20180101; C07D 213/82 20130101; C07D 295/116 20130101;
A61P 27/16 20180101; C07D 307/52 20130101; A61P 17/16 20180101;
A61P 9/14 20180101; A61P 19/02 20180101; C07C 275/34 20130101; C07D
207/404 20130101; A61P 35/04 20180101; A61P 35/00 20180101; C07D
261/14 20130101; A61P 3/10 20180101; A61P 19/00 20180101; A61P 9/10
20180101; C07C 255/58 20130101; C07D 207/335 20130101; C07C 2601/14
20170501; A61P 13/02 20180101; C07D 277/42 20130101; A61P 25/16
20180101; C07D 335/02 20130101; A61P 9/00 20180101; C07C 2603/46
20170501; A61P 33/06 20180101; C07D 261/18 20130101; A61P 25/28
20180101; A61P 1/04 20180101; A61P 1/02 20180101; A61P 13/10
20180101; A61P 37/08 20180101; A61P 25/24 20180101; A61P 25/14
20180101; C07C 323/60 20130101; A61P 1/16 20180101; C07D 213/20
20130101; A61P 9/12 20180101; A61P 31/10 20180101; C07D 307/54
20130101; C07C 271/22 20130101; A61P 19/10 20180101; C07D 211/70
20130101; A61P 27/02 20180101; C07D 231/12 20130101; A61P 1/12
20180101; A61P 17/00 20180101; A61P 25/08 20180101; C07C 2601/04
20170501; C07D 207/16 20130101; C07D 295/215 20130101; A61P 31/12
20180101; A61P 35/02 20180101; C07C 2601/02 20170501; C07D 209/44
20130101; C07D 213/89 20130101; C07D 317/66 20130101; A61P 15/14
20180101; A61P 25/00 20180101; A61P 11/00 20180101; A61P 25/18
20180101; A61P 29/02 20180101; C07D 277/56 20130101; A61P 19/08
20180101; A61P 37/06 20180101; A61P 25/20 20180101; C07C 237/26
20130101; C07D 213/64 20130101; A61P 43/00 20180101; A61P 25/22
20180101; A61P 17/02 20180101; C07D 295/155 20130101; C07C 239/20
20130101; C07D 261/10 20130101; A61P 15/00 20180101 |
Class at
Publication: |
514/152 ;
514/319; 514/370; 514/425; 546/195; 548/193; 548/546; 552/203 |
International
Class: |
A61K 31/65 20060101
A61K031/65; A61K 31/40 20060101 A61K031/40; A61K 31/426 20060101
A61K031/426; A61P 25/00 20060101 A61P025/00; A61P 29/00 20060101
A61P029/00; A61P 35/00 20060101 A61P035/00; C07D 237/26 20060101
C07D237/26; C07D 295/00 20060101 C07D295/00; C07D 277/02 20060101
C07D277/02; C07D 227/00 20060101 C07D227/00; A61P 31/04 20060101
A61P031/04; A61P 27/02 20060101 A61P027/02; A61P 11/00 20060101
A61P011/00; A61K 31/435 20060101 A61K031/435 |
Claims
1. A tetracycline compound of the formula (I): ##STR253## wherein
R.sup.1 and R.sup.2 are linked to form a ring, or pharmaceutically
acceptable salts, prodrugs and esters thereof.
2. The tetracycline compound of claim 1, wherein R.sup.1 and
R.sup.2 are linked to form a five membered ring.
3. The tetracycline compound of claim 1, wherein R.sup.1 and
R.sup.2 are linked to form a six membered ring.
4. The tetracycline compound of claim 3, wherein R.sup.1 and
R.sup.2 are linked to form a piperidine ring, morpholine ring,
pyridine ring, or a pyrazinyl ring.
5. The tetracycline compound of claim 4, wherein said compound is:
##STR254##
6. A tetracycline compound of the formula: ##STR255##
pharmaceutically acceptable salts, esters or prodrugs thereof.
7. A tetracycline compound of the formula (II): ##STR256## wherein:
J.sup.1 and J.sup.2 are each independently hydrogen, aryl,
sulfonyl, acyl, or linked to form a ring, provided that at least
one of J.sup.1 or J.sup.2 is not hydrogen; J.sup.3 and J.sup.4 are
each alkyl, halogen, or hydrogen; X is CHC(R.sup.13Y'Y),
CR.sup.6'R.sup.6, C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each independently
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety; R.sup.4 is
NR.sup.4', R.sup.4'', alkyl, alkenyl, alkynyl, aryl, hydroxyl,
halogen, or hydrogen; R.sup.2', R.sup.3, R.sup.10, R.sup.11 and
R.sup.12 are each hydrogen or a pro-drug moiety; R.sup.5 is
hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl,
heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl
carbonyloxy, or aryl carbonyloxy; R.sup.6 and R.sup.6' are each
independently hydrogen, methylene, absent, hydroxyl, halogen,
thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.9
is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a; Z is
CR.sup.9dR.sup.9e, NR.sup.9b or O; Z' is O, S, or NR.sup.9f;
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are each
independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; R.sup.8 is
hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, esters, and
prodrugs thereof.
8. The tetracycline compound of claim 7, wherein R.sup.4 is
NR.sup.4'R.sup.4'', X is CR.sup.6R.sup.6'; R.sup.2, R.sup.2',
R.sup.6, R.sup.6', R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; R.sup.4' and R.sup.4'' are lower alkyl;
and R.sup.5 is hydroxy or hydrogen.
9. The tetracycline compound of claim 8, wherein R.sup.4' and
R.sup.4'' are each methyl and R.sup.5 is hydrogen.
10. The tetracycline compound of claim 7, wherein J.sup.3 and
J.sup.4 are hydrogen.
11. The tetracycline compound of claim 7, wherein J.sup.1 is
substituted or unsubstituted alkyl.
12. The tetracycline compound of claim 7, wherein J.sup.1 is
sulfonyl.
13. The tetracycline compound of claim 7, wherein J.sup.1 and
J.sup.2 are linked to form a ring.
14. The tetracycline compound of claim 7, wherein J.sup.1 is
heteroaryl.
15. A tetracycline compound, wherein said compound is selected from
the group consisting of: ##STR257## ##STR258## ##STR259##
##STR260## ##STR261## ##STR262## wherein R is substituted or
unsubstituted alkyl, alkenyl, alkynyl, halogen, alkoxy; and Y is N,
O, or S, or pharmaceutically acceptable salts, esters, or prodrugs
thereof.
16. A tetracycline compound of formula (III): ##STR263## wherein:
J.sup.5 and J.sup.6 are each independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, sulfonyl, acyl, alkoxycarbonyl,
alkaminocarbonyl, alkaminothiocarbonyl, substituted thiocarbonyl,
substituted carbonyl, alkoxythiocarbonyl, or linked to form a ring;
J.sup.7 and J.sup.8 are each alkyl, halogen, or hydrogen; X is
CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, C.dbd.CR.sup.6'R.sup.6, S,
NR.sup.6, or O; R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety; R.sup.4 is
NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl, aryl, hydroxyl,
halogen, or hydrogen; R.sup.2', R.sup.3, R.sup.10, R.sup.11 and
R.sup.12 are each hydrogen or a pro-drug moiety; R.sup.5 is
hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl,
heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl
carbonyloxy, or aryl carbonyloxy; R.sup.6 and R.sup.6' are each
independently hydrogen, methylene, absent, hydroxyl, halogen,
thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.7
is hydrogen; R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.13 is hydrogen,
hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl; and Y' and Y are each
independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl,
amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically
acceptable salts thereof.
17. The tetracycline compound of claim 16, wherein R.sup.4 is
NR.sup.4'R.sup.4'', X is CR.sup.6R.sup.6'; R.sup.2, R.sup.2',
R.sup.6, R.sup.6', R.sup.8, R.sup.10, R.sup.11, and R.sup.12 are
each hydrogen; R.sup.4' and R.sup.4'' are lower alkyl; and R.sup.5
is hydroxy or hydrogen.
18. The tetracycline compound of claim 17, wherein R.sup.4' and
R.sup.4'' are each methyl and R.sup.5 is hydrogen.
19. The tetracycline compound of claim 16, wherein J.sup.7 and
J.sup.8 are hydrogen.
20. The tetracycline compound of claim 16, wherein J.sup.5 is
substituted or unsubstituted alkyl.
21. The tetracycline compound of claim 16, wherein J.sup.5 is
sulfonyl.
22. The tetracycline compound of claim 16, wherein J.sup.5 and
J.sup.6 are linked to form a ring.
23. The tetracycline compound of claim 16, wherein J.sup.5 is
heteroaryl.
24. The tetracycline compound of claim 16, wherein J.sup.5 is
substituted carbonyl.
25. The tetracycline compound of claim 16, wherein said compound is
selected from the group consisting of: ##STR264## ##STR265##
##STR266## ##STR267## ##STR268## ##STR269## ##STR270## wherein R is
substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen,
alkoxy; and Y is N, O, or S, or pharmaceutically acceptable salts
or prodrugs thereof.
26. A tetracycline compound of Table 1, or a pharmaceutically
acceptable salt thereof.
27. A pharmaceutical composition comprising an effective amount of
a tetracycline compound of any one of claims 1, 15, 16, 25 or 26,
and a pharmaceutically acceptable carrier.
28. The pharmaceutical composition of claim 27, wherein said
effective amount is effective to treat a tetracycline responsive
state.
29. A method for treating a tetracycline responsive state in a
subject, comprising administering to said subject a tetracycline
compound of any one of claims 1, 15, 16, 25 or 26, such that said
subject is treated.
30. The method of claim 29, wherein said tetracycline responsive
state is an inflammatory process associated state.
31. The method of claim 29, wherein said tetracycline responsive
state is cancer, a lung injury, an eye disorder, neurological
disorder or stroke.
32. The method of claim 29, wherein said tetracycline responsive
state is a bacterial infection.
33. The method of claim 32, wherein said bacterial infection is
associated with E. coli.
34. The method of claim 32, wherein said bacterial infection is
associated with S. aureus.
35. The method of claim 32, wherein said bacterial infection is
associated with E. faecalis.
36. The method of claim 32, wherein said bacterial infection is
resistant to other tetracycline antibiotics.
37. The method of claim 32, wherein said bacterial infection is
associated with gram positive bacteria.
