U.S. patent application number 13/918197 was filed with the patent office on 2014-06-05 for substituted tetracycline compounds.
The applicant listed for this patent is Paul Abato, Haregewein Assefa, Joel Berniac, Beena Bhatia, Todd Bowser, Jackson Chen, Mark Grier, Laura Honeyman, Mohamed Y. Ismail, Mark L. Nelson, Kwasi Ohemeng, Jingwen Pan. Invention is credited to Paul Abato, Haregewein Assefa, Joel Berniac, Beena Bhatia, Todd Bowser, Jackson Chen, Mark Grier, Laura Honeyman, Mohamed Y. Ismail, Mark L. Nelson, Kwasi Ohemeng, Jingwen Pan.
Application Number | 20140155357 13/918197 |
Document ID | / |
Family ID | 35842579 |
Filed Date | 2014-06-05 |
United States Patent
Application |
20140155357 |
Kind Code |
A1 |
Abato; Paul ; et
al. |
June 5, 2014 |
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: |
Abato; Paul; (Providence,
RI) ; Assefa; Haregewein; (Braintree, MA) ;
Berniac; Joel; (Stoneham, MA) ; Bhatia; Beena;
(Mansfield, MA) ; Bowser; Todd; (Charlton, MA)
; Chen; Jackson; (East Amherst, NY) ; Grier;
Mark; (Medford, MA) ; Honeyman; Laura;
(Roslindale, MA) ; Ismail; Mohamed Y.; (Bedford,
MA) ; Nelson; Mark L.; (Norfolk, MA) ;
Ohemeng; Kwasi; (Sakumono, GH) ; Pan; Jingwen;
(North Grafton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abato; Paul
Assefa; Haregewein
Berniac; Joel
Bhatia; Beena
Bowser; Todd
Chen; Jackson
Grier; Mark
Honeyman; Laura
Ismail; Mohamed Y.
Nelson; Mark L.
Ohemeng; Kwasi
Pan; Jingwen |
Providence
Braintree
Stoneham
Mansfield
Charlton
East Amherst
Medford
Roslindale
Bedford
Norfolk
Sakumono
North Grafton |
RI
MA
MA
MA
MA
NY
MA
MA
MA
MA
MA |
US
US
US
US
US
US
US
US
US
US
GH
US |
|
|
Family ID: |
35842579 |
Appl. No.: |
13/918197 |
Filed: |
June 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11258622 |
Oct 25, 2005 |
8466132 |
|
|
13918197 |
|
|
|
|
60622027 |
Oct 25, 2004 |
|
|
|
60622749 |
Oct 27, 2004 |
|
|
|
Current U.S.
Class: |
514/152 ;
546/121; 546/246; 546/285; 548/204; 548/377.1; 548/529; 549/494;
564/165 |
Current CPC
Class: |
A61P 33/06 20180101;
C07D 207/337 20130101; C07D 333/20 20130101; C07D 333/38 20130101;
C07D 405/06 20130101; A61P 9/12 20180101; A61P 13/00 20180101; A61P
19/02 20180101; C07D 405/12 20130101; C07D 413/12 20130101; A61P
31/04 20180101; C07C 259/10 20130101; C07C 271/24 20130101; A61P
25/06 20180101; A61P 25/14 20180101; C07D 295/192 20130101; A61P
43/00 20180101; C07D 213/84 20130101; C07D 239/42 20130101; C07D
263/32 20130101; C07D 295/155 20130101; C07D 487/04 20130101; C07C
2603/46 20170501; A61P 1/16 20180101; A61P 33/00 20180101; A61P
25/08 20180101; A61P 29/00 20180101; C07D 213/73 20130101; C07D
307/46 20130101; A61P 1/10 20180101; C07D 233/64 20130101; C07D
239/26 20130101; C07D 307/54 20130101; C07D 213/61 20130101; A61P
9/10 20180101; A61P 21/04 20180101; A61P 31/12 20180101; C07D
307/52 20130101; C07D 403/06 20130101; C07C 271/18 20130101; C07D
261/08 20130101; C07D 333/24 20130101; C07C 251/48 20130101; C07D
471/04 20130101; A61P 19/10 20180101; A61P 25/20 20180101; A61P
27/16 20180101; C07D 241/12 20130101; C07D 295/096 20130101; C07D
213/38 20130101; A61P 3/10 20180101; A61P 17/00 20180101; C07D
231/12 20130101; C07D 213/74 20130101; C07C 255/59 20130101; C07D
207/335 20130101; A61P 25/24 20180101; A61P 35/00 20180101; C07C
271/22 20130101; C07D 309/14 20130101; C07D 277/30 20130101; A61P
9/00 20180101; A61P 25/00 20180101; A61P 25/16 20180101; A61P 25/22
20180101; A61P 25/28 20180101; C07D 213/30 20130101; C07D 277/28
20130101; C07C 237/26 20130101; C07C 2601/02 20170501; C07D 211/70
20130101 |
Class at
Publication: |
514/152 ;
546/285; 546/121; 564/165; 549/494; 548/529; 546/246; 548/377.1;
548/204 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07C 237/26 20060101 C07C237/26; C07D 277/30 20060101
C07D277/30; C07D 207/337 20060101 C07D207/337; C07D 213/73 20060101
C07D213/73; C07D 231/12 20060101 C07D231/12; C07D 211/70 20060101
C07D211/70; C07D 307/54 20060101 C07D307/54 |
Claims
1-33. (canceled)
34. A tetracycline compound of Formula (III): ##STR00211## wherein
R.sup.9 is R'--O--N.dbd.CR''--, R'--OC(.dbd.O)--,
R.sup.9aR.sup.9bNC(.dbd.O)--, methoxycarbonyl substituted alkynyl,
pyrazinyl, alkylaminocarbonylalkyl, methoxymethyl, methoxymethyl
substituted alkynyl, dimethylaminocarbonyl, cyclopropyl, methyl,
amino substituted pyridinyl, alkoxyalkyl, alkylcarbonyl,
arylcarbonyl, pyrimidinyl, alkoxycarbonyl substituted alkynyl,
oxazolyl, pyrazolyl, carboxylate, halogen, piperidinylcarbonyl,
alkyoxyalkyl substituted alkynyl, pyridinyl, thiazolyl, substituted
or unsubstituted arylthiocarbonyl, cyano, deuterated
alkylaminoalkyl, pyrrolidonylcarbonyl, carboxylatecarbonyl,
alkylcarbonyl substituted phenyl, cyano substituted pyridinyl,
aminocarbonyl substituted phenyl, dialkylaminomethyl, substituted
or unsubstituted thiophenyl, substituted or unsubstituted furanyl,
alkylcarbonylamino substituted pyridinyl, dialkylamino substituted
phenyl, carboxylate substituted phenyl, azepanylcarbonyl, or
piperazinylcarbonyl; R.sup.10 is hydrogen or alkenyl; R' is
unsubstituted alkyl, amino substituted alkyl, methoxy substituted
alkyl, halogen substituted alkyl; R'' is alkyl; R.sup.9a is
hydrogen or alkyl; R.sup.9b is alkyl, hydroxyl, alkoxy,
hydroxyalkyl, alkoxyalkyl, alkylcarbonylaminoalkyl,
alkoxycarbonylalkyl, hydroxyalkyl, aryl, cycloalkyl or aminoalkyl;
and pharmaceutically acceptable salts, esters and prodrugs thereof,
provided that when R.sup.9 is halogen, then R.sup.10 is
alkenyl.
