U.S. patent application number 10/877928 was filed with the patent office on 2005-06-30 for substituted tetracycline compounds.
This patent application is currently assigned to Paratek Pharmaceuticals, Inc.. Invention is credited to Abato, Paul, Amoo, Victor, Assefa, Haregewein, Berniac, Joel, Bhatia, Beena, Bowser, Todd, Chen, Jackson, Grier, Mark, Honeyman, Laura, Ismail, Mohamed Y., Kim, Oak K., Mathews, Jude, Mechiche, Rachid, Nelson, Mark L., Ohemeng, Kwasi.
Application Number | 20050143352 10/877928 |
Document ID | / |
Family ID | 34108825 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050143352 |
Kind Code |
A1 |
Nelson, Mark L. ; et
al. |
June 30, 2005 |
Substituted tetracycline compounds
Abstract
The present invention pertains, at least in part, to novel
substituted tetracycline compounds. These tetracycline compounds
can be used to treat numerous tetracycline compound-responsive
states, such as bacterial infections and neoplasms, as well as
other known applications for tetracycline compounds such as
blocking tetracycline efflux and modulation of gene expression.
Inventors: |
Nelson, Mark L.; (Norfolk,
MA) ; Ohemeng, Kwasi; (Norwood, 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; (Williamsville,
NY) ; Grier, Mark; (Cambridge, MA) ; Honeyman,
Laura; (Roslindale, MA) ; Ismail, Mohamed Y.;
(Bedford, MA) ; Kim, Oak K.; (Cambridge, MA)
; Mathews, Jude; (Waltham, MA) ; Mechiche,
Rachid; (South Boston, MA) |
Correspondence
Address: |
LAHIVE & COCKFIELD, LLP.
28 STATE STREET
BOSTON
MA
02109
US
|
Assignee: |
Paratek Pharmaceuticals,
Inc.
Boston
MA
|
Family ID: |
34108825 |
Appl. No.: |
10/877928 |
Filed: |
June 25, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60486017 |
Jul 9, 2003 |
|
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60525287 |
Nov 25, 2003 |
|
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60530123 |
Dec 16, 2003 |
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Current U.S.
Class: |
514/152 ;
544/238; 546/285; 546/61; 548/364.4; 552/203 |
Current CPC
Class: |
C07C 271/54 20130101;
Y02A 50/473 20180101; A61P 19/00 20180101; A61P 19/08 20180101;
C07C 237/48 20130101; A61P 35/00 20180101; A61P 31/04 20180101;
C07C 2601/14 20170501; C07C 2603/46 20170501; Y02A 50/30 20180101;
A61K 31/65 20130101; A61P 33/00 20180101; A61P 33/06 20180101; Y02A
50/411 20180101; C07C 271/22 20130101; C07C 2601/16 20170501; A61P
31/00 20180101; A61P 29/00 20180101; C07C 275/30 20130101; C07C
2601/02 20170501; A61P 31/12 20180101; C07C 275/28 20130101; C07C
237/26 20130101; A61P 11/00 20180101 |
Class at
Publication: |
514/152 ;
544/238; 546/061; 546/285; 548/364.4; 552/203 |
International
Class: |
A61K 031/65; C07D
221/18 |
Claims
1. A substituted tetracycline compound of Formula I: 91wherein: X
is CHC(R.sup.13Y'Y), 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, 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 ethyl, perhalogenated alkenyl, substituted
pyridinyl, pyrazinyl, furanyl, or pyrazolyl; R.sup.8 is hydrogen,
hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.9--CH.sub.2NR.sup.9aR.sup.9b; R.sup.9a and
R.sup.9b are each independently hydrogen, alkyl, alkenyl or linked
to form a heterocycle; 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.
2. The tetracycline compound of claim 1, wherein 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 is
NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are lower alkyl; and
R.sup.5 is hydroxy or hydrogen.
3. The tetracycline compound of claim 2, wherein R.sup.4' and
R.sup.4" are each methyl and R.sup.5 is hydrogen.
4. The tetracycline compound of claim 1, wherein R.sup.7 is ethyl
and R.sup.9a is alkyl and R.sup.9b is alkenyl.
5. The tetracycline compound of claim 1, wherein R.sup.7 is
substituted pyrazinyl.
6. The tetracycline compound of claim 5, wherein R.sup.7 is
substituted with a fluorine.
7. The tetracycline compound of claim 5 or 6, wherein R.sup.9a is
alkyl and R.sup.9b is alkenyl.
8. The tetracycline compound of claim 5 or 6, wherein R.sup.9a and
R.sup.9b are linked to form a heterocycle.
9. The tetracycline compound of claim 5 or 6, wherein R.sup.9a is
hydrogen and R.sup.9b is alkyl.
10. The tetracycline compound of claim 1, wherein R.sup.7 is
furanyl, and R.sup.9a is hydrogen or alkyl and R.sup.9b is
alkenyl.
11. The tetracycline compound of claim 1, wherein R.sup.7 is
1,2,2-trifluoroethenyl.
12. The tetracyline compound of claim 11, wherein R.sup.9a is
hydrogen or alkyl and R.sup.9b is alkenyl.
13. The tetracycline compound of claim 1, wherein R.sup.7 is
pyrazolyl and R.sup.9a is hydrogen or alkyl and R.sup.9b is alkenyl
or alkyl.
14. A tetracycline compound selected from the group consisting of:
92939495and pharmaceutically acceptable salts, esters, and prodrugs
thereof.
15. A tetracycline compound of formula II: 96wherein: X is
CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or O; R.sup.2,
R.sup.4', R.sup.4", R.sup.7' and R.sup.7" are each 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
independently hydrogen, methylene, absent, hydroxyl, halogen,
thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.7
is NR.sup.7'R.sup.7", alkyl, alkenyl, alkynyl, aryl, hydroxyl,
halogen, or hydrogen; R.sup.8 is hydrogen, hydroxyl, halogen,
thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.9
is --CH.sub.2NR.sup.9aR.sup.9b or linked with R.sup.10 to form a
furanyl ring; R.sup.9a is hydrogen, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, or heteroaromatic; R.sup.9b is
hydrogen or alkyl; 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; 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.
16. The tetracycline compound of claim 15, wherein R.sup.4 is
NR.sup.4'R.sup.4"; X is CR.sup.6R.sup.6'; R.sup.7 is
NR.sup.7'R.sup.7", R.sup.2, R.sup.2', R.sup.5, 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; and, R.sup.4', R.sup.4", R.sup.7', and R.sup.7" are each
lower alkyl.
17. The tetracycline compound of claim 15, wherein R.sup.4 is
NR.sup.4'R.sup.4"; X is CR.sup.6R.sup.6', is hydrogen, R.sup.2,
R.sup.2', R.sup.7, R.sup.6', R.sup.8, R.sup.9, R.sup.10, R.sup.11,
and R.sup.12 are each hydrogen; R.sup.5 is hydroxy, and R.sup.4',
R.sup.4", and R.sup.6 are each lower alkyl.
18. The tetracycline compound of claim 15, wherein R.sup.9a is
alkyl, alkenyl, or arylalkyl.
19. The tetracycline compound of claim 18, wherein R.sup.9a is
alkyl substituted with an alkoxy, alkenyl, heterocyclic, cyano,
halogen, amido, carbonyl, or hydroxy moiety.
20. The tetracycline compound of claim 18, wherein R.sup.9a is
substituted or unsubstituted benzyl.
21. The tetracycline compound of claim 18, wherein R.sup.9b is
hydrogen or substituted or unsubstituted alkyl.
22. The tetracycline compound of claim 15, wherein R.sup.9a and
R.sup.9b are linked to form a pyrrolidinyl, piperazinyl,
piperidinyl, pyrazinyl, azapanyl, thiomorpholinyl, morpholinyl,
tetrahydroquinolinyl, or decahydroquinolinyl ring.
23. The tetracycline compound of claim 22, wherein said ring is
substituted with one or more halogens or halogenated alkyl
groups.
24. The tetracycline compound of claim 15, wherein R.sup.9 is
4'trifluoromethyl-piperdin-1-yl) methyl,
(4',4'-difluoro-piperdin-1-yl) methyl, or (4'-fluoropiperdin-1-yl)
methyl.
25. A tetracycline compound, selected from the group consisting of:
979899100101102103104105106107108109110111and pharmaceutically
acceptable salts, esters, and prodrugs thereof.
26. A tetracycline compound of formula III: 112wherein: 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 substituted or unsubstituted pyrazolyl, furanyl, thiophenyl,
thiazolyl, aminoalkyl substituted phenyl; R.sup.8 is hydrogen,
hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; R.sup.9 is hydrogen; 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.
27. The tetracycline compound of claim 26, 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.5, R.sup.6, R.sup.6', R.sup.8, R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; and, R.sup.4', and R.sup.4 are each
methyl.
28. The tetracycline compound of claim 26, wherein R.sup.7 is
phenyl substituted with --CH.sub.2--N(CH.sub.3).sub.2,
--CH.sub.2--NH--CH(CH.sub- .3).sub.2,
--CH.sub.2--N(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--N-piperdinyl), --CH.sub.2NH--CH.sub.3,
--CH.sub.2--NH-cyclopropyl, CH.sub.2--NH-t-butyl,
--CH.sub.2--N(CH.sub.3)- -benzyl,
--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.dbd.CH.sub.2,
CH.sub.2--NH--(CH.sub.2).sub.2--CF.sub.3,
CH.sub.2--NH--CH.sub.2--C(.dbd.- O)--NH.sub.2, or
--CH.sub.2--NH-cyclohexyl.
29. The tetracycline compound of claim 28, wherein said phenyl is
further substituted with a fluorine, methoxy, or alkyl group.
30. The tetracycline compound of claim 26, wherein R.sup.7 is
substituted furanyl.
31. The tetracycline compound of claim 30, wherein said furanyl is
substituted with an aminoalkyl moiety.
32. The tetracycline compound of claim 26, wherein R.sup.7 is
substituted or unsustituted thiophenyl.
33. The tetracycline compound of claim 26, wherein R.sup.7 is
substituted pyridinyl.
34. The tetracycline compound of claim 26, wherein said compound
is:
113114115116117118119120121122123124125126127128129130131132
35. A tetracycline compound is of formula IV: 133wherein: X is
CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or O; R.sup.2,
R.sup.4, R.sup.4, R.sup.7' and R.sup.7" are each 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
independently hydrogen, methylene, absent, hydroxyl, halogen,
thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R.sup.7
is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl,
alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,
arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl,
heterocyclic, thionitroso, or
(CH.sub.2).sub.0-3(NR.sup.7c).sub.0-1C(.dbd.W')WR.sup.7a; R.sup.8
is an aminomethyl substituted phenyl or substituted pyridinyl;
R.sup.9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a; R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f, R.sup.9a, R.sup.9b,
R.sup.9c, R.sub.9d, R.sup.9e and R.sup.9f are each independently
absent, hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety; Z is
CR.sup.9dR.sup.9e, S, NR.sup.9b or O; Z' is O, NR.sup.9f, or S; W
is CR.sup.7dR.sup.7e, S, O or NR.sup.7b; W' is O, NR.sup.7f, or S;
R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; 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.
36. The tetracycline compound of claim 35, wherein 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 is
NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are lower alkyl; and
R.sup.5 is hydroxy or hydrogen.
37. The tetracycline compound of claim 36, wherein said substituted
tetracycline compound is: 134
38. A tetracycline compound of the formula V: 135wherein: R.sup.2,
R.sup.4', R.sup.4", R.sup.7', and R.sup.7" are each 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.7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.7c).sub.0-1C(.dbd.W')WR.sup.7a; R.sup.8
is substituted phenyl or substituted pyridinyl; R.sup.9 is
hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl,
aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl,
amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic,
thionitroso, or --(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9a;
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, R.sup.8f are each
independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
W is CR.sup.7dR.sup.7e, S, O or NR.sup.7b; W' is O, NR.sup.7f or S;
R.sup.13 is 4-alkyl substituted phenyl, and pharmaceutically
acceptable salts, esters and prodrugs thereof.
39. The tetracycline compound of claim 38, wherein said
tetracycline compound is: 136
40. A method for treating a tetracycline responsive state in a
subject, comprising administering to said subject an effective
amount of a tetracycline compound of any one of claims 1, 14, 15,
25, 26, 34, 35, or 38, such that said subject is treated.
41. The method of claim 40, wherein said tetracycline responsive
state is a bacterial infection, a viral infection, or a parasitic
infection.
42. The method of claim 41, wherein said bacterial infection is
associated with E. coli.
43. The method of claim 41, wherein said bacterial infection is
associated with S. aureus.
44. The method of claim 41, wherein said bacterial infection is
associated with E. faecalis.