38. The method of claim 32, wherein said bacterial infection is
associated with gram negative bacteria.
39. The method of claim 29, wherein said tetracycline responsive
state is a viral or fungal infection.
40. The method of claim 29, wherein said tetracycline compound is
administered with a pharmaceutically acceptable carrier.
41. The method of claim 29, wherein said subject is a human.
Description
RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 10/737,361, filed Dec. 15, 2003,
allowed, which is a continuation of U.S. patent application Ser.
No. 10/384,855, filed Mar. 10, 2003, abandoned, and claims priority
to U.S. Provisional Patent Application Ser. No. 60/395,495, filed
on Jul. 12, 2002 (expired); and U.S. Provisional Patent Application
Ser. No. 60/362,654, filed Mar. 8, 2002 (expired). Each of the
aforementioned applications are hereby incorporated herein by
reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] The development of the tetracycline antibiotics was the
direct result of a systematic screening of soil specimens collected
from many parts of the world for evidence of microorganisms capable
of producing bacteriocidal and/or bacteriostatic compositions. The
first of these novel compounds was introduced in 1948 under the
name chlortetracycline. Two years later, oxytetracycline became
available. The elucidation of the chemical structure of these
compounds confirmed their similarity and furnished the analytical
basis for the production of a third member of this group in 1952,
tetracycline. A new family of tetracycline compounds, without the
ring-attached methyl group present in earlier tetracyclines, was
prepared in 1957 and became publicly available in 1967.
[0003] Recently, research efforts have focused on developing new
tetracycline antibiotic compositions effective under varying
therapeutic conditions and routes of administration. New
tetracycline analogues have also been investigated which may prove
to be equal to or more effective than the originally introduced
tetracycline compounds. Examples include U.S. Pat. Nos. 3,957,980;
3,674,859; 2,980,584; 2,990,331; 3,062,717; 3,557,280; 4,018,889;
4,024,272; 4,126,680; 3,454,697; and 3,165,531. These patents are
representative of the range of pharmaceutically active tetracycline
and tetracycline analogue compositions.
[0004] Historically, soon after their initial development and
introduction, the tetracyclines were found to be highly effective
pharmacologically against rickettsiae; a number of gram-positive
and gram-negative bacteria; and the agents responsible for
lymphogranuloma venereum, inclusion conjunctivitis, and
psittacosis. Hence, tetracyclines became known as "broad spectrum"
antibiotics. With the subsequent establishment of their in vitro
antimicrobial activity, effectiveness in experimental infections,
and pharmacological properties, the tetracyclines as a class
rapidly became widely used for therapeutic purposes. However, this
widespread use of tetracyclines for both major and minor illnesses
and diseases led directly to the emergence of resistance to these
antibiotics even among highly susceptible bacterial species both
commensal and pathogenic (e.g., pneumococci and Salmonella). The
rise of tetracycline-resistant organisms has resulted in a general
decline in use of tetracyclines and tetracycline analogue
compositions as antibiotics of choice.
SUMMARY OF THE INVENTION
[0005] In one embodiment, the invention pertains to tetracycline
compounds of the formula (I): ##STR1##
[0006] wherein
[0007] R.sup.1 and R.sup.2 are linked to form a ring, or
pharmaceutically acceptable salts, prodrugs and esters thereof.
[0008] The invention also pertains, at least in part, tetracycline
compounds of the formula: ##STR2## pharmaceutically acceptable
salts, esters or prodrugs thereof.
[0009] The invention also pertains, at least in part, to
tetracycline compounds of the formula (II): ##STR3## wherein:
[0010] J.sup.1 and J.sup.2 are each independently hydrogen, aryl,
sulfonyl, acyl, or linked to form a ring, provided that at least
one of J.sup.1 or J.sup.2 is not hydrogen;
[0011] J.sup.3 and J.sup.4 are each alkyl, halogen, or
hydrogen;
[0012] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0013] R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0014] R.sup.4 is NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl,
aryl, hydroxyl, halogen, or hydrogen;
[0015] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0016] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0017] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0018] R.sup.9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0019] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0020] Z' is O, S, or NR.sup.9f
[0021] R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety;
[0022] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0023] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0024] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, esters, and
prodrugs thereof.
[0025] The invention also pertains, at least in part, to
tetracycline compounds of formula (III): ##STR4## wherein:
[0026] J.sup.5 and J.sup.6 are each independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, sulfonyl, acyl, alkoxycarbonyl,
alkaminocarbonyl, alkaminothiocarbonyl, substituted thiocarbonyl,
substituted carbonyl, alkoxythiocarbonyl, or linked to form a
ring;
[0027] J.sup.7 and J.sup.8 are each alkyl, halogen, or
hydrogen;
[0028] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0029] R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0030] R.sup.4 is NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl,
aryl, hydroxyl, halogen, or hydrogen;
[0031] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0032] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0033] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0034] R.sup.7 is hydrogen;
[0035] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0036] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0037] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
[0038] The invention also pertains to compounds of the formulae
shown in Table 1 and pharmaceutically acceptable esters, salts, and
prodrugs thereof.
[0039] The invention also pertains, at least in part, to
pharmaceutical compositions comprising aminomethyl tetracycline
compounds of formulae (I), (II), (III), Table 1, or otherwise
described herein. The pharmaceutical compositions preferably
comprise an effective amount of a minocycline compound and a
pharmaceutically acceptable carrier.
[0040] In another embodiment, the invention also pertains, at least
in part, to methods of using the aminomethyl tetracycline compounds
of the invention (e.g., of formula (I), (III), (III), Table 1, or
otherwise described herein), to treat tetracycline associated
states in subjects.
[0041] In an embodiment, the invention pertains, at least in part,
to a method for the synthesis of an aminoalkyl tetracycline
compound. The method includes contacting a tetracycline compound
with an aminoalkylating reagent under appropriate conditions, such
that an aminoalkyl tetracycline compound is formed.
[0042] In another embodiment, the invention pertains to
pharmaceutical compositions containing the aminoalkyltetracycline
compounds of the invention and aminoalkyltetracycline compounds
synthesized by the methods of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0043] In an embodiment, the invention pertains to tetracycline
compounds of the formula (I): ##STR5##
[0044] wherein
[0045] R.sup.1 and R.sup.2 are linked to form a ring, or
pharmaceutically acceptable salts, prodrugs and esters thereof.
[0046] In one embodiment, R.sup.1 and R.sup.2 are linked to form a
five or six membered ring. In another, R.sup.1 and R.sup.2 are
linked to form a six membered ring. R.sup.1 and R.sup.2 may be
linked by a chain of atoms such as, for example,
--(CH.sub.2).sub.5-6,
--(CH.sub.2).sub.1-5--CH.dbd.CH--(CH.sub.2).sub.1-5--,
--(CH.sub.2).sub.1-5--O--(CH.sub.2).sub.1-5--,
--(CH.sub.2).sub.1-5--NR--(CH.sub.2).sub.1-5, etc. The ring formed
may be saturated or unsaturated. For example, R.sup.1 and R.sup.2
may be linked to form a piperidine ring, morpholine ring, pyridine
ring, or a pyrazinyl ring.
[0047] In a further embodiment, the tetracycline compound is:
##STR6## pharmaceutically acceptable salts, esters or prodrugs
thereof.
[0048] In one embodiment, the invention pertains to aminomethyl
tetracycline compounds of the formula (II): ##STR7## wherein:
[0049] J.sup.1 and J.sup.2 are each independently hydrogen, aryl,
sulfonyl, acyl, or linked to form a ring, provided that at least
one of J.sup.1 or J.sup.2 is not hydrogen;
[0050] J.sup.3 and J.sup.4 are each alkyl, halogen, or
hydrogen;
[0051] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0052] R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0053] R.sup.4 is NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl,
aryl, hydroxyl, halogen, or hydrogen;
[0054] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0055] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0056] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0057] R.sup.9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino,
arylalkenyl, arylalkynyl, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
[0058] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O;
[0059] Z' is O, S, or NR.sup.9f;
[0060] R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, and R.sup.9e are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety;
[0061] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0062] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0063] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts, esters, and
prodrugs thereof.
[0064] In an embodiment, the tetracycline compound is a
oxytetracycline compound (e.g., wherein R.sup.4 is
NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are each methyl, R.sup.5
is OH, X is CR.sup.6R.sup.6', R.sup.6 is OH, and R.sup.6' is
CH.sub.3). In another embodiment, the aminoalkyl tetracycline
compound is a demeclocycline compound (e.g., wherein R.sup.4 is
NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are each methyl, R.sup.5
is hydrogen, X is CR.sup.6R.sup.6', R.sup.6 is OH, R.sup.6' is
hydrogen, and R.sup.7 is chlorine). In another embodiment, the
aminoalkyl tetracycline compound is a methacycline compound (e.g.,
wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are
each methyl, R.sup.5 is OH, X is CR.sup.6R.sup.6', R.sup.6 and
R.sup.6' are, taken together, CH.sub.2). In another embodiment, the
aminoalkyl tetracycline compound is a doxycycline compound (e.g.,
wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are
each methyl, R.sup.5 is OH, X is CR.sup.6R.sup.6', R.sup.6 is OH,
and R.sup.6' is CH.sub.3). In another embodiment, the aminoalkyl
tetracycline compound is a chlorotetracycline compound (e.g.,
wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are
each methyl, R.sup.5 is hydrogen, X is CR.sup.6R.sup.6', R.sup.6 is
OH, R.sup.6' is CH.sub.3, and R.sup.4'' is chlorine). In another
embodiment, the aminoalkyl tetracycline compound is a tetracycline
compound (e.g., wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and
R.sup.4'' are each methyl, R.sup.5 is hydrogen, X is
CR.sup.6R.sup.6', R.sup.6 and R.sup.6' are each hydrogen and
R.sup.7 is N(CH.sub.3).sub.2). In a further embodiment, R.sup.5 of
formula I is a protected hydroxyl group, e.g. a prodrug moiety.
Examples of prodrug moieties include, for example, acyl esters and
esters. In certain embodiments, the prodrug moiety is aroyl,
alkanoyl, or alkaroyl and may or may not be cleaved in vivo to the
hydroxyl group. In certain embodiments, R.sup.4 is hydrogen.