35-65. (canceled)
66. The compound of claim 34, wherein R.sup.9 is methoxycarbonyl
substituted alkynyl, pyrazinyl, methoxymethyl, cyclopropyl, methyl,
methoxymethyl substituted alkynyl, amino substituted pyridinyl,
alkylcarbonyl, arylcarbonyl, pyrimidinyl, oxazolyl, pyrazolyl,
carboxylate, pyridinyl, thiazolyl, substituted or unsubstituted
thiophenyl, piperidinylcarbonyl, dialkylaminomethyl, cyano,
substituted or unsubstituted arylthiocarbonyl, deuterated
alkylaminoalkyl, substituted furanyl, isoxolazolyl, cyano
substituted pyridinyl, alkylcarbonylamino substituted pyridinyl,
dialkylamino substituted phenyl, pyrrolidonylcarbonyl,
azepanylcarbonyl, carboxylatecarbonyl, alkylcarbonyl substituted
phenyl, aminocarbonyl substituted phenyl, carboxylate substituted
phenyl or piperazinylcarbonyl.
67-78. (canceled)
79. The tetracycline compound of claim 34, wherein said compound
is: ##STR00212## ##STR00213## ##STR00214## ##STR00215##
##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220##
##STR00221## ##STR00222## ##STR00223##
80-258. (canceled)
259. A method for treating a tetracycline responsive state in a
subject, comprising administering to said subject an effective
amount of a tetracycline compound of claim 34, such that said
subject is treated.
260. The method of claim 259, wherein said tetracycline responsive
state is malaria.
261. The method of claim 259, wherein said tetracycline responsive
state is a bacterial infection, a viral infection, or a parasitic
infection.
262-265. (canceled)
266. The method of claim 259, wherein said tetracycline associated
state is multiple sclerosis.
267. The method of claim 259, wherein said subject is a human.
268. The method of claim 259, wherein said tetracycline compound is
administered with a pharmaceutically acceptable carrier.
269. A pharmaceutical composition comprising a therapeutically
effective amount of a tetracycline compound of claim 34 and a
pharmaceutically acceptable carrier.
270. The tetracycline compound of claim 79, wherein said compound
is: ##STR00224##
271. The method of claim 259, wherein the tetracycline compound is:
##STR00225##
272. The pharmaceutical composition of claim 269, wherein the
tetracycline compound is: ##STR00226##
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 60/622,027, filed on Oct. 25, 2004, and U.S.
Provisional Patent Application No. 60/622,749, filed on Oct. 27,
2004, the entire contents of each of which are 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
compound 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, at least in part,
to substituted tetracycline compounds of Formula (I)
##STR00001##
wherein [0006] R.sup.9 is substituted or unsubstituted
aminocarbonylalkyl, aminoalkylcarbonylaminoalkyl, carboxylate,
arylalkylaminoalkyl, alkylcarbonylaminoalkyl, dialkylaminoalkyl,
N-piperazinyl alkyl substituted phenyl, alkoxy substituted phenyl,
substituted furanyl, alkylaminocarbonyl and pharmaceutically
acceptable salts, esters, and prodrugs thereof.