45. The method of claim 40, wherein said bacterial infection is
resistant to other tetracycline antibiotics.
46. The method of claim 40, wherein said tetracycline associated
state is malaria.
47. The method of claim 40, wherein said subject is a human.
48. The method of anyone of claims 40, wherein said tetracycline
compound is administered with a pharmaceutically acceptable
carrier.
49. A pharmaceutical composition comprising a therapeutically
effective amount of a tetracycline compound of any one of claims 1,
14, 15, 25, 26, 34, 35, or 38 and a pharmaceutically acceptable
carrier.
Description
RELATED APPLICATIONS
[0001] This patent application claims priority to U.S. Provisional
Patent Application Ser. No. 60/530,123, filed Dec. 16, 2003; U.S.
Provisional Patent Application Ser. No. 60/525,287, filed Nov. 25,
2003; and U.S. Provisional Patent Application Ser. No. 60/486,017,
filed Jul. 9, 2003, all of which are entitled "Substituted
Tetracycline Compounds." The entire contents of each of the
aforementioned applications are hereby incorporated herein by
reference.
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; and
minocycline was in use by 1972.
[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. 2,980,584;
2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859;
3,957,980; 4,018,889; 4,024,272; and 4,126,680. 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 a
7,9-substituted tetracycline compound of Formula I: 1
[0006] wherein:
[0007] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0008] 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;
[0009] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl,
hydroxyl, halogen, or hydrogen;
[0010] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0011] 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;
[0012] 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;
[0013] R.sup.7 ethyl, perhalogenated alkenyl, substituted
pyridinyl, pyrazinyl, furanyl, or pyrazolyl;
[0014] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0015] R.sup.9--CH.sub.2NR.sup.9aR.sup.9b;
[0016] R.sup.9a and R.sup.9b are each independently hydrogen,
alkyl, alkenyl or linked to form a heterocycle;
[0017] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0018] 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.
[0019] In another embodiment, the invention pertains to a
9-substituted tetracycline compound of formula II: 2
[0020] wherein:
[0021] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0022] R.sup.2, R.sup.4', R.sup.4", R.sup.7' and R.sup.7" are each
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0023] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0024] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0025] 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;
[0026] R.sup.6 and R.sup.6' are independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0027] R.sup.7 is NR.sup.7'R.sup.7", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0028] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0029] R.sup.9 is --CH.sub.2NR.sup.9aR.sup.9b, or linked with
R.sup.10 to form a furanyl ring;
[0030] R.sup.9a is hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, or heteroaromatic;
[0031] R.sup.9b is hydrogen or alkyl;
[0032] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0033] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0034] 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.
[0035] In another embodiment, the invention pertains to
7-substituted tetracycline compounds of formula III: 3
[0036] wherein:
[0037] 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;
[0038] 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;
[0039] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0040] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0041] 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;
[0042] 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;
[0043] R.sup.7 is substituted or unsubstituted pyrazolyl, furanyl,
thiophenyl, or thiazolyl;
[0044] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0045] R.sup.9 is hydrogen;
[0046] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0047] 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.
[0048] In another embodiment, the invention pertains to
8-substituted tetracycline compound of formula IV: 4
[0049] wherein:
[0050] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0051] R.sup.2, R.sup.4', R.sup.4", R.sup.7' and R.sup.7" are each
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0052] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0053] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0054] 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;
[0055] R.sup.6 and R.sup.6' are independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0056] R.sup.7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.7c).sub.0-1C(.d- bd.W')WR.sup.7a;
[0057] R.sup.8 is an aminomethyl substituted phenyl or substituted
pyridinyl;
[0058] R.sup.9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9- a;
[0059] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e and R.sup.8f are
each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug
moiety;
[0060] W is CR.sup.7dR.sup.7e, S, O or NR.sup.7b;
[0061] W' is O, NR.sup.7f, or S;
[0062] Z is CR.sup.9dR.sup.9e, S, O or NR.sup.9b;
[0063] Z' is O, NR.sup.9f, or S;
[0064] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0065] 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.
[0066] In one embodiment, a 13-substituted tetracycline compound is
of formula V: 5
[0067] wherein:
[0068] R.sup.2, R.sup.4', R.sup.4", R.sup.7' and R.sup.7" are each
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, hetero aromatic or a pro drug moiety;
[0069] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0070] R.sup.2, R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0071] 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;
[0072] R.sup.7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.7c).sub.0-1C(.d- bd.W')WR.sup.7a;
[0073] R.sup.8 is substituted phenyl or substituted pyridinyl;
[0074] R.sup.9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9- a;
[0075] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, and R.sup.8f are
each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug
moiety;
[0076] W is CR.sup.7dR.sup.7e, S, O or NR.sup.7b;
[0077] W' is O, NR.sup.7f, or S;
[0078] R.sup.13 is 4-alkyl substituted phenyl, and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0079] In another further embodiment, the invention pertains, at
least in part, to methods for treating subjects for tetracycline
responsive states by administering to them an effective amount of a
tetracycline compound of the invention, e.g., a compound of formula
I, II, III, IV, V, or a tetracycline compound otherwise described
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0080] The present invention pertains, at least in part, to novel
substituted tetracycline compounds. These tetracycline compounds
can be used to treat numerous tetracycline compound-responsive
states, such as bacterial infections and neoplasms, as well as
other known applications for minocycline and tetracycline compounds
in general, such as blocking tetracycline efflux and modulation of
gene expression.
[0081] The term "tetracycline compound" includes many compounds
with a similar ring structure to tetracycline. Examples of
tetracycline compounds include: chlortetracycline, oxytetracycline,
demeclocycline, methacycline, sancycline, 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 (See Rogalski, "Chemical Modifications of Tetracyclines,"
the entire contents of which are hereby incorporated herein by
reference). Table 1 depicts tetracycline and several known other
tetracycline derivatives.
1 6 Oxytetracycline 7 Demeclocycline 8 Minocycline 9 Methacycline
10 Doxycycline 11 Chlortetracycline 12 Tetracycline 13 Sancycline
14 Chelocardin
[0082] 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-dedimethylaminotetrac- ycline;
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
C1-4-dedimethylaminotetracycline-4,6-hemiketal;
5a,6-anhydro-4-hydrazon-4-dedimethylamino tetracycline;
4-hydroxyimino-4-dedimethylamino tetracyclines;
4-hydroxyimino-4-dedimeth- ylamino 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-deo- xytetracyclines;
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.
[0083] 1. 7,9-Substituted Tetracycline Compounds
[0084] The invention also pertains, at least in part to
7,9-substituted tetracycline compounds.
[0085] The term "7,9-substituted tetracycline compounds" includes
tetracycline compounds with substitution at the 7 and 9-positions.
In one embodiment, the substitution at the 7- and 9-positions
enhances the ability of the tetracycline compound to perform its
intended function, e.g., treat tetracycline responsive states. In
an embodiment, the 7,9-substituted tetracycline compound is
7,9-substituted tetracycline (e.g., wherein R.sup.4 is
NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are methyl, R.sup.5 is
hydrogen and X is CR.sup.6R.sup.6', wherein R.sup.6 is methyl and
R.sup.6' is hydroxy); 7,9-substituted doxycycline (e.g., wherein
R.sup.4 is NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are methyl,
R.sup.5 is hydroxyl and X is CR.sup.6R.sup.6', wherein R.sup.6 is
methyl and R.sup.6' is hydrogen); or 7,9-substituted sancycline
(wherein R.sup.4 is NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are
methyl; R.sup.5 is hydrogen and X is CR.sup.6R.sup.6' wherein
R.sup.6 and R.sup.6' are hydrogen atoms. In an embodiment, the
substitution at the 7 position of the 7,9-substituted tetracycline
compound is not chlorine or trimethylamino. In one embodiment,
R.sup.4 is hydrogen.
[0086] In one embodiment, the invention pertains to 7,9-substituted
tetracycline compounds of Formula I: 15
[0087] wherein:
[0088] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0089] 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;
[0090] R.sup.4 is NR.sup.4, R.sup.4", alkyl, alkenyl, alkynyl,
hydroxyl, halogen, or hydrogen;
[0091] R.sup.2, R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0092] 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;
[0093] 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;
[0094] R.sup.7 is ethyl, perhalogenated alkenyl, substituted
pyridinyl, pyrazinyl, furanyl, or pyrazolyl;
[0095] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0096] R.sup.9 is --CH.sub.2NR.sup.9aR.sup.9b;
[0097] R.sup.9a and R.sup.9b are each independently hydrogen,
alkyl, alkenyl or linked to form a heterocycle;
[0098] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0099] 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, provided
that R.sup.7 and R.sup.9 are not both unsubstituted phenyl.
[0100] In a further embodiment, 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 is NR.sup.4'R.sup.4"; R.sup.4'
and R.sup.4" are lower alkyl; and R.sup.5 is hydroxy or hydrogen.
In another further embodiment, R.sup.4" and R.sup.4" are each
methyl and R.sup.5 is hydrogen.
[0101] In an embodiment, R.sup.7 is ethyl and R.sup.9a is alkyl and
R.sup.9b is alkenyl. In another embodiment, R.sup.7 is substituted
pyrazinyl Examples of possible substituents include halogens, such
as fluorine. In another embodiment, R.sup.9a is alkyl and R.sup.9b
is alkenyl. In another further embodiment, R.sup.9a and R.sup.9b
are linked to form a heterocycle. In a further embodiment, the
linked heterocycle is substituted piperidinyl. In a further
embodiment, the piperdinyl is substituted with one or more
fluorines or halogenated alkyl groups, e.g., at the 2, 3, 4, or 5
position. In another embodiment, the R.sup.9 moiety is
(4'trifluoromethyl-piperdin-1-yl) methyl,
(4',4'-difluoro-piperdin-1-y- l) methyl, or
(4'-fluoropiperdin-1-yl) methyl.
[0102] In another embodiment, R.sup.9a is hydrogen and R.sup.9b is
alkyl. Other examples of compounds include those wherein R.sup.7 is
furanyl, and R.sup.9a is hydrogen or alkyl and R.sup.9b is alkenyl,
e.g., 1,2,2-trifluoroethenyl.
[0103] In another embodiment, R.sup.9a is hydrogen or alkyl and
R.sup.9b is alkenyl. In another embodiment, R.sup.7 is pyrazolyl
and R.sup.9a is hydrogen or alkyl and R.sup.9b is alkenyl or
alkyl.
[0104] In a further embodiment, the invention pertains to
tetracycline compounds selected from the group consisting of:
16171819
[0105] and pharmaceutically acceptable salts, esters, and prodrugs
thereof.
[0106] 2. 9-Substituted Tetracycline Compounds
[0107] In another embodiment, the invention pertains to
9-substituted tetracycline compounds.
[0108] The term "9-substituted tetracycline compounds" includes
tetracycline compounds with substitution at the 9 position. In one
embodiment, the substitution at the 9-position enhances the ability
of the tetracycline compound to perform its intended function,
e.g., treat tetracycline responsive states. In an embodiment, the
9-substituted tetracycline compound is 9-substituted tetracycline
(e.g., wherein R.sup.4 is NR.sup.4'R.sup.4", R.sup.4' and R.sup.4"
are methyl, R.sup.5 is hydrogen and X is CR.sup.6R.sup.6', wherein
R.sup.6 is methyl and R.sup.6' is hydroxy, and R.sup.7 is
hydrogen); 9-substituted doxycycline (e.g., wherein R.sup.4 is
NR.sup.4"R.sup.4", R.sup.4' and R.sup.4" are methyl, R.sup.5 is
hydroxyl and X is CR.sup.6R.sup.6', wherein R.sup.6 is methyl and
R.sup.6' is hydrogen, and R.sup.7 is hydrogen); 9-substituted
minocycline (wherein R.sup.4 is NR.sup.4'R.sup.4", R.sup.4' and
R.sup.4" are methyl; R.sup.5 is hydrogen and X is CR.sup.6R.sup.6'
wherein R.sup.6 and R.sup.6' are hydrogen atoms, and R.sup.7 is
dimethylamino); 9-substituted 4-dedimethylamino tetracycline
compound, wherein X is CR.sup.6R.sup.6', R.sup.4, R.sup.5,
R.sup.6', R.sup.6, and R.sup.7 are hydrogen; and 9-substituted
sancycline (wherein R.sup.4 is NR.sup.4'R.sup.4", R.sup.4' and
R.sup.4" are methyl; R.sup.5 and R.sup.7 are hydrogen and X is
CR.sup.6R.sup.6' wherein R.sup.6 and R.sup.6' are hydrogen
atoms).