[0065] In an embodiment, J.sup.3 and J.sup.4 are hydrogen. In
another embodiment, J.sup.1 may be substituted or unsubstituted
alkyl. J.sup.1 also may be sulfonyl or J.sup.1 and J.sup.2 may be
linked to form a ring. In a further embodiment, J.sup.1 maybe
heteroaryl or substituted carbonyl.
[0066] Examples of aminoalkyltetracycline compounds synthesized by
methods of the invention include, but are not limited to, compounds
of the following formulae: ##STR8## ##STR9## ##STR10## ##STR11##
##STR12## ##STR13## wherein
[0067] R is substituted or unsubstituted alkyl, alkenyl, alkynyl,
halogen, alkoxy; and
[0068] Y is N, O, or S, or pharmaceutically acceptable salts or
prodrugs thereof.
[0069] In another embodiment, the aminoalkyl tetracycline compound
of the invention may be a compound of the formula (II): ##STR14##
wherein:
[0070] J.sup.5 and J.sup.6 are each independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, sulfonyl, acyl, alkoxycarbonyl,
alkaminocarbonyl, alkaminothiocarbonyl, substituted thiocarbonyl,
substituted carbonyl, alkoxythiocarbonyl, or linked to form a
ring;
[0071] J.sup.7 and J.sup.8 are each alkyl, halogen, or
hydrogen;
[0072] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.dbd.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0073] R.sup.2, R.sup.2', R.sup.4', and R.sup.4'' are each
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0074] R.sup.4 is NR.sup.4'R.sup.4'', alkyl, alkenyl, alkynyl,
aryl, hydroxyl, halogen, or hydrogen;
[0075] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0076] R.sup.5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl,
alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkyl carbonyloxy, or aryl carbonyloxy;
[0077] R.sup.6 and R.sup.6' are each independently hydrogen,
methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, or an arylalkyl;
[0078] R.sup.7 is hydrogen;
[0079] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0080] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0081] Y' and Y are each independently hydrogen, halogen, hydroxyl,
cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl, and pharmaceutically acceptable salts thereof.
[0082] In an embodiment, the tetracycline compound is a
oxytetracycline compound (e.g., wherein R.sup.4 is
NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are each methyl, R.sup.5
is OH, X is CR.sup.6R.sup.6', R.sup.6 is OH, and R.sup.6' is
CH.sub.3). In another embodiment, the aminoalkyl tetracycline
compound is a demeclocycline compound (e.g., wherein R.sup.4 is
NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are each methyl, R.sup.5
is hydrogen, X is CR.sup.6R.sup.6', R.sup.6 is OH, R.sup.6' is
hydrogen, and R.sup.7 is chlorine). In another embodiment, the
aminoalkyl tetracycline compound is a methacycline compound (e.g.,
wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are
each methyl, R.sup.5 is OH, X is CR.sup.6R.sup.6', R.sup.6 and
R.sup.6' are, taken together, CH.sub.2). In another embodiment, the
aminoalkyl tetracycline compound is a doxycycline compound (e.g.,
wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are
each methyl, R.sup.5 is OH, X is CR.sup.6R.sup.6', R.sup.6 is OH,
and R.sup.6' is CH.sub.3). In another embodiment, the aminoalkyl
tetracycline compound is a chlorotetracycline compound (e.g.,
wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and R.sup.4'' are
each methyl, R.sup.5 is hydrogen, X is CR.sup.6R.sup.6', R.sup.6 is
OH, R.sup.6' is CH.sub.3, and R.sup.7 is chlorine). In another
embodiment, the aminoalkyl tetracycline compound is a tetracycline
compound (e.g., wherein R.sup.4 is NR.sup.4'R.sup.4'', R.sup.4' and
R.sup.4'' are each methyl, R.sup.5 is hydrogen, X is
CR.sup.6R.sup.6', R.sup.6 and R.sup.6' are each hydrogen and
R.sup.7 is N(CH.sub.3).sub.2). In a further embodiment, R.sup.5 of
formula I is a protected hydroxyl group, e.g. a prodrug moiety.
Examples of prodrug moieties include, for example, acyl esters and
esters. In certain embodiments, the prodrug moiety is aroyl,
alkanoyl, or alkaroyl and may or may not be cleaved in vivo to the
hydroxyl group. In certain embodiments, R.sup.4 is hydrogen.
[0083] In an embodiment, J.sup.7 and J.sup.8 are hydrogen. In
another embodiment, J.sup.5 may be substituted or unsubstituted
alkyl. J.sup.5 also may be sulfonyl or J.sup.5 and J.sup.6 may be
linked to form a ring. In a further embodiment, J.sup.5 maybe
heteroaryl or substituted carbonyl.
[0084] Examples of aminoalkyltetracycline compounds synthesized by
methods of the invention include, but are not limited to, compounds
of the following formulae: ##STR15## ##STR16## ##STR17## ##STR18##
##STR19## ##STR20## ##STR21## wherein
[0085] R is substituted or unsubstituted alkyl, alkenyl, alkynyl,
halogen, alkoxy; and
[0086] Y is N, O, or S, or pharmaceutically acceptable salts or
prodrugs thereof.
[0087] Other aminoalkyl tetracycline compounds of the invention are
shown in Table 1. The invention includes pharmaceutically
acceptable esters, salts, and prodrugs of the compounds shown in
Table 1. TABLE-US-00001 TABLE 1 ##STR22## ##STR23## ##STR24##
##STR25## ##STR26## ##STR27## ##STR28## ##STR29## ##STR30##
##STR31## ##STR32## ##STR33## ##STR34## ##STR35## ##STR36##
##STR37## ##STR38## ##STR39## ##STR40## ##STR41## ##STR42##
##STR43## ##STR44## ##STR45## ##STR46## ##STR47## ##STR48##
##STR49## ##STR50## ##STR51## ##STR52## ##STR53## ##STR54##
##STR55## ##STR56## ##STR57## ##STR58## ##STR59## ##STR60##
##STR61## ##STR62## ##STR63## ##STR64## ##STR65## ##STR66##
##STR67## ##STR68## ##STR69## ##STR70## ##STR71## ##STR72##
##STR73## ##STR74## ##STR75## ##STR76## ##STR77## ##STR78##
##STR79## ##STR80## ##STR81## ##STR82## ##STR83## ##STR84##
##STR85## ##STR86## ##STR87## ##STR88## ##STR89## ##STR90##
##STR91## ##STR92## ##STR93## ##STR94## ##STR95## ##STR96##
##STR97## ##STR98## ##STR99## ##STR100## ##STR101## ##STR102##
##STR103## ##STR104## ##STR105## ##STR106## ##STR107## ##STR108##
##STR109## ##STR110## ##STR111## ##STR112## ##STR113## ##STR114##
##STR115## ##STR116## ##STR117## ##STR118## ##STR119## ##STR120##
##STR121## ##STR122## ##STR123## ##STR124## ##STR125## ##STR126##
##STR127## ##STR128## ##STR129## ##STR130## ##STR131## ##STR132##
##STR133## ##STR134## ##STR135## ##STR136## ##STR137## ##STR138##
##STR139## ##STR140## ##STR141## ##STR142## ##STR143##
##STR144## ##STR145## ##STR146## ##STR147## ##STR148## ##STR149##
##STR150## ##STR151## ##STR152## ##STR153## ##STR154## ##STR155##
##STR156## ##STR157## ##STR158## ##STR159## ##STR160## ##STR161##
##STR162## ##STR163## ##STR164## ##STR165## ##STR166## ##STR167##
##STR168## ##STR169## ##STR170## ##STR171## ##STR172## ##STR173##
##STR174## ##STR175## ##STR176## ##STR177## ##STR178## ##STR179##
##STR180## ##STR181## ##STR182## ##STR183## ##STR184## ##STR185##
##STR186## ##STR187## ##STR188## ##STR189## ##STR190## ##STR191##
##STR192## ##STR193## ##STR194## ##STR195## ##STR196## ##STR197##
##STR198## ##STR199## ##STR200## ##STR201## ##STR202## ##STR203##
##STR204## ##STR205## ##STR206## ##STR207## ##STR208## ##STR209##
##STR210## ##STR211## ##STR212## ##STR213## ##STR214## ##STR215##
##STR216## ##STR217## ##STR218## ##STR219## ##STR220## ##STR221##
##STR222## ##STR223## ##STR224## ##STR225## ##STR226## ##STR227##
##STR228## ##STR229## ##STR230##
[0088] The invention also pertains, at least in part to a method
for the synthesis of aminoalkyl tetracycline compounds, such as
those described above. The method includes contacting a
tetracycline compound with an aminoalkylating reagent under
appropriate conditions to form an aminoalkyl tetracycline
compound.
[0089] The term "tetracycline compound" includes many compounds
with a similar ring structure to tetracycline. Examples of
tetracycline compounds include: tetracycline, chlortetracycline,
oxytetracycline, demeclocycline, methacycline, sancycline,
doxycycline, minocycline, chelocardin, rolitetracycline,
lymecycline, apicycline; clomocycline, guamecycline, meglucycline,
mepylcycline, penimepicycline, pipacycline, etamocycline,
penimocycline, etc. Other derivatives and analogues comprising a
similar four ring structure are also included (for a review, see W.
Rogalski, "Chemical Modifications of Tetracyclines," the entire
contents of which are hereby incorporated herein by reference).