[0007] In another embodiment, the invention pertains, at least in
part, to substituted tetracycline compounds of Formula (II):
##STR00002##
wherein [0008] R.sup.7 is dimethylamino, substituted phenyl,
substituted pyridinyl, alkoxycarbonylalkylaminocarbonyl,
pyridinylalkylaminoalkyl, pyridinylalkylaminocarbonyl, substituted
or unsubstituted arylaminoalkylcarbonyl, substituted or
unsubstituted tetrahydropyridinyl, cycloalkylaminoalkylcarbonyl,
alkylaminoalkylcarbonyl, heteroarylaminoalkylcarbonyl,
alkoxylcarbonyl substituted alkylaminoalkylcarbonyl or
arylaminoalkylcarbonyl; [0009] R.sup.9 is ethyl, aminomethyl,
dialkylaminocarbonylalkyl, hydrogen, alkoxy substituted alkynyl,
carboxylate substituted alkynyl, alkoxycarbonyl substituted
alkynyl, dialkylamino substituted phenyl, cyano, acyl, substituted
carboxylate aminomethyl, alkylaminocarbonyl, and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0010] In yet another embodiment, the invention pertains, at least
in part, to substituted tetracycline compounds of Formula
(III):
##STR00003##
wherein [0011] R.sup.9 is R'--O--N.dbd.CR''--, R'--OC(.dbd.O)--,
R.sup.9aR.sup.9bNC(.dbd.O)--, methoxycarbonyl substituted alkynyl,
pyrazinyl, alkylaminocarbonyl alkyl, methoxymethyl, methoxymethyl
substituted alkynyl, dimethylaminocarbonyl, cyclopropyl, methyl,
amino substituted pyridinyl, alkoxyalkyl, alkylcarbonyl,
arylcarbonyl, pyrimidinyl, alkoxycarbonyl substituted alkynyl,
oxazolyl, pyrazolyl, carboxylate, halogen, piperidinylcarbonyl,
alkyoxyalkyl substituted alkynyl, pyridinyl, thiazolyl, substituted
or unsubstituted arylthiocarbonyl, cyano, deuterated
alkylaminoalkyl, pyrrolidonylcarbonyl, carboxylatecarbonyl,
alkylcarbonyl substituted phenyl, cyano substituted pyridinyl,
aminocarbonyl substituted phenyl, dialkylaminomethyl, substituted
or unsubstituted thiophenyl, substituted or unsubstituted furanyl,
alkylcarbonylamino substituted pyridinyl, dialkylamino substituted
phenyl, carboxylate substituted phenyl, azepanylcarbonyl, or
piperazinylcarbonyl; [0012] R.sup.10 is hydrogen or alkenyl; [0013]
R' is unsubstituted alkyl, amino substituted alkyl, methoxy
substituted alkyl, halogen substituted alkyl; [0014] R'' is alkyl;
[0015] R.sup.9a is hydrogen or alkyl; [0016] R.sup.9b is alkyl,
hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl,
alkylcarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl,
cycloalkyl or aminoalkyl; and pharmaceutically acceptable salts,
esters and prodrugs thereof, provided that when R.sup.9 is halogen,
then IV.degree. is alkenyl.
[0017] In yet another embodiment, the invention also pertains, at
least in part, to tetracycline compounds of Formula (IV):
##STR00004##
wherein [0018] R.sup.a is methoxy, dialkylaminomethyl, substituted
N-piperdinyl methyl, fluorine, or hydrogen; [0019] R.sup.7b is
hydrogen; [0020] R.sup.7c is alkoxyalkylaminoalkyl, halogenated
N-piperdinyl methyl, hydroxyl, dialkylaminoalkylamino,
dialkylaminomethyl, substituted N-piperidinyl methyl, substituted
N-pyrrolyl methyl, or hydrogen; [0021] R.sup.7d is
arylalkylaminoalkyl, arylalkyl substituted alkylaminoalkyl,
substituted N-piperidinylmethyl, N-piperidinyl substituted
aminomethyl, cyclopropylamino methyl, piperdinyl substituted alkyl,
dialkylaminomethyl, heteroaryl substituted dialkylaminomethyl,
alkylaminomethyl, cycloalkylaminomethyl, alkylaminoethyl, cyano
substituted dialkylaminomethyl, N-pyrrolidinyl substituted methyl,
N-pyrrolyl substituted methyl, methoxy substituted
dialkylaminomethyl, alkoxyalkylaminomethyl, substituted carboxylate
alkylaminomethyl, hydrogen or linked with R.sup.7c by a
--O--CH.sub.2--O-- linker; [0022] R.sup.7e is hydrogen, and
pharmaceutically acceptable salts, esters and prodrugs thereof,
provided that each of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e are not hydrogen.
[0023] In another further embodiment, the invention pertains, at
least in part, to tetracycline compound of Formula (V):
##STR00005##
wherein [0024] T is NH or O; [0025] R.sup.7f is dialkylaminoalkyl,
N-piperidinylamino alkyl, substituted or unsubstituted
N-piperdinylalkyl, N-pyrrolidinylamino alkyl, substituted or
unsubstituted N-pyrrolidinylalkyl, substituted or unsubstituted
N-pyrrolylalkyl, alkenenyl substituted dialkylaminoalkyl,
N-decahydroisoquinolinylalkyl, alkoxyalkylaminoalkyl, or hydrogen;
[0026] R.sup.7g is hydrogen; [0027] R.sup.7h is heteroaryl
substituted alkylaminoalkyl, dialkylaminoalkyl, substituted
N-piperidinylalkyl or hydrogen, and pharmaceutically acceptable
salts, esters and prodrugs thereof, provided that each of R.sup.7f,
R.sup.7g, and R.sup.7h are not hydrogen.
[0028] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of Formula (VI):
##STR00006##
wherein [0029] R.sup.7i is fluorine or hydrogen; [0030] R.sup.7j is
trifluoromethyl, alkyloxycarbonyl, methyl, cyano, or hydrogen, and
pharmaceutically acceptable salts, esters and prodrugs thereof,
provided that both of R.sup.7i and R.sup.7j are not hydrogen.
[0031] In yet another embodiment, the invention also pertains, at
least in part, to tetracycline compounds of Formula (VII):
##STR00007##
wherein [0032] p is a single or double bond; [0033] R.sup.7k is
alkyl, cycloalkyl, dialkylaminoalkylcarbonyl, alkoxyalkylcarbonyl,
halogen substituted alkyl, halogen substituted cycloalkyl, or
hydrogen, and pharmaceutically acceptable salts, esters and
prodrugs thereof.
[0034] In yet another embodiment, the invention also pertains, at
least in part, to tetracycline compounds of Formula (VIII):
##STR00008##
wherein [0035] R.sup.7 is fluoro substituted N-pyrrolidinylalkyl,
N-piperidinylalkylcarbonyl, dialkylaminoalkylaminocarbonyl,
aminoalkyl, N-pyrroyl alkyl, dialkylamino substituted pyridinyl,
phenyl substituted N-piperizinyl alkyl, alkylaminoalkyl, alkoxy
substituted pyrimidinyl, 1-H-pyrimidin-2-onyl, cyano substituted
pyridinyl, N-pyrrolidinyl alkyl, halogen substituted pyridinyl,
arylalkylamino alkyl, alkoxyalkylaminoalkyl,
N-imidizolylalkylcarbonyl, N-dihydroimidizolylalkylcarbonyl,
imidizopyrimidinyl, imidizopyridinyl, or pyrizinyl substituted
amino alkyl; and pharmaceutically acceptable salts, esters and
prodrugs thereof.