[0109] In another embodiment, the invention pertains to
tetracycline compounds of formula II: 20
[0110] wherein:
[0111] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0112] R.sup.2, R.sup.4', R.sup.4", R.sup.7' and R.sup.7" are each
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0113] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0114] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0115] 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;
[0116] R.sup.6 and R.sup.6' are independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0117] R.sup.7 is NR.sup.7'R.sup.7", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0118] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0119] R.sup.9 is --CH.sub.2NR.sup.9aR.sup.9b, or linked with
R.sup.10 to form a furanyl ring;
[0120] R.sup.9a is hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, or heteroaromatic;
[0121] R.sup.9b is alkoxycarbonyl, arylaminocarbonyl, or
aryloxycarbonyl;
[0122] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0123] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0124] 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.
[0125] In a further embodiment, R.sup.4 is NR.sup.4'R.sup.4"; X is
CR.sup.6R.sup.6'; R.sup.7 is NR.sup.7'R.sup.7", R.sup.2', R.sup.5,
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; and, R.sup.4', R.sup.4", R.sup.7', and
R.sup.7" are each lower alkyl. In another embodiment, R.sup.9a is
alkyl, alkenyl, or arylalkyl. Examples of R.sup.9b include
alkoxycarbonyl, alkaminocarbonyl, aryloxycarbonyl, and
arylaminocarbonyl. In another embodiment, R.sup.9a and R.sup.9b are
linked to form a heterocyle, e.g., a substituted or unsubstituted
piperdinyl ring. In a further embodiment, the piperdinyl is
substituted with one or more fluorines or halogenated alkyl groups,
e.g., at the 2, 3, 4, or 5 position. In another embodiment, the
R.sup.9 moiety is (4'trifluoromethyl-piperdin-1-yl) methyl,
(4',4'-difluoro-piperdin-1-y- l) methyl, or
(4'-fluoropiperdin-1-yl) methyl.
[0126] In another embodiment, R.sup.4 is NR.sup.4'R.sup.4",
R.sup.4' and R.sup.4" are methyl, R.sup.5 is hydroxyl and X is
CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydrogen, and R.sup.7 is hydrogen In another embodiment, R.sup.9a
is alkyl, alkenyl, or arylalkyl. In a further embodiment, the
piperdinyl is substituted with one or more fluorines or halogenated
alkyl groups, e.g., at the 2, 3, 4, or 5 position. In another
embodiment, the R.sup.9 moiety is (4'trifluoromethyl-piperdin-1-yl)
methyl, (4',4'-difluoro-piperdin-1-yl) methyl, or
(4'-fluoropiperdin-1-yl) methyl.
[0127] In another further embodiment, R.sup.9a is substituted
alkyl. Examples include alkoxy substituted alkyl (e.g.,
--(CH.sub.2).sub.2--O--C- H.sub.3), alkenyl substituted alkyl
(e.g., --CH.sub.2--CH.dbd.C(CH.sub.3).- sub.2,
--CH.sub.2--C(CH.sub.3).dbd.CHCH.sub.3,
--CH.sub.2--CH.dbd.CH-pheny- l, etc.), heterocyclic substituted
alkyl (e.g., --CH.sub.2-furanyl, --CH.sub.2--CH.dbd.CH-furanyl,
--CH.sub.2-pyridinyl, optionally substituted), cyano substituted
alkyl (e.g., (CH.sub.2).sub.2--CN, etc.), alkynyl substituted alkyl
(e.g., --(CH.sub.2).sub.2--C.dbd.CH, etc.), halogen substituted
alkyl (e.g., (CH.sub.2).sub.2--CF.sub.3,
(CH.sub.2).sub.3--CF.sub.3, --CH.sub.2--CF.sub.3,
--CH.sub.2--CH.sub.2F, etc.), amido substituted alkyl (e.g.,
--CH.sub.2--C(.dbd.O)--N(CH.sub.3).- sub.2,
--CH.sub.2--C(.dbd.O)--NH.sub.2, etc.), carbonyl substituted alkyl
(e.g., CH.sub.2--C(.dbd.O)--CH.sub.3,
--CH.sub.2--C(.dbd.O)--C(CH.sub.3).- sub.3, etc.), hydroxy
substituted alkyl (e.g., (CH.sub.2--CH(OH)--CH.sub.3- ,
--CH.sub.2--C(OH)(CH.sub.3).sub.2, etc.),
--CH.sub.2--C(.dbd.N--O--CH.su- b.3)--CH.sub.3, cycloalkyl (e.g.,
adamantyl, etc.).
[0128] In another embodiment, R.sup.9a is substituted or
unsubstituted benzyl. In a further embodiment, R.sup.9a is
substituted with one or more fluorines (e.g., at the 2, 3, 4, 5, or
6 positions).
[0129] In a further embodiment, R.sup.9b is hydrogen, substituted
or unsubstituted alkyl (e.g., methyl, ethyl,
--CH.sub.2--CH.dbd.CH-furanyl,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2, --(CH.sub.2).sub.3--CF.sub.3,
--(CH.sub.2).sub.2--CH.sub.2F, --CH.sub.2--CH.sub.2F,
--(CH.sub.2).sub.2--CF.sub.3, --CH.sub.2--CF.sub.3, etc.).
[0130] In another further embodiment, R.sup.9a and R.sup.9b may be
linked to form a pyrrolidinyl, piperazinyl, piperidinyl, pyrazinyl,
azapanyl, thiomorpholinyl, morpholinyl, tetrahydroquinolinyl, or a
decahydroquinolinyl ring. The ring maybe substituted with one or
more fluorines at the 2, 3, 4, or 5 position. The ring may also be
substituted with one or more fluorinated alkyl groups (e.g.,
CH.sub.2F, --CHF.sub.2, CF.sub.3, etc.), cyano groups, hydroxy
groups, alkyl groups (e.g., methyl, ethyl, spiro-cyclohexyl,
t-butyl, etc.), heterocyclic (e.g., optionally substituted
morpholinyl), thiol groups, alkoxy groups, alkyloxycarbonyl groups,
carbonyl groups (optionally bonded directly to an atom in the
ring), and exocyclic and endocyclic double bonds. In one
embodiment, the ring is substituted with a .dbd.CF.sub.2 group. The
ring may also be linked to a --O--(CH.sub.2).sub.2--O-- group which
maybe attached to the pyrollidinyl or piperidinyl ring through one
carbons or through two adjacent carbons.
[0131] When R.sup.9 is linked to R.sup.10 to form a furanyl ring,
the ring can be further subsituted, e.g., with phenyl or other
substituents which allow the compound of the invention to perform
its intended function.
[0132] In a further embodiment, the tetracycline compound is
selected from the group consisting of:
212223242526272829303132333435
[0133] and pharmaceutically acceptable salts, esters, and prodrugs
thereof.
[0134] 3. 7-Substituted Tetracycline Compounds
[0135] In one embodiment, the invention pertains to novel
7-substituted tetracycline compounds.
[0136] The term "7-substituted tetracycline compounds" includes
tetracycline compounds with substitution at the 7 position. In one
embodiment, the substitution at the 7-position enhances the ability
of the tetracycline compound to perform its intended function,
e.g., treat tetracycline responsive states. In an embodiment, the
7-substituted tetracycline compound is 7-substituted tetracycline
(e.g., wherein R.sup.4 is NR.sup.4'R.sup.4", R.sup.4' and R.sup.4"
are methyl, R.sup.5 is hydrogen and X is CR.sup.6R.sup.6', wherein
R.sup.6 is methyl and R.sup.6' is hydroxy); 7-substituted
doxycycline (e.g., wherein R.sup.4 is NR.sup.4'R.sup.4", R.sup.4'
and R.sup.4" are methyl, R.sup.5 is hydroxyl and X is
CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydrogen); 7-substituted tetracycline compound, wherein X is
CR.sup.6R.sup.6', R.sup.4, R.sup.5, R.sup.6', and R.sup.6 are
hydrogen; or 7-substituted sancycline (wherein R.sup.4 is
NR.sup.4'R.sup.4", R.sup.4' and R.sup.4" are methyl; R.sup.5 is
hydrogen and X is CR.sup.6R.sup.6' wherein R.sup.6 and R.sup.6' are
hydrogen atoms).
[0137] The invention pertains, at least in part, to 7-substituted
tetracycline compound of Formula III: 36
[0138] wherein:
[0139] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6,
C.ident.CR.sup.6'R.sup.6, S, NR.sup.6, or O;
[0140] 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;
[0141] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0142] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0143] 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;
[0144] 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;
[0145] R.sup.7 is substituted or unsubstituted pyrazolyl, furanyl,
thiophenyl, or thiazolyl;
[0146] R.sup.8 is hydrogen, hydroxyl, halogen, thiol, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl;
[0147] R.sup.9 is hydrogen;
[0148] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; and
[0149] 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.
[0150] In a further embodiment, R.sup.4 is N.sup.4'R.sup.4"; X is
CR.sup.6R.sup.6", R.sup.2, R.sup.2', R.sup.5, 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; and, R.sup.4', and R.sup.4 are each lower alkyl, e.g.,
methyl.
[0151] In one embodiment, the tetracycline compound is a
doxycycline compound and R.sup.7 is substituted or unsubstituted
aminomethyl (e.g., --CH.sub.2NR.sup.7aR.sup.7b).
[0152] In one embodiment, R.sup.7 is substituted (e.g., N-alkyl
substituted) or unsubstituted pyrazolyl. In another embodiment,
R.sup.7 is diethyl amino. In another, R.sup.7 is substituted amino
methyl. In a further embodiment, the substituted aminomethyl is
substituted with a pentyl group (e.g.,
--CH.sub.2--C(CH.sub.3).sub.3), two methyl groups, or fluorinated
alkyl (e.g., fluorinated propyl, e.g.,
--CH.sub.2--CH.sub.2--CF.sub.3).
[0153] In another embodiment, R.sup.7 is substituted phenyl. In a
further embodiment, R.sup.7 is phenyl substituted at the 5 position
(of the phenyl ring) with an alkyl substituted amino methyl group
(e.g., (--CH.sub.2--N(CH.sub.3).sub.2,
--CH.sub.2--NH--CH(CH.sub.3).sub.2,
--CH.sub.2--N(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--N-piperdinyl), --CH.sub.2NH--CH.sub.3,
--CH.sub.2--NH-cyclopropyl, CH.sub.2--NH-t-butyl,
--CH.sub.2--N(CH.sub.3)-benzyl,
--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.dbd- .CH.sub.2,
CH.sub.2--NH--(CH.sub.2).sub.2--CF.sub.3,
CH.sub.2--NH--CH.sub.2--C(.dbd.O)--NH.sub.2, or
--CH.sub.2--NH-cyclohexyl- ,). In a further embodiment, the
piperdine may be substituted at its 4 position (e.g., with
fluorine, methyl, etc.).
[0154] In another embodiment, when R.sup.7 is a phenyl substituted
at the 5 position with an alkyl substituted amino methyl group, the
phenyl may also be substituted with a fluorine (e.g., at the 2, 3,
4, or 6 position) or an alkoxy (e.g., methoxy group) at the 2, 3,
4, or 6 position.
[0155] In another embodiment, R.sup.7 is phenyl with a 2-position
amino alkyl substituent. In a further embodiment, the substituent
is dialkylaminomethyl (e.g., dimethylaminomethyl,
--CH.sub.2--N-piperazinyl)- . In a further embodiment, the
piperazine is substituted with one or more fluorine or methyl
groups. In another further embodiment, the phenyl R.sup.7 is
further substituted at the 3, 4, 5, or 6 position with a methoxy
group. In another embodiment, the phenyl is linked to a methylene
dioxy group through its 4 and 5 positions.
[0156] In another embodiment, R.sup.7 is phenyl with a 4-position
amino alkyl (e.g., aminomethyl) substituent. In a further
embodiment, the aminoalkyl substituent is
--CH.sub.2--NH--CH(CH.sub.3).sub.2,
--C(CH.sub.3)--NH--(CH.sub.2).sub.2--CH.sub.2F,
--CH.sub.2--NH--CH.sub.2-- cyclohexenyl, --CH.sub.2--N-piperidinyl,
--CH.sub.2--N(CH.sub.3)--CH.sub.2- --CH.dbd.CH.sub.2, or
--CH.sub.2--NH--(CH.sub.2).sub.2--CF.sub.3).
[0157] In another embodiment, R.sup.7 is phenyl substituted with a
--C(.dbd.N--O--R)--R' group, wherein R and R' are each alkyl. In a
further embodiment, the substituent is at the 4-position of the
phenyl ring. In another embodiment, R.sup.7 is phenyl substituted
at the 4-position with an alkoxyalkyl group
(--CH.sub.2--O--CH.sub.3). In another embodiment, R.sup.7 is phenyl
substituted with an alkylcarbonylamino group.