Table 2 depicts tetracycline and several known other tetracycline
derivatives. TABLE-US-00002 TABLE 2 ##STR231## ##STR232##
##STR233## ##STR234## ##STR235## ##STR236## ##STR237##
##STR238##
[0090] Other tetracycline compounds which may be modified using the
methods of the invention include, but are not limited to,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline;
tetracyclino-pyrazole; 7-chloro-4-dedimethylaminotetracycline;
4-hydroxy-4-dedimethylaminotetracycline;
12.alpha.-deoxy-4-dedimethylaminotetracycline;
5-hydroxy-6.alpha.-deoxy-4-dedimethylaminotetracycline;
4-dedimethylamino-12.alpha.-deoxyanhydrotetracycline;
7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline;
tetracyclinonitrile; 4-oxo-4-dedimethylaminotetracycline
4,6-hemiketal; 4-oxo-11a
Ch1-4-dedimethylaminotetracycline-4,6-hemiketal;
5a,6-anhydro-4-hydrazono-4-dedimethylamino tetracycline;
4-hydroxyimino-4-dedimethylamino tetracyclines;
4-hydroxyimino-4-dedimethylamino 5a,6-anhydrotetracyclines;
4-amino-4-dedimethylamino-5a,6 anhydrotetracycline;
4-methylamino-4-dedimethylamino tetracycline;
4-hydrazono-11a-chloro-6-deoxy-6-demethyl-6-methylene-4-dedimethylamino
tetracycline; tetracycline quaternary ammonium compounds;
anhydrotetracycline betaines; 4-hydroxy-6-methyl pretetramides;
4-keto tetracyclines; 5-keto tetracyclines; 5a,11a dehydro
tetracyclines; 11a C1-6, 12 hemiketal tetracyclines; 11a
C1-6-methylene tetracyclines; 6,13 diol tetracyclines;
6-benzylthiomethylene tetracyclines;
7,11a-dichloro-6-fluoro-methyl-6-deoxy tetracyclines; 6-fluoro
(.alpha.)-6-demethyl-6-deoxy tetracyclines; 6-fluoro
(.beta.)-6-demethyl-6-deoxy tetracyclines; 6-.alpha.
acetoxy-6-demethyl tetracyclines; 6-.beta. acetoxy-6-demethyl
tetracyclines; 7,13-epithiotetracyclines; oxytetracyclines;
pyrazolotetracyclines; 11a halogens of tetracyclines; 12a formyl
and other esters of tetracyclines; 5,12a esters of tetracyclines;
10,12a-diesters of tetracyclines; isotetracycline;
12-a-deoxyanhydro tetracyclines;
6-demethyl-12a-deoxy-7-chloroanhydrotetracyclines;
B-nortetracyclines; 7-methoxy-6-demethyl-6-deoxytetracyclines;
6-demethyl-6-deoxy-5a-epitetracyclines;
8-hydroxy-6-demethyl-6-deoxy tetracyclines; monardene;
chromocycline; 5a methyl-6-demethyl-6-deoxy tetracyclines; 6-oxa
tetracyclines, and 6 thia tetracyclines.
[0091] The term "aminoalkyl tetracycline compounds" includes
tetracycline compounds with an aminoalkyl substituent, (e.g.,
--CH.sub.2NR'R'') at the 7 and/or 9 positions. In an embodiment,
the substitution at the 7 and/or 9 position enhances the ability of
the tetracycline compound to perform its intended function (e.g.,
as an antibiotic, to treat a tetracycline compound responsive
state, etc.). The term "aminoalkylating reagent" includes reagents
which are capable of contacting the tetracycline compound and,
under appropriate conditions, reacting with it to form an
aminoalkyl tetracycline compound. The amino alkylating reagent may
be added to the reaction mixture or may be formed in situ. Examples
of aminoalkylating reagents, include, but are not limited to,
compounds of the formula (IV): ##STR239##
[0092] wherein [0093] R.sup.a' and R.sup.a'' are each independently
hydrogen or halogen; [0094] R' is hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, or halogen;
[0095] and [0096] R'' is hydrogen or optionally linked to R' to
form a 4-8 membered ring. The ring may be optionally substituted,
e.g., with halogens and may comprise carbons and/or heteroatoms
such as oxygen, nitrogen, and sulfur. R' may be further substituted
with any substituent which does not prevent the reagent from
reacting with the tetracycline compound of the invention, under the
appropriate conditions. In another further embodiment, R' is alkyl,
e.g., unsubstituted or substituted (e.g., with halogens, e.g.,
chlorine, fluorine, bromine, iodine, etc.). In another embodiment,
R' is aryl, e.g., phenyl, e.g., unsubstituted or substituted (e.g.,
with halogens (e.g., chlorine, bromine, fluorine, etc.), hydroxy,
alkoxy, esters, amino, etc.). In another embodiment, R.sup.a' and
R.sup.a'' are each hydrogen. Other examples of aminoalkylating
reagents include N-hydroxymethylphthalimide.
[0097] Examples of amino-alkylating reagents include, but are not
limited to: ##STR240##
[0098] The term "appropriate conditions" include those conditions
under which the aminoalkylating reagent and the tetracycline
compound interact such that an aminoalkyl tetracycline compound is
formed. In an embodiment, the appropriate conditions comprise
treating the tetracycline compound with an acid prior to, or
concurrently with the addition of the aminoalkylating reagent to
the reaction mixture. Examples of acids which maybe used alone or
in combination include acids known in the art, as well as, sulfuric
acid, hydrofluoric acid (HF), methanesulfonic acid,
trifluoromethane sulfonic acid, hydrochloric acid, hydrochloric
acid in aqueous ethanol, acetic acid, methanesulfonic acid, and
trifluoroacetic acid (TFA). In a further embodiment, appropriate
conditions may also comprise treating the resulting tetracycline
compound with a reaction quenching agent (e.g., water).
[0099] Each of the reactions described below may be applied to
other tetracycline compounds described above. In addition, although
many of the schemes depicts substituting the tetracycline compound
at the 9 position, similar substituents can be added at the 7
position by using a protecting group at the 9 position, (e.g., such
as t-butyl).
[0100] Scheme 1 depicts the reaction of sancycline with an
aminoalkylating reagent under appropriate conditions such that an
aminoalkyl tetracycline compound is formed. ##STR241##
[0101] Scheme 2 shows two aminoalkylations of a tetracycline
compound with aminoalkylating reagents which comprise a 5 membered
ring. Similar reactions can be also be carried out using reagents,
with, for example, 6- or 7-membered rings. ##STR242##
[0102] As shown in Scheme 3 below, the synthesis of
7-monosubstituted aminomethyl tetracyclines may be synthesized
using protecting groups (i.e. the 9-t-butyl protecting group) to be
cleaved using art recognized techniques, such as acid. Examples of
acids which can be used include, but are not limited to, HF,
trifluoroacetic acid (TFA), H.sub.2SO.sub.4 and mixtures thereof.
In this way, regioselective aminomethylation at position 7 is
achieved. ##STR243##
[0103] In a further embodiment, the appropriate conditions may
further comprise treating the reaction mixture (which may comprise
an intermediate aminoalkyl tetracycline compound) with a
derivatizing agent under secondary appropriate conditions such that
the desired aminoalkyl tetracycline compound is formed. The
reactions in Scheme 4 are shown for the 9 position, but the
reactions are also applicable to other positions of the
tetracycline compound. Additional derivatizing agents and secondary
appropriate conditions may be found, for example, in the chemical
literature. See, for example, R. C. LaRock, Comprehensive Organic
Transformations, (New York: VCH Publishers, Inc., 1989) and
references cited therein. Any reagent that can react with a primary
amine to form a new compound is possible. Examples of some of the
diverse structures are shown in Scheme 4 below ##STR244##
[0104] For example, in Scheme 5, an acid chloride derivatizing
agent is added to the reaction mixture to form the desired amide
aminoalkyl tetracycline compound (J. Am. Chem. Soc. 71, 2215
(1949); J. Am. Chem. Soc. 108, 1039 (1986); Org. Syn. Coll. Vol. 4,
339 (1963); Org. Syn. Coll. Vol. 5, 387 (1973)). ##STR245##
[0105] Scheme 6 depicts the reaction of an intermediate aminoalkyl
tetracycline compound with an appropriate sulfonyl chloride
derivatizing agent, such that the desired sulfonamide aminoalkyl
compound is formed (Org. Syn. Coll. Vol. 5, 736, 758 (1973)).
##STR246##
[0106] Scheme 7 depicts the reaction of a derivatizing agent with
an aminoalkyl tetracycline intermediate to form the resulting
carbamate aminoalkyl tetracycline compound. ##STR247##
[0107] The term "alkyl" includes saturated aliphatic groups,
including straight-chain alkyl groups, branched-chain alkyl groups,
cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups,
and cycloalkyl substituted alkyl groups. The term alkyl further
includes alkyl groups, which can further include oxygen, nitrogen,
sulfur or phosphorous atoms replacing one or more carbons of the
hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorous
atoms. In preferred embodiments, a straight chain or branched chain
alkyl has 6 or fewer carbon atoms in its backbone (e.g.,
C.sub.1-C.sub.6 for straight chain, C.sub.3-C.sub.6 for branched
chain), and more preferably 4 or fewer. Likewise, preferred
cycloalkyls have from 4-7 carbon atoms in their ring structure, and
more preferably have 5 or 6 carbons in the ring structure.
[0108] Moreover, the term alkyl includes both "unsubstituted
alkyls" and "substituted alkyls", the latter of which refers to
alkyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylthiocarbonyl, alkoxyl, aryloxy, phosphate, phosphonato,
phosphinato, cyano, amino (including alkyl amino, dialkylamino,
arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an
aromatic or heteroaromatic moiety. Cycloalkyls can be further
substituted, e.g., with the substituents described above. An
"alkylaryl" moiety is an alkyl substituted with an aryl (e.g.,
phenylmethyl(benzyl)).
[0109] The term "aryl" includes aryl groups, including 5- and
6-membered single-ring aromatic groups that may include from zero
to four heteroatoms, for example, benzene, pyrrole, furan,
thiophene, imidazole, benzoxazole, benzothiazole, triazole,
tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine,
and the like. Aryl groups also include polycyclic fused aromatic
groups such as naphthyl, quinolyl, indolyl, and the like. Those
aryl groups having heteroatoms in the ring structure may also be
referred to as "aryl heterocycles", "heteroaryls" or
"heteroaromatics". The aromatic ring can be substituted at one or
more ring positions with such substituents as described above, as
for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano,
amino (including alkyl amino, dialkylamino, arylamino, diarylamino,
and alkylarylamino), acylamino (including alkylcarbonylamino,
arylcarbonylamino, carbamoyl and ureido), amidino, imino,
sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,
sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano,
azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety. Aryl groups can also be fused or bridged with alicyclic or
heterocyclic rings which are not aromatic so as to form a polycycle
(e.g., tetralin).
[0110] The terms "alkenyl" and "alkynyl" include unsaturated
aliphatic groups analogous in length and possible substitution to
the alkyls described above, but that contain at least one double or
triple bond, respectively.
[0111] Unless the number of carbons is otherwise specified, "lower
alkyl" as used herein means an alkyl group, as defined above, but
having from one to five carbon atoms in its backbone structure.
Likewise, "lower alkenyl" and "lower alkynyl" have similar chain
lengths.