[0036] In yet another embodiment, the invention also pertains, at
least in part, to tetracycline compounds of Formula (IX):
##STR00009##
wherein [0037] R.sup.7 is dialkylaminomethyl, alkoxy substituted
phenyl, hydroxy, halogen substituted phenyl, halogenated alkyl
substituted phenyl, naphthyl; [0038] R.sup.9c is hydrogen,
fluorinated alkyl or unsubstituted alkyl and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0039] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of the Formula (X):
##STR00010##
wherein [0040] R.sup.1 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl,
arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl,
alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy,
thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, or
halogen, optionally linked to R.sup.2 to form a ring; [0041]
R.sup.2 is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl,
hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino,
alkylamino, heterocyclic, or absent, optionally linked to R.sup.1
to form a ring; [0042] R.sup.2', R.sup.2'', R.sup.4a, and R.sup.4b
are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0043]
R.sup.10 is hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug
moiety; [0044] R.sup.11b is hydroxyl, alkoxy, aryloxy, or
alkylamino; [0045] R.sup.4 and R.sup.4' are each independently
NR.sup.4aR.sup.4b, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or
hydrogen; [0046] R.sup.5 and R.sup.5' are each independently
hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl,
heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkylcarbonyloxy, or arylcarbonyloxy; [0047] 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; [0048]
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.7n).sub.0-1C(.dbd.W')WR.sup.7l; [0049]
R.sup.8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.8c).sub.0-1CC(=E')ER.sup.8a; [0050]
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.0-3(NR.sup.9f).sub.0-1CC(.dbd.Z')ZR.sup.9d; [0051]
R.sup.7l, R.sup.7m, R.sup.7n, R.sup.7o, R.sup.7p, R.sup.7q,
R.sup.8a, R.sup.8b, R.sup.8c, R.sup.8d, R.sup.8e, R.sup.8f,
R.sup.9d, R.sup.9e, R.sup.9f, R.sup.9g, R.sup.9h, and R.sup.9i are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0052]
R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0053] E is CR.sup.8dR.sup.8e, S, NR.sup.8b or O; [0054]
E' is O, NR.sup.8f, or S; [0055] Q is a double bond when R.sup.2 is
absent, Q is a single bond when R.sup.2 is hydrogen, alkyl,
halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, formyl,
alkoxy, amino, alkylamino, cyano, nitro, or heterocyclic; [0056] W
is CR.sup.7oR.sup.7p, S, NR.sup.7m or O; [0057] W' is O, NR.sup.7q,
or S; [0058] X is CHC(R.sup.13Y'Y), C.dbd.CR.sup.13Y,
CR.sup.6'R.sup.6, S, NR.sup.6, or O; [0059] Y' and Y are each
independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl,
amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl; [0060] Z is
CR.sup.9gR.sup.9h, S, NR.sup.9e or O; [0061] Z' is O, S, or
NR.sup.9i, and pharmaceutically acceptable salts, esters and
enantiomers thereof.
[0062] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of the Formula (XI):
##STR00011##
wherein [0063] R.sup.7r is substituted or unsubstituted
N-piperidinylalkyl, dialkylaminoalkyl and pharmaceutically
acceptable salts, esters and enantiomers thereof. [0064] In yet
another embodiment, the invention pertains, at least in part, to
tetracycline compounds of the Formula (XII):
##STR00012##
[0064] wherein [0065] W is N or CH; and [0066] R.sup.7s is
substituted or unsubstituted alkyl, aryl, alkoxycarbonyl,
alkylcarbonyl, cycloalkyl, or aminocarbonyl; and pharmaceutically
acceptable salts, esters and enantiomers thereof.
[0067] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of Formula (XIII):
##STR00013##
wherein [0068] n is 0, 1 or 2; [0069] R.sup.7t' is hydrogen, alkyl,
alkenyl or cycloalkyl;
[0070] R.sup.7t'' is unsubstituted alkyl, dialkylaminoalkyl,
halogenated alkyl, alkoxyalkyl, substituted or unsubstituted
arylalkyl, cycloalkyl, alkenylalkyl, heterocyclic, cyano
substituted alkyl, alkoxy substituted alkyl, heteroarylalkyl,
aminocarbonylalkyl, aryl, hydrogen, alkylcarbonyl, aminoalkyl or
alkoxycarbonyl; and pharmaceutically acceptable salts, esters and
enantiomers thereof.
[0071] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of Formula (XIV):
##STR00014##
wherein [0072] R.sup.7u is substituted or unsubstituted
N-piperidinylalkyl, dialkylaminoalkyl, alkoxyaminoalkyl,
alkylaminoalkyl or dipiperidinium methyl; and pharmaceutically
acceptable salts, esters and enantiomers thereof.
[0073] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of formula (XV):
##STR00015##
wherein [0074] R.sup.7v is heterocyclic; and pharmaceutically
acceptable salts, esters and enantiomers thereof.
[0075] In yet another embodiment, the invention pertains, at least
in part, to tetracycline compounds of formula (XVI):
##STR00016##
wherein: [0076] R.sup.2', R.sup.2'', R.sup.4a, and R.sup.4b are
each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0077]
R.sup.10, R.sup.11 and R.sup.12 are each independently hydrogen,
alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; [0078]
R.sup.3' is hydroxyl, hydrogen, or a pro-drug moiety; [0079]
R.sup.4 is NR.sup.4aR.sup.4b, alkyl, alkenyl, alkynyl, hydroxyl,
halogen, or hydrogen; [0080] R.sup.5 and R.sup.5' are each
independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl,
aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkylcarbonyloxy, or arylcarbonyloxy; [0081] 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; [0082]
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; [0083]
R.sup.8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.8c).sub.0-1(=E')ER.sup.8a; [0084]
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.0-3(NR.sup.9c).sub.0-1C(.dbd.Z')ZR.sup.9a; [0085]
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.8a, R.sup.8b, R.sup.8c, R.sup.8d, R.sup.8e, R.sup.8f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, and R.sup.9f are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0086]
R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0087] E is CR.sup.8dR.sup.8e, S, NR.sup.8b or O; [0088]
E' is O, NR.sup.8f, or S; [0089] W is CR.sup.7dR.sup.7e, S,
NR.sup.7b or O; [0090] W' is O, NR.sup.7f, or S; [0091] X is
CHC(R.sup.13Y'Y), C.dbd.CR.sup.13Y, CR.sup.6'R.sup.6, S, NR.sup.6,
or O; [0092] Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0093] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O; [0094]
Z' is O, S, or NR.sup.9f, and pharmaceutically acceptable salts,
esters and enantiomers thereof.