[0158] In another embodiment, R.sup.7 is substituted furanyl. In a
further embodiment, the furanyl is attached at the 2-position of
the furanyl ring. In a further embodiment, the furanyl is
substituted with an amino alkyl, e.g., aminomethyl group at its
5-position. Examples of aminomethyl groups include:
--CH.sub.2N(CH.sub.3)--CH.sub.2--C.sub.6H.sub.5,
--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.dbd.CH.sub.2,
--CH.sub.2--N(CH.sub.3)--CH(CH.sub.3).sub.2, or
--CH.sub.2--N-piperidinyl- . In another embodiment, the furanyl is
substituted at the 3-position, e.g., with an aminoalkyl
substituent. Examples of such substituents include
--CH.sub.2--N(CH.sub.3).sub.2, --CH.sub.2--N-piperidinyl.
[0159] In another embodiment, R.sup.7 is substituted furanyl
attached at its 3-position. In a further embodiment, the furanyl is
substituted with an aminoalkyl substituent. In another further
embodiment, the aminoalkyl substituent is --CH.sub.2--N-piperazinyl
or --CH.sub.2--N--(CH.sub.3).sub- .2.
[0160] In another embodiment, R.sup.7 is substituted or
unsubstituted thiophenyl. In a further embodiment R.sup.7 is is
substituted with an aminoalkyl moiety. In another further
embodiment, the aminoalkyl moiety is
--CH.sub.2--N--(CH.sub.3).sub.2.
[0161] In another further embodiment, R.sup.7 is substituted
pyridinyl. In a further embodiment, R.sup.7 is attached to the
phenyl ring at its 3-position. In another further embodiment, it is
substituted with a aminoalkyl moiety at its 5-position. Examples of
aminoalkyl moieties include --CH.sub.2--N--(CH.sub.3).sub.2,
--CH.sub.2--N-piperidinyl,
--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.dbd.CH.sub.2, or
--CH.sub.2--N(CH.sub.3)--CH(CH.sub.3).sub.2.
[0162] In another further embodiment, R.sup.7 is
alkylcarbonylaminoalkyl. In another further embodiment, R.sup.7 is
--CH.sub.2--NH--C(.dbd.O)--CH.s- ub.3.
[0163] In another further embodiment, R.sup.7 is amino substituted
alkenyl. In another further embodiment, R.sup.7 is
--CH.dbd.CH--CH.sub.2--N(CH.sub.3).sub.2 or
--CH.dbd.CH--CH.sub.2--N-pipe- ridinyl. In another embodiment,
R.sup.7 is amino substituted alkynyl (e.g.,
--C.ident.C--CH.sub.2--N(CH.sub.3)--(CH.sub.2).sub.2--CF.sub.3 or
--C.ident.C--(CH.sub.2).sub.2--N-piperidinyl.
[0164] In another further embodiment, R.sup.7 is substituted
--CH.sub.2--N-piperidinyl. In certain embodiments, the piperidinyl
is substituted with one or more fluorines, e.g., at the 4-position
of the piperdine ring.
[0165] In another embodiment, the R.sup.7 substitutuent is
alkylaminocarbonyl. In a further embodiment, the substituent is
--C(.dbd.O)--NH--(CH.sub.2).sub.2--N(CH.sub.3).sub.2.
[0166] In another further embodiment, the R.sup.7 substituent is
aminoalkylcarbonyl. In a further embodiment, the substituent is
--C(.dbd.O)--CH.sub.2--N(CH.sub.3).sub.2,
--C(.dbd.O)--CH.sub.2--NH--(CH.- sub.2).sub.2--OCH.sub.3,
--C(.dbd.O)--CH.sub.2--N-piperidinyl and
--C(.dbd.O)--CH.sub.2--N-pyrollidinyl.
[0167] In another further embodiment, the R.sup.7 substituent is
N-piperdinyl substituted alkyl. In a further embodiment, the
R.sup.7 substituent is --(CH.sub.2).sub.4--N-piperdinyl or
--(CH.sub.2).sub.2--N-piperdinyl.
[0168] In another embodiment, the R.sup.7 substituted is
--(CH.sub.2).sub.2--N(CH.sub.3).sub.2 or C(.dbd.O)--CH.sub.3.
[0169] In another further embodiment, the R.sup.7 substituent is
aminoalkyloxycarbonyl. Examples of aminoalkyloxycarbonyl
substituents include C(.dbd.O)--O--(CH.sub.2).sub.2--N-piperdinyl
and --C(.dbd.O)--O--(CH.sub.2).sub.2--N(CH.sub.3).sub.2.
[0170] In a further embodiment, the compounds of the invention are:
3738394041424344454647484950515253545556
[0171] and pharmaceutically acceptable esters, prodrugs, and salts
thereof.
[0172] 4. 8-Substituted Tetracycline Compounds
[0173] The invention also pertains, at least in part to
8-substituted tetracycline compounds.
[0174] The term "8-substituted tetracycline compounds" includes
tetracycline compounds with substitution at the 8-position. In one
embodiment, the substitution at the 8-position enhances the ability
of the tetracycline compound to perform its intended function,
e.g., treat tetracycline responsive states. In an embodiment, the
8-substituted tetracycline compound is 8-substituted tetracycline
(e.g., wherein R.sup.4 is NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4"
are methyl, R.sup.5 is hydrogen and X is CR.sup.6R.sup.6', wherein
R.sup.6 is methyl and R.sup.6' is hydroxy); 8-substituted
doxycycline (e.g., wherein R.sup.4 is NR.sup.4'R.sup.4"; R.sup.4'
and R.sup.4" are methyl, R.sup.5 is hydroxyl and X is
CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydrogen); or 8-substituted sancycline (wherein R.sup.4 is
NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are methyl; R.sup.5 is
hydrogen and X is CR.sup.6R.sup.6" wherein R.sup.6 and R.sup.6' are
hydrogen atoms. In an embodiment, the substitution at the 7
position of the 8-substituted tetracycline compound is not chlorine
or trimethylamino. In one embodiment, R.sup.4 is hydrogen.
[0175] In one embodiment, the 8-substituted tetracycline compound
is of formula IV: 57
[0176] wherein:
[0177] X is CHC(R.sup.13Y'Y), CR.sup.6'R.sup.6, S, NR.sup.6, or
O;
[0178] R.sup.2, R.sup.4', R.sup.4", R.sup.7' and R.sup.7" are each
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0179] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0180] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0181] 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;
[0182] R.sup.6 and R.sup.6' are independently hydrogen, methylene,
absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0183] R.sup.7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.7c).sub.0-1C(.d- bd.W')WR.sup.7a;
[0184] R.sup.8 is substituted phenyl or substituted pyridinyl;
[0185] R.sup.9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9- a;
[0186] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, and R.sup.8f are
each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug
moiety;
[0187] W is CR.sup.7dR.sup.7e, S, O or NR.sup.7b;
[0188] W' is O, NR.sup.7f, or S;
[0189] R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl;
[0190] 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.
[0191] In a further embodiment, the invention pertains to compounds
wherein 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 is NR.sup.4'R.sup.4"; R.sup.4' and R.sup.4" are
lower alkyl; and R.sup.5 is hydroxy or hydrogen.
[0192] In a further embodiment, R.sup.8 is substituted phenyl,
e.g., o-substituted phenyl, e.g., aminomethyl substituted phenyl.
In a further embodiment, the 8-substituted tetracycline compound
is: 58
[0193] and pharmaceutically acceptable salts, esters, and prodrugs
thereof.
[0194] In another further embodiment, R.sup.9 is substituted
pyridinyl, e.g., halo-substituted pyridinyl, e.g.,
6-fluoro-pyrindin-3-yl. In a further embodiment, R.sup.9 is amino.
In yet a further embodiment, the 8-substituted tetracycline
compound is: 59
[0195] and pharmaceutically acceptable salts, esters, and prodrugs
thereof.
[0196] 5. 13-Substituted Methacycline Compounds
[0197] In one embodiment, a 13-substituted tetracycline compound is
of formula V: 60
[0198] wherein:
[0199] R.sup.2, R.sup.4', R.sup.4", R.sup.7' and R.sup.7" are each
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heteroaromatic or a prodrug moiety;
[0200] R.sup.4 is NR.sup.4'R.sup.4", alkyl, alkenyl, alkynyl, aryl,
hydroxyl, halogen, or hydrogen;
[0201] R.sup.2', R.sup.3, R.sup.10, R.sup.11 and R.sup.12 are each
hydrogen or a pro-drug moiety;
[0202] 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;
[0203] R.sup.7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.7c).sub.0-1C(.d- bd.W')WR.sup.7a;
[0204] R.sup.8 is substituted phenyl or substituted pyridinyl;
[0205] R.sup.9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3NR.sup.9cC(=Z')ZR.sup.9- a;
[0206] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e and R.sup.8f are
each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug
moiety;
[0207] W is CR.sup.7dR.sup.7e, S, O or NR.sup.7b;
[0208] W' is O, NR.sup.7f, or S;
[0209] R.sup.13 is 4-alkyl substituted phenyl, and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0210] In a further embodiment, the invention pertains to compounds
wherein R.sup.2, R.sup.2', R.sup.8, R.sup.10, R.sup.11, and
R.sup.12 are each hydrogen; R.sup.4 is NR.sup.4'R.sup.4"; R.sup.4'
and R.sup.4" are lower alkyl; and R.sup.5 is hydroxy or
hydrogen.
[0211] In a further embodiment, the phenyl R.sup.13 group is
substituted with an aminomethyl substituent. In another further
embodiment, the aminomethyl substituent is dimethylaminomethyl. In
another further embodiment, the invention pertains to compounds of
the formula: 61
[0212] and pharmaceutically acceptable salts, esters, and prodrugs
thereof.
[0213] In one embodiment, the tetracycline compounds of the
invention do not include those described in U.S. Ser. No.
09/660,598, 09/823,884, 09/852,908, 10/819,343, 10/820,456,
09/894,805, 09/895,796, 09/895,812, 09/895,797, 09/895,857,
10/097,634, 10/759,484, 10/337,914, 10/636,437, 10/752,378, or
10/740,961. The entire contents of each of these applications are
hereby incorporated herein in their entirety.
[0214] 6. Methods for Synthesizing Tetracycline Compounds of the
Invention
[0215] The tetracycline compounds of this invention can be
synthesized using the methods described in the Schemes and/or by
other techniques known to those of ordinary skill in the art.
[0216] The substituted tetracycline compounds of the invention can
be synthesized using the methods described in the following schemes
and by using art recognized techniques. All novel substituted
tetracycline compounds described herein are included in the
invention as compounds. 62
[0217] 9- and 7-substituted tetracyclines can be synthesized by the
method shown in Scheme 1. As shown in Scheme 1, 9- and
7-substituted tetracycline compounds can be synthesized by treating
a tetracycline compound (e.g., doxycycline, 1A), with sulfuric acid
and sodium nitrate. The resulting product is a mixture of the
7-nitro and 9-nitro isomers (1B and 1C, respectively). The 7-nitro
(1B) and 9-nitro (1C) derivatives are treated by hydrogenation
using hydrogen gas and a platinum catalyst to yield amines 1D and
1E. The isomers are separated at this time by conventional methods.
To synthesize 7- or 9-substituted alkenyl derivatives, the 7- or
9-amino tetracycline compound (1E and 1F, respectively) is treated
with HONO, to yield the diazonium salt (1G and 1H). The salt (1G
and 1H) is treated with an appropriate reactive reagent to yield
the desired compound(e.g., in Scheme 1,7-cyclopent-1-enyl
doxycycline (1H) and 9-cyclopent-1-enyl doxycycline (1I)). 63
[0218] As shown in Scheme 2, tetracycline compounds of the
invention wherein R.sup.7 is a carbamate or a urea derivative can
be synthesized using the following protocol. Sancycline (2A) is
treated with NaNO.sub.2 under acidic conditions forming 7-nitro
sancycline (2B) in a mixture of positional isomers.
7-nitrosancycline (2B) is then treated with H.sub.2 gas and a
platinum catalyst to form the 7-amino sancycline derivative (2C).
To form the urea derivative (2E), isocyanate (2D) is reacted with
the 7-amino sancycline derivative (2C). To form the carbamate (2G),
the appropriate acid chloride ester (2F) is reacted with 2C. 64
[0219] As shown in Scheme 3, tetracycline compounds of the
invention, wherein R.sup.7 is a heterocyclic (i.e. thiazole)
substituted amino group can be synthesized using the above
protocol. 7-amino sancycline (3A) is reacted with
Fmoc-isothiocyanate (3B) to produce the protected thiourea (3C).