[0112] The terms "alkoxyalkyl", "polyaminoalkyl" and
"thioalkoxyalkyl" include alkyl groups, as described above, which
further include oxygen, nitrogen or sulfur atoms replacing one or
more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or
sulfur atoms.
[0113] The terms "polycyclyl" or "polycyclic radical" refer to two
or more cyclic rings (e.g., cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls and/or heterocyclyls) in which two or more
carbons are common to two adjoining rings, e.g., the rings are
"fused rings". Rings that are joined through non-adjacent atoms are
termed "bridged" rings. Each of the rings of the polycycle can be
substituted with such substituents as described above, as for
example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl,
phosphate, phosphonato, phosphinato, cyano, amino (including alkyl
amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,
sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,
alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
[0114] The term "heterocyclic ring" refers to a ring containing one
or more heteroatoms as part of the ring. Examples of "heterocyclic
rings" include tetrahydrofuran, furan, ethylene oxide, pyrrolidine,
piperidine, thiophene, and pyrrole.
[0115] The term "heteroatom" as used herein means an atom of any
element other than carbon or hydrogen. Preferred heteroatoms are
nitrogen, oxygen, sulfur and phosphorus.
[0116] The term "bicyclic ring" includes rings where 2 atoms share
more than one ring. Examples of bicyclic rings include
bicyclbutane, camphene, decalin, and phthalimide.
[0117] The term "carbonyl" includes moieties which contain a carbon
double bonded to an oxygen atom. The term "substituted carbonyl"
includes groups wherein the carbon of the carbonyl group is further
bonded to another carbon or a heteroatom. Examples of substituents
include, but are not limited to, alkyl, alkenyl, alkynyl, aryl,
halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, alkoxy, aryloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, aphosphate, phosphonato,
phosphinato, cyano, amino (including alkyl amino, dialkylamino,
arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an
aromatic or heteroaromatic moiety.
[0118] The term "thiocarbonyl" includes moieties which contain a
carbon double bonded to a sulfur atom. The term "substituted
thiocarbonyl" includes groups wherein the carbon of the carbonyl
group is further bonded to another carbon or a heteroatom. Examples
of substituents include, but are not limited to, alkyl, alkenyl,
alkynyl, aryl, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, alkoxy,
aryloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, aphosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,
sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,
alkylaryl, or an aromatic or heteroaromatic moiety.
[0119] Suitable alkanoyl groups include groups having 1 to about 4
or 5 carbonyl groups. Suitable aroyl groups include groups having
one or more carbonyl groups as a substituent to an aryl group such
as phenyl or other carbocyclic aryl. Suitable alkaroyl groups have
one or more alkylcarbonyl groups as a substituent to an aryl group
such as phenylacetyl and the like. Suitable carbocyclic aryl groups
have 6 or more carbons such as phenyl, naphthyl and the like.
Suitable aryloyl groups are carbocyclic aryl groups that are
substituted with one or more carbonyl groups, typically 1 or 2
carbonyl groups.
[0120] Prodrugs are compounds which are converted in vivo to active
forms (see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of
Drug Design and Drug Action", Academic Press, Chp. 8). Prodrugs can
be used to alter the biodistribution (e.g., to allow compounds
which would not typically enter the reactive site of the protease)
or the pharmacokinetics for a particular compound. For example, a
hydroxyl group, can be esterified, e.g., with a carboxylic acid
group to yield an ester. When the ester is administered to a
subject, the ester is cleaved, enzymatically or non-enzymatically,
reductively or hydrolytically, to reveal the hydroxyl group.
Prodrugs may be metabolized in vivo by esterases or by other
mechanisms to hydroxyl groups or other advantageous groups.
Examples of prodrugs and their uses are well known in the art (See,
e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.
66:1-19). The prodrugs can be prepared in situ during the final
isolation and purification of the compounds, or by separately
reacting the purified compound in its free acid form or hydroxyl
with a suitable esterifying agent. Hydroxyl groups can be converted
into esters via treatment with a carboxylic acid. Examples of
prodrugs include substituted and unsubstituted, branch or
unbranched lower alkyl ester moieties, (e.g., propionoic acid
esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl
esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl
esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters
(e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester),
aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g.,
with methyl, halo, or methoxy substituents) aryl and aryl-lower
alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides,
and hydroxy amides.
[0121] It will be noted that the structure of some of the compounds
of this invention includes asymmetric carbon atoms. It is to be
understood accordingly that the isomers arising from such asymmetry
(e.g., all enantiomers and diastereomers) are included within the
scope of this invention, unless indicated otherwise. Such isomers
can be obtained in substantially pure form by classical separation
techniques and by stereochemically controlled synthesis.
[0122] The invention also pertains, at least in part, to methods of
treating a subject, e.g., a mammal, e.g., a human, for a
tetracycline responsive state by administering an effective amount
of an aminomethyl tetracycline compound of the invention, e.g., a
compound of Formula (I), (III), (III), Table 1, or otherwise
described herein.
[0123] The language "tetracycline compound responsive state" or
"tetracycline responsive state" includes states which can be
treated, prevented, or otherwise ameliorated by the administration
of a tetracycline compound of the invention, e.g., a 9-aminomethyl
tetracycline compound. Tetracycline compound responsive states
include bacterial, viral, and fungal infections (including those
which are resistant to other tetracycline compounds), cancer (e.g.,
prostate, breast, colon, lung melanoma and lymph cancers and other
disorders characterized by unwanted cellular proliferation,
including, but not limited to, those described in U.S. Pat. No.
6,100,248), arthritis, osteoporosis, diabetes, cystic fibrosis,
neurological disorders and other states for which tetracycline
compounds have been found to be active (see, for example, U.S. Pat.
Nos. 5,789,395; 5,834,450; 6,277,061 and 5,532,227, each of which
is expressly incorporated herein by reference). Compounds of the
invention can be used to prevent or control important mammalian and
veterinary diseases such as diarrhea, urinary tract infections,
infections of skin and skin structure, ear, nose and throat
infections, wound infection, mastitis and the like. In addition,
methods for treating neoplasms using tetracycline compounds of the
invention are also included (van der Bozert et al., Cancer Res.,
48:6686-6690 (1988)). In a further embodiment, the tetracycline
responsive state is not a bacterial infection. Other tetracycline
compound responsive states include, for example, those described in
U.S. Ser. No. 10/196,010.
[0124] Tetracycline compound responsive states also include
inflammatory process associated states (IPAS). The term
"inflammatory process associated state" includes states in which
inflammation or inflammatory factors (e.g., matrix
metalloproteinases (MMPs), nitric oxide (NO), TNF, interleukins,
plasma proteins, cellular defense systems, cytokines, lipid
metabolites, proteases, toxic radicals, adhesion molecules, etc.)
are involved or are present in an area in aberrant amounts, e.g.,
in amounts which may be advantageous to alter, e.g., to benefit the
subject. The inflammatory process is the response of living tissue
to damage. The cause of inflammation may be due to physical damage,
chemical substances, micro-organisms, tissue necrosis, cancer or
other agents. Acute inflammation is short-lasting, lasting only a
few days. If it is longer lasting however, then it may be referred
to as chronic inflammation.
[0125] IPAS's include inflammatory disorders. Inflammatory
disorders are generally characterized by heat, redness, swelling,
pain and loss of function. Examples of causes of inflammatory
disorders include, but are not limited to, microbial infections
(e.g., bacterial and fungal infections), physical agents (e.g.,
burns, radiation, and trauma), chemical agents (e.g., toxins and
caustic substances), tissue necrosis and various types of
immunologic reactions.
[0126] Examples of inflammatory disorders include, but are not
limited to, osteoarthritis, rheumatoid arthritis, acute and chronic
infections (bacterial and fungal, including diphtheria and
pertussis); acute and chronic bronchitis, sinusitis, and upper
respiratory infections, including the common cold; acute and
chronic gastroenteritis and colitis; acute and chronic cystitis and
urethritis; acute and chronic dermatitis; acute and chronic
conjunctivitis; acute and chronic serositis (pericarditis,
peritonitis, synovitis, pleuritis and tendinitis); uremic
pericarditis; acute and chronic cholecystis; acute and chronic
vaginitis; acute and chronic uveitis; drug reactions; insect bites;
burns (thermal, chemical, and electrical); and sunburn.
[0127] Tetracycline compound responsive states also include NO
associated states. The term "NO associated state" includes states
which involve or are associated with nitric oxide (NO) or inducible
nitric oxide synthase (iNOS). NO associated state includes states
which are characterized by aberrant amounts of NO and/or iNOS.
Preferably, the NO associated state can be treated by administering
tetracycline compounds of the invention, e.g., compounds of formula
I, II, III, Table 1, or otherwise described herein. The disorders,
diseases and states described in U.S. Pat. Nos. 6,231,894;
6,015,804; 5,919,774; and 5,789,395 are also included as NO
associated states. The entire contents of each of these patents are
hereby incorporated herein by reference.
[0128] Other examples of NO associated states include, but are not
limited to, malaria, senescence, diabetes, vascular stroke,
neurodegenerative disorders (Alzheimer's disease, Huntington's
disease), cardiac disease (reperfusion-associated injury following
infarction), juvenile diabetes, inflammatory disorders,
osteoarthritis, rheumatoid arthritis, acute and chronic infections
(bacterial, viral, and fungal); cystic fibrosis, acute and chronic
bronchitis, sinusitis, and respiratory infections, including the
common cold; acute and chronic gastroenteritis and colitis; acute
and chronic cystitis and urethritis; acute and chronic dermatitis;
acute and chronic conjunctivitis; acute and chronic serositis
(pericarditis, peritonitis, synovitis, pleuritis and tendinitis);
uremic pericarditis; acute and chronic cholecystis; acute and
chronic vaginitis; acute and chronic uveitis; drug reactions;
insect bites; burns (thermal, chemical, and electrical); and
sunburn.
[0129] The term "inflammatory process associated state" also
includes, in one embodiment, matrix metalloproteinase associated
states (MMPAS). MMPAS include states characterized by aberrant
amounts of MMPs or MMP activity. These are also include as
tetracycline compound responsive states which may be treated using
compounds of the invention, e.g., 9-aminomethyl tetracycline
compounds such as those described herein, e.g., in formula I.