[0095] In yet another embodiment, the invention pertains, at least
in part, to tetracycline compounds of formula (XVII):
##STR00017##
wherein: [0096] R.sup.2a is alkyl or aryl; [0097] R.sup.4a and
R.sup.4b are each independently hydrogen, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
[0098] R.sup.10, R.sup.11 and R.sup.12 are each independently
hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety;
[0099] R.sup.3' is hydroxyl, hydrogen, or a pro-drug moiety; [0100]
R.sup.4 is NR.sup.4aR.sup.4b, alkyl, alkenyl, alkynyl, hydroxyl,
halogen, or hydrogen; [0101] R.sup.5 and R.sup.5' are each
independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl,
aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
alkylcarbonyloxy, or arylcarbonyloxy; [0102] 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; [0103]
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; [0104]
R.sup.8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.8c).sub.0-1C(=E')ER.sup.8a; [0105]
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.0-3(NR.sup.9c).sub.0-1C(.dbd.Z')ZR.sup.9a; [0106]
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.8a, R.sup.8b, R.sup.8c, R.sup.8d, R.sup.8e, R.sup.8f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, and R.sup.9f are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0107]
R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0108] E is CR.sup.8dR.sup.8e, S, NR.sup.8b or O; [0109]
E' is O, NR.sup.8f, or S; [0110] W is CR.sup.7dR.sup.7e, S,
NR.sup.7b or O; [0111] W' is O, NR.sup.7f, or S; [0112] X is
CHC(R.sup.13Y'Y), C.dbd.CR.sup.13Y, CR.sup.6'R.sup.6, S, NR.sup.6,
or O; [0113] Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0114] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O; [0115]
Z' is O, S, or NR.sup.9f, and pharmaceutically acceptable salts,
esters and enantiomers thereof.
[0116] 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, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV,
XVI or XVII or a tetracycline compound otherwise described
herein.
[0117] In another further embodiment, the invention pertains, at
least in part, to pharmaceutical compositions which comprise an
effective amount of a tetracycline compound of the invention, e.g.,
a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, XIII, XIV, XV, XVI or XVII or a tetracycline compound
otherwise described herein, and a pharmaceutically acceptable
carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0118] 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.
[0119] 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.
TABLE-US-00001 TABLE 1 ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026##
[0120] Other tetracycline compounds which may be modified using the
methods of the invention include, but are not limited to,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline;
tetracyclino-pyrazole; 7-chloro-4-dedimethylaminotetracycline;
4-hydroxy-4-dedimethylaminotetracycline;
12.alpha.-deoxy-4-dedimethylaminotetracycline;
5-hydroxy-6.alpha.-deoxy-4-dedimethylaminotetracycline;
4-dedimethylamino-12.alpha.-deoxyanhydrotetracycline;
7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline;
tetracyclinonitrile; 4-oxo-4-dedimethylaminotetracycline
4,6-hemiketal; 4-oxo-11a
Cl-4-dedimethylaminotetracycline-4,6-hemiketal;
5a,6-anhydro-4-hydrazon-4-dedimethylamino tetracycline;
4-hydroxyimino-4-dedimethylamino tetracyclines;
4-hydroxyimino-4-dedimethylamino 5a,6-anhydrotetracyclines;
4-amino-4-dedimethylamino-5a, 6 anhydrotetracycline;
4-methylamino-4-dedimethylamino tetracycline;
4-hydrazono-11a-chloro-6-deoxy-6-demethyl-6-methylene-4-dedimethylamino
tetracycline; tetracycline quaternary ammonium compounds;
anhydrotetracycline betaines; 4-hydroxy-6-methyl pretetramides;
4-keto tetracyclines; 5-keto tetracyclines; 5a, 11a dehydro
tetracyclines; 11a Cl-6,12 hemiketal tetracyclines; 11a
Cl-6-methylene tetracyclines; 6,13 diol tetracyclines;
6-benzylthiomethylene tetracyclines;
7,11a-dichloro-6-fluoro-methyl-6-deoxy tetracyclines; 6-fluoro
(a)-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-12.alpha.-deoxy-7-chloroanhydrotetracyclines;
B-nortetracyclines; 7-methoxy-6-demethyl-6-deoxytetracyclines;
6-demethyl-6-deoxy-5a-epitetracyclines;
8-hydroxy-6-demethyl-6-deoxy tetracyclines; monardene;
chromocycline; 5a methyl-6-demethyl-6-deoxy tetracyclines; 6-oxa
tetracyclines, and 6 thia tetracyclines.
[0121] In one embodiment, the invention pertains, at least in part,
to substituted tetracycline compounds of Formula (I):
##STR00027##
wherein [0122] R.sup.9 is substituted or unsubstituted
aminocarbonylalkyl, aminoalkylcarbonylaminoalkyl, carboxylate,
arylalkylaminoalkyl, alkylcarbonylaminoalkyl, dialkylaminoalkyl,
N-piperazinyl alkyl substituted phenyl, alkoxy substituted phenyl,
substituted furanyl, alkylaminocarbonyl and pharmaceutically
acceptable salts, esters, and prodrugs thereof.
[0123] In one embodiment, R.sup.9 is substituted aminocarbonylalkyl
(e.g., t-butyl substituted aminoalkylcarbonyl). In another
embodiment, R.sup.9 is dialkylaminoalkyl, such as
dimethylaminoalkyl. In yet another embodiment R.sup.9 is
arylalkylaminoalkyl, such as phenylalkylaminoalkyl. In another
embodiment, R.sup.9 is alkoxy substituted phenyl which is further
substituted by a pyrrolidinyl alkyl moiety. In yet another
embodiment, R.sup.9 is substituted furanyl, such as carbonyl
substituted furanyl, dialkylaminoalkyl (e.g., dimethylaminoalkyl)
substituted furanyl and pyrrolidinylalkyl substituted furanyl.