The protected thiourea (3C) is then deprotected yielding the active
sancycline thiourea (3D) compound. The sancycline thiourea (3D) is
reacted with an .alpha.-haloketone (3E) to produce a thiazole
substituted 7-amino sancycline (3F). 65
[0220] 7-alkenyl tetracycline compounds, such as 7-alkynyl
sancycline (4A) and 7-alkenyl sancycline (4B), can be hydrogenated
to form 7-alkyl substituted tetracycline compounds (e.g., 7-alkyl
sancycline, 4C). Scheme 4 depicts the selective hydrogenation of
the 7-position double or triple bond, in saturated methanol and
hydrochloric acid solution with a palladium/carbon catalyst under
pressure, to yield the product. 66
[0221] In Scheme 5, a general synthetic scheme for synthesizing
7-position aryl derivatives is shown. A Suzuki coupling of an aryl
boronic acid with an iodosancycline compound is shown. An iodo
sancycline compound (5B) can be synthesized from sancycline by
treating sancycline (5A) with at least one equivalent
N-iodosuccinimide (NIS) under acidic conditions. The reaction is
quenched, and the resulting 7-iodo sancycline (5B) can then be
purified using standard techniques known in the art. To form the
aryl derivative, 7-iodo sancycline (5B) is treated with an aqueous
base (e.g., Na.sub.2CO.sub.3) and an appropriate boronic acid (5C)
and under an inert atmosphere. The reaction is catalyzed with a
palladium catalyst (e.g., Pd(OAc).sub.2). The product (5D) can be
purified by methods known in the art (such as HPLC). Other 7-aryl,
alkenyl, and alkynyl tetracycline compounds can be synthesized
using similar protocols.
[0222] The 7-substituted tetracycline compounds of the invention
can also be synthesized using Stille cross couplings. Stille cross
couplings can be performed using an appropriate tin reagent (e.g.,
R----SnBu.sub.3) and a halogenated tetracycline compound, (e.g.,
7-iodosancycline). The tin reagent and the iodosancycline compound
can be treated with a palladium catalyst (e.g.,
Pd(PPh.sub.3).sub.2Cl.sub.2 or Pd(AsPh.sub.3).sub.2Cl.sub- .2) and,
optionally, with an additional copper salt, e.g., CuI. The
resulting compound can then be purified using techniques known in
the art. 67
[0223] The compounds of the invention can also be synthesized using
Heck-type cross coupling reactions. As shown in Scheme 6, Heck-type
cross-couplings can be performed by suspending a halogenated
tetracycline compound (e.g., 7-iodosancycline, 6A) and an
appropriate palladium or other transition metal catalyst (e.g.,
Pd(OAc).sub.2 and CuI) in an appropriate solvent (e.g., degassed
acetonitrile). The substrate, a reactive alkene (6B) or alkyne
(6D), and triethylamine are then added and the mixture is heated
for several hours, before being cooled to room temperature. The
resulting 7-substituted alkenyl (6C) or 7-substituted alkynyl (6E)
tetracycline compound can then be purified using techniques known
in the art. 68
[0224] To prepare 7-(2'-Chloro-alkenyl)-tetracycline compounds, the
appropriate 7-(alkynyl)-sancycline (7A) is dissolved in saturated
methanol and hydrochloric acid and stirred. The solvent is then
removed to yield the product (7B). 69
[0225] As depicted in Scheme 8,5-esters of 9-substituted
tetracycline compounds can be formed by dissolving the
9-substituted compounds (8A) in strong acid (e.g. HF,
methanesulphonic acid, and trifluoromethanesulfonic acid) and
adding the appropriate carboxylic acid to yield the corresponding
esters (8B).
[0226] As shown in Scheme 9 below, 7 and 9 aminomethyl
tetracyclines may be synthesized using reagents such as
hydroxymethyl-carbamic acid benzyl ester. 70
[0227] The term "alkyl" includes saturated aliphatic groups,
including straight-chain alkyl groups (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.),
branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl,
etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl), 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. In certain 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 3-8 carbon atoms in their ring
structure, and more preferably have 5 or 6 carbons in the ring
structure. The term C.sub.1-C.sub.6 includes alkyl groups
containing 1 to 6 carbon atoms.
[0228] 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, alkenyl, alkynyl, halogen, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, 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, alkylsulfinyl, 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" or an "arylalkyl" moiety is an
alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The
term "alkyl" also includes the side chains of natural and unnatural
amino acids.
[0229] The term "aryl" includes groups, including 5- and 6-membered
single-ring aromatic groups that may include from zero to four
heteroatoms, for example, benzene, phenyl, pyrrole, furan,
thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole,
pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and
pyrimidine, and the like. Furthermore, the term "aryl" includes
multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g.,
naphthalene, benzoxazole, benzodioxazole, benzothiazole,
benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,
isoquinoline, napthridine, indole, benzofuran, purine, benzofuran,
deazapurine, or indolizine. Those aryl groups having heteroatoms in
the ring structure may also be referred to as "aryl heterocycles",
"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,
alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,
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, alkylsulfinyl, 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).
[0230] The term "alkenyl" includes unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but that contain at least one double bond.
[0231] For example, the term "alkenyl" includes straight-chain
alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl,
hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain
alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or
alkenyl substituted cycloalkenyl groups, and cycloalkyl or
cycloalkenyl substituted alkenyl groups. The term alkenyl further
includes alkenyl groups which include oxygen, nitrogen, sulfur or
phosphorous atoms replacing one or more carbons of the hydrocarbon
backbone. In certain embodiments, a straight chain or branched
chain alkenyl group has 6 or fewer carbon atoms in its backbone
(e.g., C.sub.2-C.sub.6 for straight chain, C.sub.3-C.sub.6 for
branched chain). Likewise, cycloalkenyl groups may have from 3-8
carbon atoms in their ring structure, and more preferably have 5 or
6 carbons in the ring structure. The term C.sub.2-C.sub.6 includes
alkenyl groups containing 2 to 6 carbon atoms.
[0232] Moreover, the term alkenyl includes both "unsubstituted
alkenyls" and "substituted alkenyls", the latter of which refers to
alkenyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, 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, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0233] The term "alkynyl" includes unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but which contain at least one triple bond.
[0234] For example, the term "alkynyl" includes straight-chain
alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl,
hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain
alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl
groups. The term alkynyl further includes alkynyl groups which
include oxygen, nitrogen, sulfur or phosphorous atoms replacing one
or more carbons of the hydrocarbon backbone. In certain
embodiments, a straight chain or branched chain alkynyl group has 6
or fewer carbon atoms in its backbone (e.g., C.sub.2-C.sub.6 for
straight chain, C.sub.3-C.sub.6 for branched chain). The term
C.sub.2-C.sub.6 includes alkynyl groups containing 2 to 6 carbon
atoms.
[0235] Moreover, the term alkynyl includes both "unsubstituted
alkynyls" and "substituted alkynyls", the latter of which refers to
alkynyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, 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, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0236] 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.
"Lower alkenyl" and "lower alkynyl" have chain lengths of, for
example, 2-5 carbon atoms.
[0237] The term "acyl" includes compounds and moieties which
contain the acyl radical (CH.sub.3CO--) or a carbonyl group. It
includes substituted acyl moieties. The term "substituted acyl"
includes acyl groups where one or more of the hydrogen atoms are
replaced by for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, 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, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0238] The term "acylamino" includes moieties wherein an acyl
moiety is bonded to an amino group. For example, the term includes
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido
groups.
[0239] The term "aroyl" includes compounds and moieties with an
aryl or heteroaromatic moiety bound to a carbonyl group. Examples
of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
[0240] The terms "alkoxyalkyl", "alkylaminoalkyl" 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.
[0241] The term "alkoxy" includes substituted and unsubstituted
alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen
atom. Examples of alkoxy groups include methoxy, ethoxy,
isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of
substituted alkoxy groups include halogenated alkoxy groups. The
alkoxy groups can be substituted with groups such as alkenyl,
alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, 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, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
Examples of halogen substituted alkoxy groups include, but are not
limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
[0242] The term "amine" or "amino" includes compounds where a
nitrogen atom is covalently bonded to at least one carbon or
heteroatom. The term includes "alkyl amino" which comprises groups
and compounds wherein the nitrogen is bound to at least one
additional alkyl group. The term "dialkyl amino" includes groups
wherein the nitrogen atom is bound to at least two additional alkyl
groups. The term "arylamino" and "diarylamino" include groups
wherein the nitrogen is bound to at least one or two aryl groups,
respectively. The term "alkylarylamino," "alkylaminoaryl" or
"arylaminoalkyl" refers to an amino group which is bound to at
least one alkyl group and at least one aryl group. The term
"alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound
to a nitrogen atom which is also bound to an alkyl group.
[0243] The term "amide," "amido" or "aminocarbonyl" includes
compounds or moieties which contain a nitrogen atom which is bound
to the carbon of a carbonyl or a thiocarbonyl group. The term
includes "alkaminocarbonyl" or "alkylaminocarbonyl" groups which
include alkyl, alkenyl, aryl or alkynyl groups bound to an amino
group bound to a carbonyl group. It includes arylaminocarbonyl and
arylcarbonylamino groups which include aryl or heteroaryl moieties
bound to an amino group which is bound to the carbon of a carbonyl
or thiocarbonyl group. The terms "alkylaminocarbonyl,"
"alkenylaminocarbonyl," "alkynylaminocarbonyl,"
"arylaminocarbonyl," "alkylcarbonylamino," "alkenylcarbonylamino,"
"alkynylcarbonylamino," and "arylcarbonylamino" are included in
term "amide." Amides also include urea groups (aminocarbonylamino)
and carbamates (oxycarbonylamino).
[0244] The term "carbonyl" or "carboxy" includes compounds and
moieties which contain a carbon connected with a double bond to an
oxygen atom. The carbonyl can be further substituted with any
moiety which allows the compounds of the invention to perform its
intended function. For example, carbonyl moieties may be
substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos,
etc. Examples of moieties which contain a carbonyl include
aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,
etc.
[0245] The term "thiocarbonyl" or "thiocarboxy" includes compounds
and moieties which contain a carbon connected with a double bond to
a sulfur atom.
[0246] The term "ether" includes compounds or moieties which
contain an oxygen bonded to two different carbon atoms or
heteroatoms. For example, the term includes "alkoxyalkyl" which
refers to an alkyl, alkenyl, or alkynyl group covalently bonded to
an oxygen atom which is covalently bonded to another alkyl
group.
[0247] The term "ester" includes compounds and moieties which
contain a carbon or a heteroatom bound to an oxygen atom which is
bonded to the carbon of a carbonyl group. The term "ester" includes
alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl,
alkenyl, or alkynyl groups are as defined above.
[0248] The term "thioether" includes compounds and moieties which
contain a sulfur atom bonded to two different carbon or hetero
atoms. Examples of thioethers include, but are not limited to
alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term
"alkthioalkyls" include compounds with an alkyl, alkenyl, or
alkynyl group bonded to a sulfur atom which is bonded to an alkyl
group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls"
refer to compounds or moieties wherein an alkyl, alkenyl, or
alkynyl group is bonded to a sulfur atom which is covalently bonded
to an alkynyl group.
[0249] The term "hydroxy" or "hydroxyl" includes groups with an
--OH or --O.
[0250] The term "halogen" includes fluorine, bromine, chlorine,
iodine, etc. The term "perhalogenated" generally refers to a moiety
wherein all hydrogens are replaced by halogen atoms.
[0251] 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, alkylaminoacarbonyl, arylalkylaminocarbonyl,
alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl
carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,
alkoxyl, phosphate, phosphonato, phosphinato, cyano, amido, amino
(including alkyl amino, dialkylamino, arylamino, diarylamino, and
alkylarylamino), acylamino (including alkylcarbonylamino,
arylcarbonylamino, carbamoyl and ureido), amidino, imino,
sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or
an aromatic or heteroaromatic moiety.
[0252] The term "heteroatom" includes atoms of any element other
than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorus.
[0253] The term "prodrug moiety" includes moieties which can be
metabolized in vivo to a hydroxyl group and moieties which may
advantageously remain esterified in vivo. Preferably, the prodrugs
moieties are 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
prodrug moieties 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. Preferred prodrug moieties are propionoic acid
esters and acyl esters.
[0254] It will be noted that the structure of some of the
tetracycline 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. Furthermore, the structures and other
compounds and moieties discussed in this application also include
all tautomers thereof.
[0255] 7. Methods for Treating Tetracycline Responsive States
[0256] The invention also pertains to methods for treating a
tetracycline responsive states in subjects, by administering to a
subject an effective amount of a tetracycline compound of the
invention (e.g., a compound of Formula I, II, III, IV, V or
otherwise described herein), such that the tetracycline responsive
state is treated.