[0130] Examples of matrix metalloproteinase associated states
("MMPAS's") include, but are not limited to, arteriosclerosis,
corneal ulceration, emphysema, osteoarthritis, multiple sclerosis
(Liedtke et al., Ann. Neurol. 1998, 44:35-46; Chandler et al., J.
Neuroimmunol. 1997, 72:155-71), osteosarcoma, osteomyelitis,
bronchiectasis, chronic pulmonary obstructive disease, skin and eye
diseases, periodontitis, osteoporosis, rheumatoid arthritis,
ulcerative colitis, inflammatory disorders, tumor growth and
invasion (Stetler-Stevenson et al., Annu. Rev. Cell Biol. 1993,
9:541-73; Tryggvason et al., Biochim. Biophys. Acta 1987,
907:191-217; Li et al., Mol. Carcinog. 1998, 22:84-89), metastasis,
acute lung injury, stroke, ischemia, diabetes, aortic or vascular
aneurysms, skin tissue wounds, dry eye, bone and cartilage
degradation (Greenwald et al., Bone 1998, 22:33-38; Ryan et al.,
Curr. Op. Rheumatol. 1996, 8; 238-247). Other MMPAS include those
described in U.S. Pat. Nos. 5,459,135; 5,321,017; 5,308,839;
5,258,371; 4,935,412; 4,704,383, 4,666,897, and RE 34,656,
incorporated herein by reference in their entirety.
[0131] In another embodiment, the tetracycline compound responsive
state is cancer. Examples of cancers which the tetracycline
compounds of the invention may be useful to treat include all solid
tumors, i.e., carcinomas e.g., adenocarcinomas, and sarcomas.
Adenocarcinomas are carcinomas derived from glandular tissue or in
which the tumor cells form recognizable glandular structures.
Sarcomas broadly include tumors whose cells are embedded in a
fibrillar or homogeneous substance like embryonic connective
tissue. Examples of carcinomas which may be treated using the
methods of the invention include, but are not limited to,
carcinomas of the prostate, breast, ovary, testis, lung, colon, and
breast. The methods of the invention are not limited to the
treatment of these tumor types, but extend to any solid tumor
derived from any organ system. Examples of treatable cancers
include, but are not limited to, colon cancer, bladder cancer,
breast cancer, melanoma, ovarian carcinoma, prostatic carcinoma,
lung cancer, and a variety of other cancers as well. The methods of
the invention also cause the inhibition of cancer growth in
adenocarcinomas, such as, for example, those of the prostate,
breast, kidney, ovary, testes, and colon.
[0132] In an embodiment, the tetracycline responsive state of the
invention is cancer. The invention pertains to a method for
treating a subject suffering or at risk of suffering from cancer,
by administering an effective amount of a substituted tetracycline
compound, such that inhibition cancer cell growth occurs, i.e.,
cellular proliferation, invasiveness, metastasis, or tumor
incidence is decreased, slowed, or stopped. The inhibition may
result from inhibition of an inflammatory process, down-regulation
of an inflammatory process, some other mechanism, or a combination
of mechanisms. Alternatively, the tetracycline compounds may be
useful for preventing cancer recurrence, for example, to treat
residual cancer following surgical resection or radiation therapy.
The tetracycline compounds useful according to the invention are
especially advantageous as they are substantially non-toxic
compared to other cancer treatments. In a further embodiment, the
compounds of the invention are administered in combination with
standard cancer therapy, such as, but not limited to,
chemotherapy.
[0133] The language "in combination with" another therapeutic agent
or treatment includes co-administration of the tetracycline
compound and with the other therapeutic agent or treatment,
administration of the tetracycline compound first, followed by the
other therapeutic agent or treatment and administration of the
other therapeutic agent or treatment first, followed by the
tetracycline compound. The other therapeutic agent may be any agent
which is known in the art to treat, prevent, or reduce the symptoms
of a tetracycline responsive state. Furthermore, the other
therapeutic agent may be any agent of benefit to the patient when
administered in combination with the administration of an
tetracycline compound. In one embodiment, the cancers treated by
methods of the invention include those described in U.S. Pat. Nos.
6,100,248; 5,843,925; 5,837,696; or 5,668,122, incorporated herein
by reference in their entirety.
[0134] In another embodiment, the tetracycline compound responsive
state is diabetes, e.g., juvenile diabetes, diabetes mellitus,
diabetes type I, diabetes type II, diabetic ulcers, or other
diabetic complications. In a further embodiment, protein
glycosylation is not affected by the administration of the
tetracycline compounds of the invention. In another embodiment, the
tetracycline compound of the invention is administered in
combination with standard diabetic therapies, such as, but not
limited to insulin therapy. In a further embodiment, the IPAS
includes disorders described in U.S. Pat. Nos. 5,929,055; and
5,532,227, incorporated herein by reference in their entirety.
[0135] In another embodiment, the tetracycline compound responsive
state is a bone mass disorder. Bone mass disorders include
disorders where a subjects bones are disorders and states where the
formation, repair or remodeling of bone is advantageous. For
examples bone mass disorders include osteoporosis (e.g., a decrease
in bone strength and density), bone fractures, bone formation
associated with surgical procedures (e.g., facial reconstruction),
osteogenesis imperfecta (brittle bone disease), hypophosphatasia,
Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone
disease, and the depletion of calcium in bone, such as that which
is related to primary hyperparathyroidism. Bone mass disorders
include all states in which the formation, repair or remodeling of
bone is advantageous to the subject as well as all other disorders
associated with the bones or skeletal system of a subject which can
be treated with the tetracycline compounds of the invention. In a
further embodiment, the bone mass disorders include those described
in U.S. Pat. Nos. 5,459,135; 5,231,017; 5,998,390; 5,770,588; RE
34,656; 5,308,839; 4,925,833; 3,304,227; and 4,666,897, each of
which is hereby incorporated herein by reference in its
entirety.
[0136] In another embodiment, the tetracycline compound responsive
state is acute lung injury. Acute lung injuries include adult
respiratory distress syndrome (ARDS), post-pump syndrome (PPS), and
trauma. Trauma includes any injury to living tissue caused by an
extrinsic agent or event. Examples of trauma include, but are not
limited to, crush injuries, contact with a hard surface, or cutting
or other damage to the lungs.
[0137] The invention also pertains to a method for treating acute
lung injury by administering a tetracycline compound of the
invention.
[0138] The tetracycline responsive states of the invention also
include chronic lung disorders. The invention pertains to methods
for treating chronic lung disorders by administering a tetracycline
compound, such as those described herein. The method includes
administering to a subject an effective amount of a substituted
tetracycline compound such that the chronic lung disorder is
treated. Examples of chronic lung disorders include, but are not
limited, to asthma, cystic fibrosis, and emphysema. In a further
embodiment, the tetracycline compounds of the invention used to
treat acute and/or chronic lung disorders such as those described
in U.S. Pat. Nos. 5,977,091; 6,043,231; 5,523,297; and 5,773,430,
each of which is hereby incorporated herein by reference in its
entirety.
[0139] In yet another embodiment, the tetracycline compound
responsive state is ischemia, stroke, or ischemic stroke. The
invention also pertains to a method for treating ischemia, stroke,
or ischemic stroke by administering an effective amount of a
substituted tetracycline compound of the invention. In a further
embodiment, the tetracycline compounds of the invention are used to
treat such disorders as described in U.S. Pat. No. 6,231,894;
5,773,430; 5,919,775 or 5,789,395, incorporated herein by
reference.
[0140] In another embodiment, the tetracycline compound responsive
state is a skin wound. The invention also pertains, at least in
part, to a method for improving the healing response of the
epithelialized tissue (e.g., skin, mucosae) to acute traumatic
injury (e.g., cut, burn, scrape, etc.). The method may include
using a tetracycline compound of the invention (which may or may
not have antibacterial activity) to improve the capacity of the
epithelialized tissue to heal acute wounds. The method may increase
the rate of collagen accumulation of the healing tissue. The method
may also decrease the proteolytic activity in the epthithelialized
tissue by decreasing the collagenolytic and/or gelatinolytic
activity of MMPs. In a further embodiment, the tetracycline
compound of the invention is administered to the surface of the
skin (e.g., topically). In a further embodiment, the tetracycline
compound of the invention is used to treat a skin wound, and other
such disorders as described in, for example, U.S. Pat. Nos.
5,827,840; 4,704,383; 4,935,412; 5,258,371; 5,308,8391 5,459,135;
5,532,227; and 6,015,804; each of which is incorporated herein by
reference in its entirety.
[0141] Examples of tetracycline responsive states also include
neurological disorders which include both neuropsychiatric and
neurodegenerative disorders, but are not limited to, such as
Alzheimer's disease, dementias related to Alzheimer's disease (such
as Pick's disease), Parkinson's and other Lewy diffuse body
diseases, senile dementia, Huntington's disease, Gilles de la
Tourette's syndrome, multiple sclerosis, amyotrophic lateral
sclerosis (ALS), progressive supranuclear palsy, epilepsy, and
Creutzfeldt-Jakob disease; autonomic function disorders such as
hypertension and sleep disorders, and neuropsychiatric disorders,
such as depression, schizophrenia, schizoaffective disorder,
Korsakoff's psychosis, mania, anxiety disorders, or phobic
disorders; learning or memory disorders, e.g., amnesia or
age-related memory loss, attention deficit disorder, dysthymic
disorder, major depressive disorder, mania, obsessive-compulsive
disorder, psychoactive substance use disorders, anxiety, phobias,
panic disorder, as well as bipolar affective disorder, e.g., severe
bipolar affective (mood) disorder (BP-1), bipolar affective
neurological disorders, e.g., migraine and obesity. Further
neurological disorders include, for example, those listed in the
American Psychiatric Association's Diagnostic and Statistical
manual of Mental Disorders (DSM), the most current version of which
is incorporated herein by reference in its entirety.
[0142] In yet another embodiment, the tetracycline compound
responsive state is an aortic or vascular aneurysm in vascular
tissue of a subject (e.g., a subject having or at risk of having an
aortic or vascular aneurysm, etc.). The tetracycline compound may
by effective to reduce the size of the vascular aneurysm or it may
be administered to the subject prior to the onset of the vascular
aneurysm such that the aneurysm is prevented. In one embodiment,
the vascular tissue is an artery, e.g., the aorta, e.g., the
abdominal aorta. In a further embodiment, the tetracycline
compounds of the invention are used to treat disorders described in
U.S. Pat. Nos. 6,043,225 and 5,834,449, incorporated herein by
reference in their entirety.