[0124] Examples of substituted tetracycline compounds of Formula
(I) include:
##STR00028## ##STR00029##
[0125] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of Formula (II):
##STR00030##
wherein [0126] R.sup.7 is dimethylamino, substituted phenyl,
substituted pyridinyl, alkoxycarbonylalkylamino carbonyl,
pyridinylalkylaminoalkyl, pyridinylalkylamino carbonyl, substituted
or unsubstituted arylaminoalkylcarbonyl, substituted or
unsubstituted tetrahydropyridinyl, cycloalkylaminoalkylcarbonyl,
alkylaminoalkylcarbonyl, heteroarylaminoalkylcarbonyl,
alkoxylcarbonyl substituted alkylaminoalkylcarbonyl or
arylaminoalkylcarbonyl; [0127] R.sup.9 is ethyl, aminomethyl,
dialkylaminocarbonylalkyl, hydrogen, alkoxy substituted alkynyl,
carboxylate substituted alkynyl, alkoxycarbonyl substituted
alkynyl, dialkylamino substituted phenyl, cyano, acyl, substituted
carboxylate aminomethyl, alkylaminocarbonyl, and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0128] In one embodiment, R.sup.7 is dimethylamino. In another
embodiment, R.sup.9 is ethyl, dialkylaminocarbonylalkyl (e.g.,
dimethylaminocarbonylalkyl) alkyoxysubstituted alkynyl (e.g.,
methoxysubstituted alkynyl), carboxylate substituted alkynyl,
alkoxycarbonyl substituted alkynyl (e.g methoxycarbonyl substituted
alkynyl), dialkylamino substituted phenyl (e.g. dimethylamino
substituted phenyl), cyano, acyl, substituted carboxylate
aminomethyl or alkylaminocarbonyl (e.g., n-propylaminocarbonyl or
t-butylaminocarbonyl).
[0129] In another embodiment, R.sup.9 is hydrogen. In yet another
embodiment, R.sup.7 is substituted pyridinyl (e.g., methyl
substituted pyridinyl), alkoxycarbonylalkylaminocarbonyl (e.g.,
methyoxycarbonylalkylaminocarbonyl), pyridinylalkylaminoalkyl,
substituted or unsubstituted arylaminoalkylcarbonyl (e.g.,
phenylaminoalkylcarbonyl), substituted or unsubstituted
tetrahydropyridinyl (e.g., isopropyl substituted
tetrahydropyridinyl or dimethylaminoalkylcarbonyl substituted
tetrahydropyridinyl), cycloalkylaminoalkylcarbonyl (e.g.,
cyclohexylaminoalkylcarbonyl or morpholinoaminoalkylcarbonyl),
alkylaminoalkylcarbonyl, heteroarylaminoalkylcarbonyl (e.g.,
pyrimidinylaminoalkylcarbonyl) or alkoxylcarbonyl substituted
alkylaminoalkylcarbonyl.
[0130] In yet another embodiment, R.sup.9 is aminomethyl. In
another embodiment, R.sup.7 is substituted phenyl such as dichloro
substituted phenyl.
[0131] Examples of tetracycline compounds of Formula (I)
include:
##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035##
[0132] In another further embodiment, the invention pertains to
tetracycline compounds of Formula (III):
##STR00036##
wherein [0133] R.sup.9 is R'--O--N.dbd.CR''--, R'--OC(.dbd.O)--,
R.sup.9aR.sup.9bNC(.dbd.O)--, methoxycarbonyl substituted alkynyl,
pyrazinyl, alkylaminocarbonyl alkyl, methoxymethyl, methoxymethyl
substituted alkynyl, dimethylaminocarbonyl, cyclopropyl, methyl,
amino substituted pyridinyl, alkoxyalkyl, alkylcarbonyl,
arylcarbonyl, pyrimidinyl, alkoxycarbonyl substituted alkynyl,
oxazolyl, pyrazolyl, carboxylate, halogen, piperidinylcarbonyl,
alkyoxyalkyl substituted alkynyl, pyridinyl, thiazolyl, substituted
or unsubstituted arylthiocarbonyl, cyano, deuterated
alkylaminoalkyl, pyrrolidonylcarbonyl, carboxylatecarbonyl,
alkylcarbonyl substituted phenyl, cyano substituted pyridinyl,
aminocarbonyl substituted phenyl, dialkylaminomethyl, substituted
or unsubstituted thiophenyl, substituted or unsubstituted furanyl,
alkylcarbonylamino substituted pyridinyl, dialkylamino substituted
phenyl, carboxylate substituted phenyl, azepanylcarbonyl, or
piperazinylcarbonyl; [0134] R.sup.10 is hydrogen or alkenyl; [0135]
R' is unsubstituted alkyl, amino substituted alkyl, methoxy
substituted alkyl, halogen substituted alkyl; [0136] R'' is alkyl;
[0137] R.sup.9a is hydrogen or alkyl; [0138] R.sup.9b is alkyl,
hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl,
alkylcarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl,
cycloalkyl or aminoalkyl; and pharmaceutically acceptable salts,
esters and prodrugs thereof, provided that when R.sup.9 is halogen,
then R.sup.10 is alkenyl.
[0139] In one embodiment, R.sup.10 is alkenyl. In another
embodiment R.sup.9 is halogen, for example, iodine.
[0140] In another embodiment, R.sup.10 is hydrogen. In a further
embodiment, R.sup.9 is R'--O--N.dbd.CR''--, wherein R'' is alkyl,
such as methyl and R' is unsubstituted alkyl, for example,
methyl.