[0257] The term "treating" includes curing as well as ameliorating
at least one symptom of the state, disease or disorder, e.g., the
tetracycline compound responsive state.
[0258] 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 3, 10, and/or
12a substituted 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 characheterized by unwanted
cellular proliferation, including, but not limited to, those
described in U.S. Pat. No. 6,100,248), arthritis, osteoporosis,
diabetes, 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. In another
embodiment, the tetracycline compounds of the invention are
essentially non-antibacterial. For example, non-antibacterial
tetracycline compounds of the invention may have MIC values greater
than about 4 .mu.g/ml (as measured by assays known in the art
and/or the assay given in Example 2).
[0259] 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.
[0260] IPAF'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.
[0261] 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.
[0262] 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., a 3, 10, and/or 12a
substituted tetracycline compound. 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.
[0263] 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, recurrent and chronic
infections (bacterial, viral and fungal); 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 tendonitis);
uremic pericarditis; acute and chronic cholecystis; cystic
fibrosis, acute and chronic vaginitis; acute and chronic uveitis;
drug reactions; insect bites; burns (thermal, chemical, and
electrical); and sunburn.
[0264] The term "inflammatory process associated state" also
includes, in one embodiment, matrix metalloproteinase associated
states (MMPAS). MMPAS include states charachterized by abberrant
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., 3, 10, and/or 12a substituted
tetracycline compounds.
[0265] 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.
[0266] 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.
[0267] 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.
[0268] 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, amylotrophic 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.
[0269] Other examples of tetracycline compound responsive states
are described in WO 03/005971A2, U.S. Ser. No. 60/421,248, and U.S.
Ser. No. 60/480,482, each incorporated herein by reference.
[0270] The language "in combination with" another therapeutic agent
or treatment includes co-administration of the tetracycline
compound, (e.g., inhibitor) 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 an IPAS. 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. No. 6,100,248; 5,843,925;
5,837,696; or 5,668,122, incorporated herein by reference in their
entirety.
[0271] In another embodiment, the tetracycline compound responsive
state is diabetes, e.g., juvenile diabetes, diabetes mellitus,
diabetes type I, or diabetes type II. 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.
[0272] 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.
[0273] 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.
[0274] The invention also pertains to a method for treating acute
lung injury by administering a substituted tetracycline compound of
the invention.
[0275] 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 emphesema. 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.
[0276] 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.
[0277] 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, mucusae) 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 gellatinolytic
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 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.
[0278] 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.
[0279] 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).
[0280] The tetracycline compounds 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.
[0281] 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.
[0282] The invention also pertains to methods of treatment against
microorganism infections and associated diseases. The methods
include administration of an effective amount of one or more
tetracycline compounds to a subject. The subject can be either a
plant or, advantageously, an animal, e.g., a mammal, e.g., a
human.
[0283] In the therapeutic methods of the invention, one or more
tetracycline compounds of the invention may be administered alone
to a subject, or more typically a compound of the invention will be
administered as part of a pharmaceutical composition in mixture
with conventional excipient, i.e., pharmaceutically acceptable
organic or inorganic carrier substances suitable for parenteral,
oral or other desired administration and which do not deleteriously
react with the active compounds and are not deleterious to the
recipient thereof.
[0284] 7. Pharmaceutical Compositions of the Invention
[0285] The invention also pertains to pharmaceutical compositions
comprising a therapeutically effective amount of a tetracycline
compound (e.g., a compound of Formula I, II, III, IV, V or any
other compound described herein) and, optionally, a
pharmaceutically acceptable carrier.
[0286] 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 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.
[0287] 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-na- phthoate)] 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. 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.
[0288] 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.
[0289] 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.
[0290] 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.
[0291] 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.
[0292] The pharmaceutical compositions of the invention may be
administered alone or in combination with other known compositions
for treating tetracycline responsive states in a subject, e.g., a
mammal. Preferred mammals 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). 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.
[0293] The tetracycline 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 (e.g.,
aerosols, etc.), 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.
[0294] 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.
The compositions of the invention may be formulated such that the
tetracycline compositions are released over a period of time after
administration.
[0295] 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.
[0296] 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.
[0297] 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.
[0298] 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.
[0299] 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.
[0300] In general, compounds of the invention for treatment can 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. 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.
[0301] Furthermore, the invention also pertains to the use of a
tetracycline compound of formula I, II, III, IV, V, or any other
compound described herein, for the preparation of a medicament. The
medicament may include a pharmaceutically acceptable carrier and
the tetracycline compound is an effective amount, e.g., an
effective amount to treat a tetracycline responsive state.
EXEMPLIFICATION OF THE INVENTION
Example 1
Synthesis of Selected Compounds of the Invention
[0302] 71
[0303] The above compound was prepared from 7-iodo-sancycline (15.0
g, 22.9 mmol) combined with Pd(dppf).sub.2Cl.sub.2 (1.7 g, 2.29
mmol) and DMF (300 mL) in a 1 L round bottom 2 neck flask.
Na.sub.2CO.sub.3 (7.2 g, 68.2 mmol) was dissolved in water (15 mL)
was added to reaction solution. 2-fluoro-pyridine-5-boronic acid
(6.4 g, 45.9 mmol) was dissolved in DMF (25 mL) and also added to
reaction solution. Reaction mixture was stirred at 65.degree. C.
(oil bath temperature) under an argon atmosphere and reaction was
monitored by HPLC and LC/MS. Reaction shown to be complete within 3
hr. Filtered through celite and evaporated solvent in vacuo.
Redissolved in MeOH (30 mL) and precipitated in MTBE (3 L) to
produce a yellow precipitate. Filtered and dried under vacuum
overnight to yield 15 g of yellow powder. This crude material (9 g,
17.8 mmol) was dissolved in TFA/Triflic acid (83 mL/7 mL) and
cooled to 0.degree. C. using an ice bath. N-iodo-succinimide (8 g,
35.6 mmol) was added portionwise to reaction solution over 2 hr.
Reaction complete after 3 hrs- and 20% more NIS added to reaction.
Evaporated TFA in vacuo and precipitated remaining acid in MTBE
(1.4 L) at room temp. Yellow precipitate. Filtered and dried under
vacuum overnight to yield 8.4 g of crude product. This crude
material (4 g, 6.3 mmol) was combined with NaOAc (0.52 g, 6.3 mmol)
in an oven-dried 250 mL 2 neck round bottom flask. Anhydrous DMF
(60 mL) was syringed into reaction flask. Stirred under argon at
room temp 1 hr. Diluted with more anhydrous DMF (120 mL) and a
CO-filled balloon was placed on top neck of reaction flask. CO was
purged through reaction direction from lecture bottle for 15 min.
Flask then open to CO-filled balloon and allowed to stir at
60.degree. C. (oil bath temp) while Pd(PPh.sub.3).sub.4 (2.2 g, 1.9
mmol) was added as a DMF slurry via syringe. Stirred at temperature
1 hr. SnBu.sub.3H (1.6 g, 6.3 mmol) was added via syringe pump over
2 hr. Reaction monitored by HPLC and LC/MS and shown to be complete
upon completion of tin addition. Evaporated solvent in vacuo.
Purified by preparative HPLC in 20% yield in preparation for final
synthesis step. This purified material (0.25 g, 0.46 mmol) was
combined with anhydrous DMF (15 mL) in an oven-dried 100 mL flask.
InCl.sub.3 (0.005 g, 0.023 mmol), N-methyl-allylamine (0.17 g, 0.23
mmol) were added to reaction and stirred at room temperature under
argon 1 hr. NaCNBH.sub.3 (0.035 g, 0.55 mmol) was added to reaction
solution and was monitored by HPLC and LC/MS. Reaction 80% complete
within 6 hrs of reaction time. Evaporated solvent in vacuo. Final
product was isolated by preparative HPLC in 10% yield as a yellow
solid. ESI-MS: m/z (M+H) 593.
[0304] 7-Ethyl-9-(4',4'-Difluoro-N-Piperidinyl methyl)-Sancycline
72
[0305] The compound was prepared from 7-ethyl-9-formyl-sancycline
(0.23 g, 0.49 mmol) combined with InCl.sub.3 (0.011 g, 0.049 mmol),
4,4-difluoropiperidine.HCl (0.17 g, 0.98 mmol), Et.sub.3N (0.099 g,
0.98 mmol), and DMF (8 mL) in a glass vial. Stirred under argon at
room temperature 30 min. NaCNBH.sub.3 (0.043 g, 0.69 mmol) was
added to reaction vial and continued to stir at room temperature
under argon. Reaction was monitored by LC/MS and HPLC and shown to
be complete in 2 hrs. Quenched reaction with MeOH (15 mL) and
evaporated solvent in vacuo. Product was isolated by preparative
HPLC in 20% yield as a yellow solid. ESI-MS: m/z (M+H) 576.
[0306]
7-(Trifluoroalkenyl)-9-(2'-trans-2-methyl-2-butene)aminomethyl
Sancycline 73
[0307] To a stirred solution of powered Zn (5.00 g, 76.5 mmol) in
dry THF (50.0 mL) at 0 C was added iodo-trifluor alkene (2.00 mL,
4.50 g, 21.0 mmol) slowly over a 0.5 h time period. The reaction
was stirred for an additional 1.5 h before it was filtered under an
inert atmosphere and reduced of all solvent using rotary
evaporation (25.0 C, 5.00 mm Hg) to yield the
trifluoro-zinc-iodo-alkene reagent (approximately 3 mL). Dry DMF
(10 mL) was added to the above zinc-reagent and this solution was
added to a stirred solution of 7-Iodo-9-trans-2-methyl-2-butene
sancycline free base (1.00 g, 1.57 mmol) and
tetrakis(triphenylphosphine)- palladium (0.181 g, 0.156 mmol) in
dry DMF (10 mL). The contents were heated to 40 C and allowed to
stir for 20 minutes. The reaction was then filtered and purified
using reverse phase HPLC to give 7-trifluoroalkene sancycline
product (557 mg, 0.0942 mmol, 60% yield) LCMS m/z=592.2392
(M+H).
[0308]
7-(2'-Pyrazinyl)-9-(3,3',3'-Trifluoro-propylamino)-methyl-Sancyclin-
e 74
[0309] Step 1:
[0310] 7-Iodo-9-aminomethyl sancycline (569 mg, 1 mmol), indium
trichloride (22 mg, 0.1 mmol) and trifluoropropionaldehyde (224
.mu.L, 2 mmol) were taken in DMF (25 mL) and stirred at room
temperature for 10 minutes. To this solution, sodium
triacetoxyborohydride (635 mg, 3 mmol) was added at once and the
reaction mixture was stirred at room temperature for another 30
minutes. Progress of the reaction was monitored by HPLC and LC/MS.
Reaction was completed in 30 minutes. DMF was then removed and the
crude material obtained was then precipitated using diethyl
ether/MeOH (100/10 mL). Filteration of the precipitate gave a
yellow powder, which was used for the next step without further
purification.
[0311] Step 2:
[0312] 7-Iodo-9-(3,3,3-trifluoro-propylamino)-methyl-sancycline
(665 mg, 1 mmol), Pd(PPh.sub.3).sub.4 (115 mg, 0.1 mmol),
Pd(OAc).sub.2 (22 mg, 0.1 mmol), CuI (19 mg, 0.1 mmol) were taken
in anhydrous DMF (30 mL) and purged with argon for 5 minutes. To
this solution, 2-pyrazine-stannane (738 mg, 2 mmol) was added and
the reaction mixture was stirred at room temperature for 2 hours.
Reaction was completed by then (monitored by HPLC/LCMS). It was
then filtered through celite, washed with 5 mL of methanol. Solvent
was evaporated to dryness. The crude material obtained was purified
using preparative HPLC. A yellow solid was obtained after
evaporating the fractions, which was converted to its HCl salt
using MeOH/HCl solution. LC-MS (M+1 618).
[0313] 7-Amino-9-Iodo-Doxycycline 75
[0314] To 500 mg of 9-iodo-doxycycline in 10 ml of methanesulfonic
acid was added 1.1 eq. of sodium nitrate. The reaction mixture was
left stirring for several hrs and was monitored by analytical HPLC.
The intermediate (9-Iodo-7-nitro-doxycycline) was isolated by
diluting he solution with ice-water, adjusting the pH with sodium
hydroxide (pH.about.4) and extracting the product with n-butanol.
The solvent was evaporated under reduced pressure and the crude
material was subjected to hydrogenation using 10% Pd/C in methanol.
The final product was obtained via preparative HPLC. The LCMS
showed the desired material; MS: 586. The structure was confirmed
by NMR.