[0143] Bacterial infections may be caused by a wide variety of gram
positive and gram negative bacteria. The compounds of the invention
are useful as antibiotics against organisms which are resistant to
other tetracycline compounds. The antibiotic activity of the
tetracycline compounds of the invention may be determined using the
method discussed in Example 2, or by using the in vitro standard
broth dilution method described in Waitz, J. A., National
Commission for Clinical Laboratory Standards, Document M7-A2, vol.
10, no. 8, pp. 13-20, 2.sup.nd edition, Villanova, Pa. (1990).
[0144] The tetracycline compounds of the invention may also be used
to treat infections traditionally treated with tetracycline
compounds such as, for example, rickettsiae; a number of
gram-positive and gram-negative bacteria; and the agents
responsible for lymphogranuloma venereum, inclusion conjunctivitis,
psittacosis. The tetracycline compounds may be used to treat
infections of, e.g., K. pneumoniae, Salmonella, E. hirae, A.
baumanii, B. catarrhalis, H. influenzae, P. aeruginosa, E. faecium,
E. coli, S. aureus or E. faecalis. In one embodiment, the
tetracycline compound is used to treat a bacterial infection that
is resistant to other tetracycline antibiotic compounds. The
tetracycline compound of the invention may be administered with a
pharmaceutically acceptable carrier.
[0145] The language "effective amount" of the compound is that
amount necessary or sufficient to treat or prevent a tetracycline
compound responsive state. The effective amount can vary depending
on such factors as the size and weight of the subject, the type of
illness, or the particular tetracycline compound. For example, the
choice of the tetracycline compound can affect what constitutes an
"effective amount". One of ordinary skill in the art would be able
to study the aforementioned factors and make the determination
regarding the effective amount of the tetracycline compound without
undue experimentation.
[0146] In an embodiment, the invention pertains to pharmaceutical
composition comprising a tetracycline compound of the invention,
e.g., a compound of Formula (I), (II), (III), or otherwise
described herein. Preferrably, the tetracycline compound is
provided in an effective amount, e.g., effective to treat a
tetracycline responsive state in a subject, e.g., a mammal, e.g., a
human. In a further embodiment, the pharmaceutical composition of
the invention also comprises an appropriate pharmaceutically
acceptable carrier.
[0147] The language "pharmaceutically acceptable carrier" includes
substances capable of being coadministered with the tetracycline
compound(s), and which allow both to perform their intended
function, e.g., treat or prevent a tetracycline compound responsive
state. Suitable pharmaceutically acceptable carriers include but
are not limited to water, salt solutions, alcohol, vegetable oils,
polyethylene glycols, gelatin, lactose, amylose, magnesium
stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, petroethral fatty acid
esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The
pharmaceutical preparations can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, colorings, flavorings and/or aromatic
substances and the like which do not deleteriously react with the
active compounds of the invention.
[0148] The tetracycline compounds of the invention that are basic
in nature are capable of forming a wide variety of salts with
various inorganic and organic acids. The acids that may be used to
prepare pharmaceutically acceptable acid addition salts of the
tetracycline compounds of the invention that are basic in nature
are those that form non-toxic acid addition salts, i.e., salts
containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and palmoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such
salts must be pharmaceutically acceptable for administration to a
subject, e.g., a mammal, it is often desirable in practice to
initially isolate a tetracycline compound of the invention from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent and subsequently convert the
latter free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of this
invention are readily prepared by treating the base compound with a
substantially equivalent amount of the chosen mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salt is readily obtained.
[0149] The tetracycline compounds of the invention that are acidic
in nature are capable of forming a wide variety of base salts. The
chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of those tetracycline
compounds of the invention that are acidic in nature are those that
form non-toxic base salts with such compounds. Such non-toxic base
salts include, but are not limited to those derived from such
pharmaceutically acceptable cations such as alkali metal cations
(e.g., potassium and sodium) and alkaline earth metal cations
(e.g., calcium and magnesium), ammonium or water-soluble amine
addition salts such as N-methylglucamine-(meglumine), and the lower
alkanolammonium and other base salts of pharmaceutically acceptable
organic amines. The pharmaceutically acceptable base addition salts
of tetracycline compounds of the invention that are acidic in
nature may be formed with pharmaceutically acceptable cations by
conventional methods. Thus, these salts may be readily prepared by
treating the tetracycline compound of the invention with an aqueous
solution of the desired pharmaceutically acceptable cation and
evaporating the resulting solution to dryness, preferably under
reduced pressure. Alternatively, a lower alkyl alcohol solution of
the tetracycline compound of the invention may be mixed with an
alkoxide of the desired metal and the solution subsequently
evaporated to dryness.
[0150] The preparation of other tetracycline compounds of the
invention not specifically described in the foregoing experimental
section can be accomplished using combinations of the reactions
described above that will be apparent to those skilled in the
art.
[0151] The tetracycline compounds of the invention and
pharmaceutically acceptable salts thereof can be administered via
either the oral, parenteral or topical routes. In general, these
compounds are most desirably administered in effective dosages,
depending upon the weight and condition of the subject being
treated and the particular route of administration chosen.
Variations may occur depending upon the species of the subject
being treated and its individual response to said medicament, as
well as on the type of pharmaceutical formulation chosen and the
time period and interval at which such administration is carried
out.
[0152] The pharmaceutical compositions of the invention may be
administered alone or in combination with other known compositions
for treating tetracycline responsive states in subjects, e.g.,
mammals. The subjects may be suffering from or at risk of suffering
from a tetracycline responsive state. Examples of subjects include
pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows, sheep,
pigs, horses, goats, etc.), lab animals (rats, mice, monkeys,
etc.), and primates (chimpanzees, humans, gorillas).
[0153] The language "in combination with" a known composition is
intended to include simultaneous administration of the composition
of the invention and the known composition, administration of the
composition of the invention first, followed by the known
composition and administration of the known composition first,
followed by the composition of the invention. Any of the
therapeutically composition known in the art for treating
tetracycline responsive states can be used in the methods of the
invention.
[0154] The compounds of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers or
diluents by any of the routes previously mentioned, and the
administration may be carried out in single or multiple doses. For
example, the novel therapeutic agents of this invention can be
administered advantageously in a wide variety of different dosage
forms, i.e., they may be combined with various pharmaceutically
acceptable inert carriers in the form of tablets, capsules,
lozenges, troches, hard candies, powders, sprays, creams, salves,
suppositories, jellies, gels, pastes, lotions, ointments, aqueous
suspensions, injectable solutions, elixirs, syrups, and the like.
Such carriers include solid diluents or fillers, sterile aqueous
media and various non-toxic organic solvents, etc. Moreover, oral
pharmaceutical compositions can be suitably sweetened and/or
flavored. In general, the therapeutically-effective compounds of
this invention are present in such dosage forms at concentration
levels ranging from about 5.0% to about 70% by weight.
[0155] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration, the active ingredient may be
combined with various sweetening or flavoring agents, coloring
matter or dyes, and, if so desired, emulsifying and/or suspending
agents as well, together with such diluents as water, ethanol,
propylene glycol, glycerin and various like combinations
thereof.
[0156] For parenteral administration (including intraperitoneal,
subcutaneous, intravenous, intradermal or intramuscular injection),
solutions of a therapeutic compound of the present invention in
either sesame or peanut oil or in aqueous propylene glycol may be
employed. The aqueous solutions should be suitably buffered
(preferably pH greater than 8) if necessary and the liquid diluent
first rendered isotonic. These aqueous solutions are suitable for
intravenous injection purposes. The oily solutions are suitable for
intraarticular, intramuscular and subcutaneous injection purposes.
The preparation of all these solutions under sterile conditions is
readily accomplished by standard pharmaceutical techniques well
known to those skilled in the art. For parenteral application,
examples of suitable preparations include solutions, preferably
oily or aqueous solutions as well as suspensions, emulsions, or
implants, including suppositories. Therapeutic compounds may be
formulated in sterile form in multiple or single dose formats such
as being dispersed in a fluid carrier such as sterile physiological
saline or 5% saline dextrose solutions commonly used with
injectables.
[0157] Additionally, it is also possible to administer the
compounds of the present invention topically when treating
inflammatory conditions of the skin. Examples of methods of topical
administration include transdermal, buccal or sublingual
application. For topical applications, therapeutic compounds can be
suitably admixed in a pharmacologically inert topical carrier such
as a gel, an ointment, a lotion or a cream. Such topical carriers
include water, glycerol, alcohol, propylene glycol, fatty alcohols,
triglycerides, fatty acid esters, or mineral oils. Other possible
topical carriers are liquid petrolatum, isopropylpalmitate,
polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5%
in water, sodium lauryl sulfate 5% in water, and the like. In
addition, materials such as anti-oxidants, humectants, viscosity
stabilizers and the like also may be added if desired.
[0158] For enteral application, particularly suitable are tablets,
dragees or capsules having talc and/or carbohydrate carrier binder
or the like, the carrier preferably being lactose and/or corn
starch and/or potato starch. A syrup, elixir or the like can be
used wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
component is protected with differentially degradable coatings,
e.g., by microencapsulation, multiple coatings, etc.
[0159] In addition to treatment of human subjects, the therapeutic
methods of the invention also will have significant veterinary
applications, e.g. for treatment of livestock such as cattle,
sheep, goats, cows, swine and the like; poultry such as chickens,
ducks, geese, turkeys and the like; horses; and pets such as dogs
and cats. Also, the compounds of the invention may be used to treat
non-animal subjects, such as plants.
[0160] It will be appreciated that the actual preferred amounts of
active compounds used in a given therapy will vary according to the
specific compound being utilized, the particular compositions
formulated, the mode of application, the particular site of
administration, etc. Optimal administration rates for a given
protocol of administration can be readily ascertained by those
skilled in the art using conventional dosage determination tests
conducted with regard to the foregoing guidelines.