[0141] In yet another embodiment, R.sup.10 is hydrogen and R.sup.9
is R'--OC(.dbd.O)--. In one embodiment R' is unsubstituted alkyl
(e.g., ethyl or isopropyl), amino substituted alkyl (e.g.,
dialkylamino substituted alkyl, such as dimethylamino substituted
alkyl), halogen substituted alkyl (such as trifluoromethyl
substituted alkyl) or methoxy substituted alkyl.
[0142] In another embodiment, R.sup.10 is hydrogen and R.sup.9 is
R.sup.9aR.sup.9bNC(.dbd.O)--. In one embodiment, R.sup.9a and
R.sup.9b are each alkyl, such as, for example methyl or ethyl. In
one embodiment, R.sup.9a is alkyl (e.g., methyl) and R.sup.9b is
alkoxyalkyl, such as methoxyalkyl. In yet another embodiment,
R.sup.9a is ethyl and R.sup.9b is n-propyl. In a further
embodiment, R.sup.9a is hydrogen and R.sup.9b is hydrogen, hydroxy,
alkoxy (e.g., methoxy, ethoxy or t-butyloxy), hydroxyalkyl, alkyl
(e.g., methyl-t-butyl, n-propyl, ethyl, t-butyl or n-butyl),
cycloalkyl (such as cyclopropyl), alkylcarbonylaminoalkyl (e.g.,
methylcarbonylaminoalkyl), alkoxycarbonylalkyl (e.g.,
methoxycarbonylalkyl), aryl (e.g., phenyl) or aminoalkyl.
[0143] In another embodiment, R.sup.10 is hydrogen and R.sup.9 is
methoxycarbonyl substituted alkynyl, pyrazinyl, methoxymethyl,
cyclopropyl, methyl, methoxymethyl substituted alkynyl, amino
substituted pyridinyl, alkylcarbonyl (e.g., ethylcarbonyl or
isopropylcarbonyl), arylcarbonyl (e.g., phenylcarbonyl),
pyrimidinyl, oxazolyl, pyrazolyl, carboxylate, pyridinyl,
thiazolyl, substituted or unsubstituted thiophenyl (e.g.,
carboxylate substituted thiophenyl), piperidinylcarbonyl,
dialkylaminomethyl (e.g., di-n-butylaminomethyl), cyano,
substituted or unsubstituted arylthiocarbonyl (e.g.,
p-methylphenylthiocarbonyl), deuterated alkylaminoalkyl,
substituted furanyl (e.g., methoxyalkylaminomethyl substituted
furanyl, alkylaminomethyl substituted furanyl or halogenated
alkylaminomethyl substituted furanyl, such as
fluoroalkylaminomethyl substituted furanyl), isoxolazolyl, cyano
substituted pyridinyl, alkylcarbonylamino substituted pyridinyl
(such as acylamino substituted pyridinyl), dialkylamino substituted
phenyl (e.g., para-dimethylamino substituted phenyl),
pyrrolidonylcarbonyl, azepanylcarbonyl, carboxylatecarbonyl,
alkylcarbonyl substituted phenyl (e.g., meta-acyl substituted
phenyl), aminocarbonyl substituted phenyl (e.g., is
para-aminocarbonyl substituted phenyl or meta-aminocarbonyl
substituted phenyl), carboxylate substituted phenyl (e.g.,
meta-carboxylate substituted phenyl) or piperazinylcarbonyl.
[0144] Examples of tetracycline compounds of Formula (III)
include:
##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047## ##STR00048##
[0145] In another embodiment, the invention pertains to
tetracycline compounds of Formula (IV):
##STR00049##
wherein [0146] R.sup.7a is methoxy, dialkylaminomethyl, substituted
N-piperdinyl methyl, fluorine, or hydrogen; [0147] R.sup.7b is
hydrogen; [0148] R.sup.7c is alkoxyalkylaminoalkyl, halogenated
N-piperdinyl methyl, hydroxyl, dialkylaminoalkylamino,
dialkylaminomethyl, substituted N-piperidinyl methyl, substituted
N-pyrrolyl methyl, or hydrogen; [0149] R.sup.7d is
arylalkylaminoalkyl, arylalkyl substituted alkylaminoalkyl,
substituted N-piperidinylmethyl, N-piperidinyl substituted
aminomethyl, cyclopropylamino methyl, piperdinyl substituted alkyl,
dialkylaminomethyl, heteroaryl substituted dialkylaminomethyl,
alkylaminomethyl, cycloalkylaminomethyl, alkylaminoethyl, cyano
substituted dialkylaminomethyl, N-pyrrolidinyl substituted methyl,
N-pyrrolyl substituted methyl, methoxy substituted
dialkylaminomethyl, alkoxyalkylaminomethyl, substituted carboxylate
alkylaminomethyl, hydrogen or linked with R.sup.7c by a
--O--CH.sub.2--O-- linker; [0150] R.sup.7e is hydrogen, and
pharmaceutically acceptable salts, esters and prodrugs thereof,
provided that each of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e are not hydrogen.
[0151] In one embodiment, R.sup.7e is hydrogen and R.sup.7b and
R.sup.7c are each hydrogen. In a further embodiment, R.sup.7a is
methoxy and R.sup.7d is substituted N-piperidinylmethyl, R.sup.7a
is halogen (e.g., fluorine) and R.sup.7d is substituted
N-piperidinylmethyl or R.sup.7a is methoxy and R.sup.7d is
arylalkyl substituted alkylaminoalkyl, such as phenylmethyl
substituted alkylaminoalkyl
[0152] In another embodiment, R.sup.7e and R.sup.7a, R.sup.7b and
R.sup.c are each hydrogen. In a further embodiment, R.sup.7d is
dialkylaminomethyl, for example, methylisopropylaminomethyl,
methylcyclohexylaminomethyl, methylethylaminomethyl,
methylpropylaminomethyl, methyl isobutylaminomethyl,
propylisopropylaminomethyl, ethylisopropylaminomethyl,
propylcyclopropylmethylaminomethyl, cyano-substituted
ethylmethylaminomethyl, methoxy-substituted ethylaminomethyl,
t-butoxy substituted ethylmethylaminomethyl or pyridine substituted
methymethylaminomethyl. In another embodiment, R.sup.7d is
substituted N-piperidinylmethyl, such as dimethyl substituted
N-piperidinylmethyl, trifluoromethyl substituted
N-piperidinylmethyl or halogen (e.g., fluorine) substituted
N-piperidinylmethyl, cycloalkylaminomethyl (e.g.,
cyclopropylaminomethyl, dimethylpyrrolidinylaminomethyl or
dimethylpyrrolylaminomethyl) or alkylaminomethyl (e.g.,
t-butylmethylaminomethyl).