[0315] 7-(Dimethylamino)-9-(4',4'-Difluoropiperdinyl)-Doxycycline
76
[0316] To a solution of 105 mg (0.16 mmol) of
9-(4-difluoropiperdinyl)-dox- ycycline dihydrochloride in 10 mL of
methanesulfonic acid at room temperature, was added 19.4 mg (0.19
mmol) of potassium nitrate dissolved in 4 mL of methanesulfonic
acid. The reaction was monitored by LCMS. After 30 minutes, the
reaction mixture was poured over ice and diluted to 160 mL with ice
water. The solution was loaded onto a 2.5.times.1 cm column of
divinylbenzene resin (1000 angstrom, 5-25 .mu.m) equilibrated with
water. The crude reaction mixture was washed with excess water to
remove methanesulfonic acid followed an excess of 1N ammonium
acetate to neutralize the crude mixture. The excess ammonium
acetate was removed by a water wash and the crude compound was
purified by elution with 40% methanol in water with 0.1% HCl. The
purified material was evaporated to dryness to yield 70 mg of
9-(4-difluoropiperdinyl)-7-nitro-doxycycline as the dihydrochloride
salt (Yield=63%). LCMS (MH+) 623. To 70 mg (0.10 mmol) of
9-(4-difluoropiperdinyl)-7-nitro-doxycycline dihydrochloride in 20
mL of methoxyethanol was added 200 mL of sulfuric acid and 162 mL
(2 mmol) of 37% formaldehyde in water. The reaction mixture was
purged with Argon gas and 40 mg of 10% wet Palladium on carbon was
added with stirring. The reaction was hydrogenated at room
temperature and 760 torr hydrogen gas for 12 hours. The crude
reaction was passed through Celite and evaporated to dryness. The
crude reaction mixture was purified by preparative HPLC (1
inch.times.25 cm, Phenomenex Luna C18, 10 mm, Gradient 5-40% B
buffer, A=water+0.1% TFA, B=acetonitrile+0.1% TFA, detection at 280
nm) to yield 20 mg of the product as the dihydrochloride salt
(Yield=30%). LCMS (MH+) 621.
[0317] 7-Diethylamino-9-(4'-Fluoro-N-Piperidinyl methyl)-Sancycline
77
[0318] 7-NH.sub.2-sancycline (4.0 g, 9.32 mmol) was combined with
2-methoxyethanol (100 mL), H.sub.2SO.sub.4 (5 mL of 1N solution) in
a 2-neck 250 mL round bottom flask. Acetaldehyde (5.2 mL, 9.32
mmol) was added to reaction solution and contents were stirred at
room temperature under argon for 20 minutes. Pd/C (1.25 g) was
added to reaction and contents were evacuated/flushed with argon 3
times. A balloon filled with H.sub.2 was placed on top neck of
reaction flask and reaction solution was evacuated/flushed with
H.sub.2 three times. The reaction was stirred overnight under
H.sub.2 pressure at room temperature. The reaction was monitored by
HPLC and LC/MS and shown to be complete by morning. The mixture was
filtered through celite and solvent evaporated in vacuo. The
residue was redissolved in water (1 L) and the pH was adjusted with
Et.sub.3N to pH.about.5. The mixture was filtered again through
celite and loaded onto a DVB column. The compound eluted at 15%
CH.sub.3CN. Clean fractions were evaporated and dried overnight
under vacuum. A yellow/brown solid (7-diethylamino sancycline) was
isolated in 40% yield.
[0319] 7-diethylamino sancycline (1.4 g, 2.88 mmol)was dissolved in
TFA/Triflic acid (22 mL/6 mL) in a 100 mL flask. N-iodosuccinimide
(1.2 g, 5.78 mmol) was added portionwise to reaction solution every
20 minutes. The reaction monitored by HPLC and LC/MS and shown to
be complete within 3 hours. The reaction solution was diluted with
H.sub.2O (0.1% TFA) (30 mL) and the solvent was evaporated. The
residue was redissolved in H.sub.2O (100 mL) and loaded onto a 5 g
DVB cartridge. The crude product eluted at 30-50% CH.sub.3CN. A
yellow/brown crude product was isolated in 90% yield.
[0320] This crude material, 7-diethylamino-9-iodo-sancycline, (1.8
g, 2.95 mmol) was dissolved in anhydrous DMF (100 mL) in a 2 neck 1
L round bottom flask and placed under argon. NaOAc (0.61 g, 7.36
mmol) was added to reaction solution and stirred at room
temperature 45 min. Pd(PPh.sub.3).sub.4 (1.02 g, 8.85 mmol) was
added to reaction and a CO-filled balloon was placed on top neck of
reaction flask. CO was bubbled through reaction solution for 10
min. then flask opened to CO balloon. SnBu.sub.3H (0.8 g, 2.95
mmol) was added via syringe pump to reaction solution over 1 hour
while heating to 65.degree. C. (oil bath temperature). The reaction
was monitored by LC/MS and shown to be complete upon addition of
tin hydride. H.sub.2O (0.1% TFA, 0.3 L) was added to the reaction
flask and a precipitate formed. The mixture was filtered through
celite and the filtrate was evaporated in vacuo. A brown solid in
90% yield (crude material) was isolated.
[0321] 7-diethylamino-9-formyl-sancycline (0.25 g, 0.49 mmol) was
dissolved in DMF (10 mL). InCl.sub.3 (0.01 g, 0.049 mmol),
4-fluoropiperidine.HCl (0.15 g, 0.98 mmol), and Et.sub.3N (0.09 g,
0.98 mmol) were added to reaction solution. The reaction was
stirred at room temperature under argon 45 minutes. NaCNBH.sub.3
(0.043 g, 0.68 mmol) was added to the reaction and it was monitored
by HPLC and LC/MS. The reaction was shown to be complete in 3 hours
and it was quenched with MeOH (30 mL). The final product was
isolated by preparative HPLC in 10% yield as a yellow solid.
ESI-MS: m/z (M+H) 601.
[0322] Synthesis of 7-Aminomethyl Doxycycline 78
[0323] To 1 gram of 9-tert-butyl-doxycycline, dissolved in 15 ml of
methanesulfonic acid, was added an excess of HMBC
(Hydroxymethyl-carbamic acid benzyl ester). The reaction mixture
was monitored by analytical HPLC. The LCMS showed MS: 530
corresponding to the desired material, 7-aminomethyl-9-t-butyl
doxycycline. The product was isolated via preparative HPLC and the
structure confirmed by NMR. Removal of the t-butyl in triflic acid
afforded the 7-aminomethyl doxycycline in good yield.
[0324] Synthesis of 9-(3',3',3'-Trifluoropropylamino)methyl
Minocycline 79
[0325] 9-formyl-minocycline (0.2 g, 0.42 mmol) was combined with
InCl.sub.3 (0.01 g, 0.005 mmol), 3,3,3-trifluoropropylamine.HCl
(0.25 g, 1.7 mmol), Et.sub.3N (0.17 g, 1.7 mmol), and DMF (10 mL)
in a glass vial. The reaction was stirred at room temperature under
argon for 1 hour. NaCNBH.sub.3 (0.032 g, 0.50 mmol) was added to
reaction solution and was monitored by HPLC and LC/MS. The reaction
was complete within 1 hour, quenched with MeOH (20 mL) and the
solvent evacuated in vacuo. The final product was isolated by
preparative HPLC in 25% yield as a yellow solid. ESI-MS: m/z (M+H)
583.
[0326] 9-(4'-Difluoromethylene-N-pilperidinyl)methyl Minocycline
80
[0327] Anhydrous tetrahydrofuran (THF, 200 mL) was placed in a
flame-dried 500 mL round bottom flask at 0.degree. C. in an ice
bath. Dibromodifluoromethane (97%, Aldrich, 10.00 mL, 106.19 mmol,
4.3 eq.) was added via syringe. Ten minutes later,
Hexamethylphosphorous triamide (HMPT, 97%, Aldrich, 19.50 mL,
104.07 mmol, 4.2 eq.) was added dropwise. The clear solution turned
milky white and was stirred for 1 hour at 0.degree. C. A solution
of tert-Butyl 4-oxo-1-piperidinecarboxylate (98%, Aldrich, 5.00 g,
24.59 mmol, 1.0 eq.) in anhydrous THF (50 mL) was then added
dropwise via syringe at 0.degree. C. and the solution was allowed
to warm up slowly to room temperature over 1 hour by removing the
ice bath. The powdered zinc (99.998%, Aldrich, powdered, -100 mesh,
6.56 g, 98.34 mmol, 4.0 eq.) was then added followed by HMPT (1.15
mL, 6.14 mmol, 25%) and the reaction mixture was refluxed for 3
hours. Water (250 mL) and Diethyl ether (Et.sub.2O, 250 mL) were
added and the mixture was extracted with Et.sub.2O (3 times 100
mL). The combined organic layers were washed with a saturated
solution of Copper(II) sulfate (CuSO.sub.4) in Water (150 mL) then
with water (150 mL). The organic layer was dried over Magnesium
sulfate (MgSO.sub.4), filtered, and evaporated under reduced
pressure to yield the desired fluorinated piperidine as a yellow
oil, which was used without further purification in the next
step.
[0328] A 100 mL round bottom flask equipped with a magnetic
stirring bar was loaded with the BOC-protected piperidine (2.00 g,
8.57 mmol, 1.0 eq.) in a saturated HCl solution in Methanol (50 mL)
at room temperature. The mixture was then stirred at 40.degree. C.
for 30 minutes and the solvent was evaporated under reduced
pressure to a minimal volume. The HCl salt was then precipitated
from Et.sub.2O, filtered, and dried in vacuo to yield the desired
fluorinated piperidine (1.10 g, 6.49 mmol, 76% yield) as a beige
solid used without further purification in the next step.
[0329] A flame-dried 50 mL round bottom flask equipped with a
magnetic stirring bar was loaded with 9-Formyl-minocycline (500 mg,
1.03 mmol, 1.0 eq.) in anhydrous Dimethylformamide (DMF, 10.00 mL)
at room temperature. Indium chloride (InCl.sub.3, 99.999%, Aldrich,
59 mg, 0.27 mmol, 26%) was added and the reaction mixture was
stirred at 30.degree. C. for 10 minutes. The amine (350 mg, 2.06
mmol, 2.0 eq.) was added in anhydrous DMF (2 mL), followed by
Triethylamine (NEt.sub.3, 99.5%, Alfa-Aesar, 290 .mu.L, 2.08 mmol,
2.0 eq.). The mixture was then stirred at 30.degree. C. for 1 hour
and Sodium triacetoxyborohydride (NaBH(OAc).sub.3, 95%, Aldrich,
220 mg, 1.04 mmol, 1.0 eq.) was added followed by more NEt.sub.3
(300 .mu.L). After 2 hours, the reaction was done and the solvent
evaporated under reduced pressure. The residue was purified by
preparative HPLC (Acetonitrile/Water/0.1% Trifluoroacetic acid
gradient) to yield the desired product as a yellow solid. MS m/z
603.
[0330] Synthesis of 9-(4'-Fluoro-N-Piperdinyl)methyl Doxycycline
81
[0331] The compound was prepared from Doxycycline (2.5 g, 5.0 mmol)
dissolved in MeOH (anhydrous) (25 mL) and combined with AgSO4 (3.7
g, 11 mmol) and 12 (3.1 g, 11 mmol) in a 100 mL round bottom flask.
H.sub.2SO.sub.4conc (2 drops) was added to the reaction solution
and stirred at room temperature under argon for 1 hour. The
reaction solution turned bright yellow after 30 minutes and the
reaction was monitored by LC/MS and shown to be complete in 1 hour.
Sodium sulfite (sat) (8 mL) was added to the reaction solution and
a thick yellow precipitate was formed. The mixture was stirred at
room temperature for 20 minutes. The mixture was diluted with
CH.sub.3CN (75 mL), filtered through celite and evaporated solvent
in vacuo to yield 1.7 g of crude 9-iodo-doxycycline material.
[0332] 9-iodo-doxycycline (1.3 g, 2.4 mmol) was dissolved in
anhydrous DMF (20 mL) in a 200 mL 2 neck round bottom flask and
Pd(PPh.sub.3).sub.4 (0.82 g, 0.71 mmol) was added. A CO-filled
balloon was placed on top neck of reaction flask and CO was bubbled
directly into reaction from lecture bottole. The flask was then
opened to the balloon and SnBu.sub.3H (0.70 g, 2.7 mmol) was added
via syringe pump over 1 hour. The reaction solution was heated to
65.degree. C. during the tin addition. The reaction was monitored
by LC/MS and it was shown to be complete once the tin addition was
complete. Water (0.1% TFA) (200 mL) was then added to reaction
solution and a yellow precipitate formed. The mixture was then
filtered through celite and the filtrate was evaporated in vacuo. A
brown/yellow solid in 50% yield was isolated.