[0161] In general, compounds of the invention for treatment may, in
certain embodiments, be administered to a subject in dosages used
in prior tetracycline therapies. See, for example, the Physicians'
Desk Reference. For example, a suitable effective dose of one or
more compounds of the invention will be in the range of from 0.01
to 100 milligrams per kilogram of body weight of recipient per day,
preferably in the range of from 0.1 to 50 milligrams per kilogram
body weight of recipient per day, more preferably in the range of 1
to 20 milligrams per kilogram body weight of recipient per day. The
desired dose is suitably administered once daily, or several
sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate
intervals through the day, or other appropriate schedule.
[0162] It will also be understood that normal, conventionally known
precautions will be taken regarding the administration of
tetracyclines generally to ensure their efficacy under normal use
circumstances. Especially when employed for therapeutic treatment
of humans and animals in vivo, the practitioner should take all
sensible precautions to avoid conventionally known contradictions
and toxic effects. Thus, the conventionally recognized adverse
reactions of gastrointestinal distress and inflammations, the renal
toxicity, hypersensitivity reactions, changes in blood, and
impairment of absorption through aluminum, calcium, and magnesium
ions should be duly considered in the conventional manner.
[0163] The invention is further illustrated by the following
examples, which should not be construed as further limiting.
EXEMPLIFICATION OF THE INVENTION
Example 1
Synthesis of 9-Aminomethyl Minocycline and Derivatives Thereof
[0164] Trifluoroacetic acid (1 L) was charged into a 2 L flask
under argon and minocycline. HCl (200 g, 1 eq) and
N-hydroxymethylphthalimide (100 g) were added to the flask while
stirring. Once the entire solid dissolved, H.sub.2SO.sub.4 (200 mL)
was added to the reaction. The reaction was heated to 40-50.degree.
C. for 5-6 hours. N-hydroxymethylamine (10 g) was added
portionwise. When HPLC analysis confirmed that all the starting
material was converted to
2,9-bis-aminomethylphthalimidominocycline, the mixture was
precipitated out of 4 L of acetone. An exotherm of 15-20.degree. C.
was observed. After 1 hour of stirring, the solid was filtered,
washed with acetone (200 ml), and dried with the aid of a latex
rubber dam. The solid was reslurried in a methanol (1 L)/t-BME (2
L) mixture and the pH was adjusted to 3 using triethylamine. The
solid was filtered and washed with 50 mL of methanol. The yield was
97% of 2,9-bis-aminomethylphthalimideminocycline.
[0165] 2,9-bis-aminomethylphthalimideminocycline (100 g) was
suspended in 2M solution of methylamine in methanol (10 eq). The
reaction was stirred at room temperature for 2-3 hours, at which
point HPLC analysis confirmed total conversion of the starting
material to 2,9-bis aminomethylminocycline. The reaction mixture
was poured into t-BME (5 volumes), and stirred for thirty minutes.
Next, the suspension was filtered and washed with t-BME (200 mL) to
isolate the desired product, 2,9-bis-aminomethylminocycline.
[0166] 2,9-bis-aminomethylminocycline (40 g) was slurried in 200 mL
water/methanol 1/9 and the pH was adjusted to 3 by the dropwise
addition of trifluoroacetic acid. The mixture was heated to
40.degree. C. for 1-2 hours. When HPLC analysis confirmed the
hydrolysis of 2,9-bis-aminomethylminocycline to
9-aminomethylminocycline, the reaction was allowed to return to
room temperature and the pH was adjusted to 7 using triethylamine.
Isopropyl alcohol (200 mL) was added to precipitate out the solid.
The product was filtered and washed with 50 mL IPA followed by 100
mL diethyl ether and dried under reduced pressure toisolate
9-aminomethylminocycline.
9-[(Benzylamino)-methyl]-minocycline dihydrochloride
[0167] ##STR248##
[0168] To 1.0 mmol (600 mg) of 9-(aminomethyl)-minocycline
dihydrochloride and in 5 mL of dimethylformamide was added 0.2 mmol
(5 mg) of indium trichloride and 1.5 mmol (160 mg) of benzaldehyde
at room temperature. After 30 minutes of shaking, 2 mmol (424 mg)
of sodium triacetoxyborohydride was added and the reaction was
monitored by HPLC. After 1.5 hours, 3 equivalents of triethylamine
and 1 equivalent of sodium triacetoxyborohydride. The reaction was
complete after 3 hours. The solvent was removed in vacuo and the
crude product was purified by preparative HPLC to yield 60 mg of
9-[(benzylamino)-methyl]-minocycline dihydrochloride. LCMS
(MH+)=577.
9-[(2,2, dimethyl-propyl amino)-methyl]-minocycline
dihydrochloride
[0169] 9-dimethylaminominocycline (200 mg, 1 eq.), DMF, and
trimethylacetaldehyde (45 .mu.l, 1 eq.) were combined in 40 mL
flasks and stirred. Triethylamine (150 .mu.L, 3 eq.) was then
added. After stirring at room temperature for several minutes,
NaBH(OAc).sub.3 (175 mg, 2 eq.) and InCl.sub.3 (9 mg, 0.1 eq.) was
added. After one hour, the reactions were clear and red. Liquid
chromatography showed a single product for the reaction. The
reaction was quenched with methanol, the solvent was removed, and
the product was purified using column chromatography.
9-[3,4-(Methylenedioxo)phenyl-ureido]-methylminocycline
dihydrochloride
[0170] ##STR249##
[0171] To 0.25 mmol (150 mg) of 9-(aminomethyl)-minocycline
dihydrochloride and 2 equivalents of triethylamine in 3 mL of
dimethylformamide was added 0.5 mmol (81.5 mg) of
3,4-(methylenedioxo)phenyl isocyanate at room temperature. Solution
was shaken until reaction was complete (3 hours). Solvent was
removed in vacuo and crude product was purified by preparative HPLC
to yield 66 mg of
9-[3,4-(methylenedioxo)phenyl-ureido]-methylminocycline
dihydrochloride. Yield 41%. LCMS (MH+)=650.
9-[4-(Trifluoromethoxy)phenyl-ureido]-methylminocycline
dihydrochloride
[0172] ##STR250##
[0173] To 0.25 mmol (150 mg) of 9-(aminomethyl)-minocycline
dihydrochloride and 2 equivalents of triethylamine in 3 mL of
dimethylformamide was added 0.5 mmol (101.5 mg) of
4-(trifluoromethoxy)phenyl isocyanate at room temperature. The
solution was shaken until the reaction was complete (3 hours).
Solvent was removed in vacuo and crude product was purified by
preparative HPLC to yield 68 mg of
9-[4-(trifluoromethoxy)phenyl-ureido]-methylminocycline
dihydrochloride. Yield 39%. LCMS (MH+)=690.
7-[(Bis-dimethoxymethyl-amino)-methyl]-sancycline
dihydrochloride
[0174] ##STR251##
[0175] To 1.34 mmol (1 g) of 7-(aminomethyl)-sancycline
dihydrochloride and 2 equivalents of triethylamine in 5 mL of
dimethylformamide was added 0.134 mmol (29 mg) of indium
trichloride and 2.68 mmol (465 mg) of 60% aqueous
dimethoxyacetaldehyde at room temperature. After 30 minutes of
shaking, 2.68 mmol (568 mg) of sodium triacetoxyborohydride was
added and the reaction was monitored by HPLC. The reaction was
complete after 1 hour. The solvent was removed in vacuo and the
crude product was purified by preparative HPLC to yield 100 mg of
7-[(Bis-dimethoxymethyl-amino)-methyl]-sancycline dihydrochloride.
LCMS (MH+)=620.
9-(2'-Phenyl-ethyl-1'-amino)-methyl]-doxycycline
[0176] ##STR252##
[0177] Under an N.sub.2 atmosphere, a stirred solution of
9-aminomethyldoxycycline dihydrochloride (1.21 g, 2.21 mmol) in DMF
(10 mL), was treated with InCl.sub.3 (0.076 g, 0.34 mmol) and
phenylacetaldehyde (0.511 mL; 4.4 mmol). HPLC and LCMS monitoring
of the reaction indicated the complete consumption of the starting
material over the course of 12 hours. The products were both the
mono-(major) and bis-(minor) substituted aminodoxycyclines.
Methanol (10 mL) was added to quench the reaction. The reaction
mixture was filtered through a bed of Celite, the celite washed
with methanol (2.times.5 mL), and the combined organic layer was
concentrated to about 7-8 mL and diluted with ether. The resulting
amorphous solid was filtered, washed with ether (6.times.15 mL) and
dried under vacuum to afford a red powder, which was purified by
preparative HPLC. The final product was characterized by HPLC, MS,
and .sup.1H NMR spectroscopic methods. MS (m/z): Theor. 577.24;
Found: 578.17 (M+1).
Example 2
In Vitro Minimum Inhibitory Concentration (MIC) Assay
[0178] The following assay is used to determine the efficacy of
tetracycline derivatives compounds against common bacteria. 2 mg of
each compound is dissolved in 100 .mu.l of DMSO. The solution is
then added to cation-adjusted Mueller Hinton broth (CAMHB), which
results in a final compound concentration of 200 .mu.g per ml. The
compound solutions are diluted to 50 .mu.L volumes, with a test
compound concentration of 0.098 .mu.g/ml. Optical density (OD)
determinations are made from fresh log-phase broth cultures of the
test strains. Dilutions are made to achieve a final cell density of
1.times.10.sup.6 CFU/ml. At OD=1, cell densities for different
genera should be approximately: TABLE-US-00003 E. coli 1 .times.
10.sup.9 CFU/ml S. aureus 5 .times. 10.sup.8 CFU/ml Enterococcus
sp. 2.5 .times. 10.sup.9 CFU/ml
[0179] 50 .mu.l of the cell suspensions are added to each well of
microtiter plates. The final cell density should be approximately
5.times.10.sup.5 CFU/ml. These plates are incubated at 35.degree.
C. in an ambient air incubator for approximately 18 hr. The plates
are read with a microplate reader and are visually inspected when
necessary. The MIC is defined as the lowest concentration of the
compound that inhibits growth.
EQUIVALENTS
[0180] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of the present
invention and are covered by the following claims. The contents of
all references, patents, and patent applications cited throughout
this application are hereby incorporated by reference. The
appropriate components, processes, and methods of those patents,
applications and other documents may be selected for the present
invention and embodiments thereof.
[0181] The application is related to "9-Substituted Minocycline
Compounds," WO 02/04406, filed Jun. 29, 2001, the entire contents
of which are hereby incorporated herein by reference.
* * * * *