[0333] (9-formyl-doxycycline (0.20 g, 0.42 mmol) combined with
InCl.sub.3 (0.01 g, 0.042 mmol), 4-fluoropiperidine (0.13 g, 0.84
mmol), Et.sub.3N (0.09 g, 0.84 mmol), and DMF (5 mL) in a glass
vial. The mixture was stirred under argon at room temperature for
30 minutes. NaCNBH.sub.3 (0.037 g, 0.59 mmol) was added to the
reaction vial and the reaction continued to be stirred at room
temperature under argon. The reaction was monitored by LC/MS and
HPLC and shown to be complete after 1 hour. The reaction was
quenched with MeOH (15 mL) and the solvent was evacuated in vacuo.
The product was isolated by preparative HPLC in 10% yield as a
yellow solid. ESI-MS: m/z (M+H) 559.
[0334] Synthesis of 9-(Benzyl-methyl-amino)-Propynyl)-Minocycline
82
[0335] 7-Iodo-minocycline (1.08 g, 1.86 mmol), taken in 25 mL of
acetonitrile was degassed and purged with nitrogen (three times).
To this suspension Pd(OAc).sub.2 (20 mg, 0.089 mmol), CuI (10 mg,
0.053 mmol), (o-tolyl).sub.3P (56 mg, 0.186 mmol) were added and
purged with nitrogen for few minutes.
Benzyl-methyl-prop-2-ynyl-amine (318 .mu.L, 2 mmol) and
triethylamine (1 mL) were added to the suspension. It turned into a
brown solution after the addition of Et.sub.3N. The reaction
mixture was then heated to 70.degree. C. for 2 hours. The progress
of the reaction was monitored by HPLC/LCMS. It was then cooled down
to room temperature and was filtered through celite. Evaporation of
the solvent gave a brown solid, which was then purified on
preparative HPLC to afford the desired compound. LC-MS (M+1
615).
[0336] Synthesis of
8-(2'-[(2'-Fluoro-ethylamino)-methyl]-phenyl)-Sancycli- ne 83
[0337] Step 1:
[0338] To a stirred solution (cooled at 0.degree. C., ice-bath) of
9-amino-sancycline (7 g, 16.3 mmol) in 200 mL of MeOH, 48%
HBF.sub.4 solution (5.32 mL, 40.75 mmol) was added slowly under an
argon atmosphere. After 5 minutes, n-BuNO2 (2.1 mL, 17.93 mmol) was
added slowly (dropwise). The reaction mixture was then stitrred at
0.degree. C. for 3 hours (monitored by HPLC/LC-MS). NaN.sub.3 (1.06
g, 16.3 mmol) was then added the reaction mixture (all at once).
The reaction mixture was stirred at 0.degree. C. for another 3
hours (monitored by HPLC/LC-MS). The reaction mixture was then
poured slowly into stirring diethyl ether (1 L at ice-bath
temperature). A yellow precipitate was obtained and it was
filtered, washed with ether (20 ml.times.3) and dried under vaccum,
sealed in a vial and stored at 0.degree. C. Isolated yield 7 g.
[0339] Step 2:
[0340] Hydrobromic acid (30% in acetic acid) (14 mL) was added to a
flask and cooled to 0 C. 9-Azido-sancycline (1 g, 2.2 mmol) was
added to the flask and the reaction was left to stir for one hour.
After 1 hour, the reaction was complete. The reaction mixture was
precipitated in 300 mL of diethyl ether. After letting the solution
settle, the top layer of diethyl ether was decanted and the
reaction mixture was dried under vaccum. A brown-black solid was
then dissolved in methanol and precipitated using diethyl ether.
The solid obtained was filtered and dried under vaccum.
[0341] Step 3:
[0342] To a stirred solution (cooled at 0 C, ice-bath) of
8-bromo-9-amino-sancycline (828 mg, 1.6 mmol) in 200 mL of MeOH,
48% HBF.sub.4 solution (0.53 mL, 4.0 mmol) was added slowly under
an argon atmosphere. After 5 minutes, n-BuNO.sub.2 (0.2 mL, 1.79
mmol) was added slowly (dropwise). The reaction mixture was then
stitrred at 0 C for 2 hours and left overnight at room temperature
(monitored by HPLC/LC-MS). The solvent was evaporated and the crude
material obtained was precipitated using diethyl ether (300 mL).
The solid obtained was filtered and dried under vaccum.
[0343] Step 4:
[0344] 8-Bromo-sancycline (492 mg, 1 mmol) and Pd(OAc).sub.2 (22
mg, 0.1 mmol) were taken in methanol (150 mL) and purged with argon
while heating the reaction mixture at 65 C (oil bath temperature).
After 10 minutes, an aqueous solution of sodium carbonate (315 mg,
3 mmol in 10 mL of water) was added. A yellow precipitate was
obtained which was further heated for another 10 minutes, before
adding a DMF solution of the boronic acid(300 mg, 2 mmol in 10 mL
of DMF). The reaction was then heated at 65 C for 3 hours. The
reaction was monitored by HPLC/LCMS. The mixture was cooled down to
room temperature and then filtered through celite. The solvent was
then evaporated and the crude material obtained was precipitated
using methanol/diethyl ether (10/200 mL). The crude material was
then filtered and dried under vacuum. The yellow-brown material
obtained was used as such without further purification.
[0345] Step 5:
[0346] To a solution of 8-(2-formyl-phenyl)-sancycline (518 mg, 1
mmol) in 30 mL of DCE under an argon atmosphere,
2-fluoro-ethylamine hydrochloride (198 mg, 2 mmol) and
triethylamine (202 .mu.L, 2 mmol) were added. The reaction mixture
was then stirred at room temperature for 2 hours. The reaction was
monitored by using HPLC/LCMS, and was completed in 2 hours. The
solvent was then evaporated and the crude material was purified
using preparative HPLC to afford the desired compound. LC-MS (M+1
566).
[0347] 7-Pyrazolyl-Sancycline 84
[0348] To a stirred solution of 7-Iodo sancycline (100 mg, 0.153
mmol) in DMF (1 mL) was added pyrozole-4-boronic acid pinacole
cyclic ester (77 mg, 0.40 mmol), methanol (1.5 mL),
tetrakis(triphenylphosphine)palladium (18 mg, 0.015 mmol) and a
solution containing 250 mg CsCO.sub.3 in 0.7 mL water. The reaction
mixture was then subject to microwave irradiation at a temperature
of 100 C for 5 minutes. The reaction was then diluted with 100 mL
of water and TFA was used to lower the pH to 2. This solution was
then filtered through celite, and loaded onto a plug of divinyl
benzene resin (DVB). The plug containing the product was washed
with water (200 mL) before the final compound was eluted with MeCN
and reduced by rotary evaporation. The crude material was purified
by reverse phase HPLC to give the final product (64 mg, 0.12 mmol,
75% yield) LCMS m/z=481.2115 (M+H).
[0349] Synthesis of
9-[(2,2,2-Trifluoro-ethyl)-hydrazonomethyl]-Minocyclin- e 85
[0350] To a solution of 9-formyl minocycline (485 mg, 1 mmol) in 30
mL of DMF under an argon atmosphere, indium trichloride (22 mg, 0.1
mmol) and trifluoroethylhydrazine (228 .mu.L, 2 mmol) were added.
The reaction mixture was then stirred at room temperature for 30
minutes. The reaction was monitored by using HPLC/LCMS, and was
completed in 30 minutes. The solvent was then evaporated and the
crude material was purified using preparative HPLC to afford the
desired compound. LC-MS (M+1 582).
[0351] Synthesis of 9-(1'-Isopropyl-4'-piperidinyl)amino Sancycline
86
[0352] To a solution of 9-amino sancycline HCl salt (0.5 g, 1 mmol)
in 40 ml of methanol and was added 1-isopropyl-4-piperidone (0.14
g, 2 mmol). The solution was stirred for 5 minutes at room
temperature. Sodium cyanoborohydride (62.5 mg, 1 mmol) was
introduced, followed by the addition of 4 ml of AcOH. The mixture
was stirred at room temperature for 1 hour until all starting
material disappeared. The suspension was filtered and purified by
HPLC to afford the title compound (210 mg). LC-MS (M+1 555).
[0353] Synthesis of 9-(3-t-butyl-N-imidazolyl)-methyl)-Minocycline
87
[0354] To a stirred solution of 9-aminomethyl-minocycline (2.50 g,
4.14 mmol) in DMF (25 mL) and MeOH (15 mL) was added
1-bromopinacolone (1.34 mL, 1.01 g, 5.63 mmol) and Cs.sub.2CO.sub.3
(5.0 mL of a 1N aqueous solution, 5.0 mmol). The reaction was
heated to 100.degree. C. for 15 minutes in a pressure vesicle using
microwave irradiation. The contents were then diluted with water
(1.0 L) and Na.sub.2CO.sub.3 was used to adjust the pH to 6. This
solution was then filtered through celite and loaded onto a plug of
divinyl benzene resin. The product was washed with water (500 mL)
before it was eluted with MeCN and reduced by rotary evaporation.
The crude material was purified by reverse phase HPLC to give the
tert-butyl-ketone intermediate (680 mg, 1.90 mmol, 50% yield). To a
stirred solution of the tert-butyl-ketone intermediate (68 mg,
0.190 mmol) in formamide (1.0 mL) was added triethyl-amine (0.020
mL, 28 mg, 0.27 mmol) to adjust the pH to 8. The reaction was
heated to 100.degree. C. for 5 minutes in a pressure vesicle using
microwave irradiation. The contents were then diluted with water
(100 mL) and TFA was used to adjust the pH to 2. This solution was
then filtered through celite, and loaded onto a plug of divinyl
benzene resin. The product was washed with water (200 mL) before it
was eluted with MeCN and reduced by rotary evaporation. The crude
material was purified by reverse phase HPLC to give the final
compound (6.0 mg, 10 .mu.mol, 4% yield) LCMS m/z=594.4863
(M+H).
[0355] Synthesis of 9-(2-thiol 5-methyl-N-imidazolyl)-methyl
Minocycline 88
[0356] To a stirred solution of 9-aminomethyl-minocycline (2.00 g,
4.12 mmol) in DMF (12 mL), MeOH (6.0 mL) and acetic acid (3.0 mL)
was added KSCN (0.400 g, 4.12 mmol) and Acetol 0.400 mL, 0.370 g,
5.00 mmol). The reaction was heated to 100.degree. C. for 15
minutes in a pressure vesicle using microwave irradiation. The
contents were then diluted with water (1.0 L) and Na.sub.2CO.sub.3
was used to adjust the pH to 6. This solution was then filtered
through celite and loaded onto a plug of divinyl benzene resin. The
product was washed with water (500 mL) before it was eluted with
MeCN and reduced by rotary evaporation. The crude material was
purified by reverse phase HPLC to give the final product (620 mg,
1.06 mmol, 26% yield) LCMS m/z=584.3998 (M+H).
[0357] Synthesis of 7-(2',2'-dimethyl-propyl)amino Methyl
Sancycline 89
[0358] 1 g of 7-aminomethyl-sancycline, 3 equivalents of
trimethylacetaldehyde and one equivalent of indium trichloride were
dissolved in 10 ml of DMF. The mixture was stirred at room
temperature for 15 minutes. To this mixture was added 3 equivalents
of sodium triacetoxyborohydride. The resulting reaction mixture was
left stirring for several hours. The reaction was monitored by
analytical HPLC. The LCMS showed MS: 514 which corresponds to the
desired material. The product was isolated via preparative HPLC and
the structure was confirmed by NMR.
[0359] Synthesis of 9-(Benzoimidazolyl)-Minocycline 90
[0360] To a stirred solution of the trifluoroacetic acid (TFA) salt
of 9-formyl minocycline (488 mg, 1.47 mmol) in DMF (3 mL) and MeOH
(2 mL) was added 1,2-phenylenediamine (80 mg, 0.74 mmol). The
reaction was heated to 50 C and was complete in 5 minutes. The
contents were then diluted with water (500 mL) and TFA was used to
adjust the pH to 2. This solution was then filtered through celite,
and loaded onto a plug of divinyl benzene resin. The plug
containing the product was washed with water (300 mL) before it was
eluted with MeCN and reduced by rotary evaporation. The crude
material was purified by reverse phase HPLC to give the
Benzoimidazol product (100 mg, 0.175 mmol, 10% yield) LCMS
m/z=574.3637 (M+H).
Example 2
In vitro Minimum Inhibitory Concentration (MIC) Assay
[0361] The following assay is used to determine the efficacy of the
tetracycline 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
tetracycline 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:
2 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
[0362] 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
tetracycline compound that inhibits growth.
[0363] Equivalents
[0364] 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.
* * * * *