[0153] In yet another embodiment, R.sup.7e and R.sup.7a, R.sup.7b
and R.sup.7d are each hydrogen. In a further embodiment, R.sup.7c
is alkoxyalkylaminoalkyl (e.g., methoxyalkylaminoalkyl), hydroxy,
dialkylaminoalkylamino (e.g., diisopropylaminomethyl),
dialkylaminomethyl, substituted N-piperidinylmethyl, substituted
N-pyrrolyl or substituted carboxylate alkylaminomethyl.
[0154] In another embodiment, R.sup.7e and R.sup.7b, R.sup.7c and
R.sup.7d are each hydrogen. In a further embodiment, lea is
dialkylaminomethyl, such as dimethylaminomethyl.
[0155] In yet another embodiment, R.sup.7e and R.sup.7b are each
hydrogen and R.sup.7a is substituted N-piperidinylmethyl and
R.sup.7d is linked with R.sup.7c by a --O--CH.sub.2--O--
linker.
[0156] Examples of tetracycline compounds of Formula (IV)
include:
##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054##
##STR00055## ##STR00056## ##STR00057## ##STR00058##
[0157] In another embodiment, the invention pertains to
tetracycline compounds of Formula (V):
##STR00059##
wherein [0158] T is NH or O; [0159] R.sup.7f is dialkylaminoalkyl,
N-piperidinylamino alkyl, substituted or unsubstituted
N-piperdinylalkyl, N-pyrrolidinylamino alkyl, substituted or
unsubstituted N-pyrrolidinylalkyl, substituted or unsubstituted
N-pyrrolylalkyl, alkenenyl substituted dialkylaminoalkyl,
N-decahydroisoquinolinylalkyl, alkoxyalkylaminoalkyl, or hydrogen;
[0160] R.sup.7g is hydrogen; [0161] R.sup.7h is heteroaryl
substituted alkylaminoalkyl, dialkylaminoalkyl, substituted
N-piperidinylalkyl or hydrogen, and pharmaceutically acceptable
salts, esters and prodrugs thereof, provided that each of R.sup.7f,
R.sup.7g, and R.sup.7h are not hydrogen.
[0162] In one embodiment, T is NH and R.sup.7f and R.sup.7g are
each hydrogen. In a further embodiment, R.sup.7h is
dialkylaminoalkyl (e.g., dimethylaminomethyl) or substituted
N-piperidinylalkyl (e.g., methyl substituted
N-piperidinylmethyl).
[0163] In another embodiment, T is O and R.sup.7f and R.sup.7g are
each hydrogen. In a further embodiment, R.sup.7h is heteroaryl
substituted alkylaminoalkyl, such as, for example, pyridinyl
substituted methylaminomethyl or methyl substituted
isoxazolylmethylaminomethyl.
[0164] In yet another embodiment, T is O and R.sup.7g and R.sup.7h
are each hydrogen. In a further embodiment, R.sup.7f is
dialkylaminoalkyl (e.g., methylisopropylaminomethyl or
allylmethylaminomethyl), substituted N-piperidinylalkyl (e.g.,
methyl substituted N-piperidinylmethyl or halogen substituted
N-piperidinylmethyl, such as fluorine substituted
N-piperidinylmethyl) substituted N-pyrrolylalkyl (e.g., methyl
substituted N-pyrrolylmethyl), substituted N-pyrrolidinylalkyl
(e.g., methyl substituted N-pyrrolidinylmethyl),
N-decahydroisoquinolinylalkyl or alkoxyalkylaminoalkyl (e.g.,
methoxyalkylaminomethyl).
[0165] Examples of tetracycline compounds of Formula (V)
include:
##STR00060## ##STR00061## ##STR00062##
[0166] In another embodiment, the invention pertains to
tetracycline compounds of Formula (VI):
##STR00063##
wherein [0167] R.sup.7i is fluorine or hydrogen; [0168] R.sup.7j is
trifluoromethyl, alkyloxycarbonyl, methyl, cyano, or hydrogen, and
pharmaceutically acceptable salts, esters and prodrugs thereof,
provided that both of R.sup.7i and R.sup.7j are not hydrogen.
[0169] In one embodiment, R.sup.7i is hydrogen. In a further
embodiment, R.sup.7j is methyl, cyano, trifluoromethyl, or
alkyloxycarbonyl, such as, for example, methoxycarbonyl.
[0170] In another embodiment, R.sup.7i is fluorine and R.sup.7j is
hydrogen.
[0171] Examples of tetracycline compounds of Formula (VI)
include:
##STR00064##
[0172] In another embodiment, the invention pertains to
tetracycline compounds of Formula (VII):
##STR00065##
wherein [0173] p is a single or double bond; [0174] R.sup.7k is
alkyl, cycloalkyl, dialkylaminoalkylcarbonyl, alkoxyalkylcarbonyl,
halogen substituted alkyl, halogen substituted cycloalkyl, or
hydrogen, and pharmaceutically acceptable salts, esters and
prodrugs thereof.
[0175] In one embodiment, p is a single bond and R.sup.7k is alkyl,
such as isopropyl, or hydrogen.
[0176] In another embodiment, p is a double bond. In a further
embodiment, R.sup.7k is hydrogen, alkyl (e.g., isopropyl),
cycloalkyl (e.g., cyclohexyl or cyclopropylmethyl), halogen
substituted alkyl (e.g., trifluoromethyl substituted propyl),
halogen substituted cycloalkyl (e.g., trifluoromethyl substituted
cyclohexyl), alkoxyalkylcarbonyl (e.g., methoxymethylcarbonyl) or
dialkylaminoalkylcarbonyl (e.g., dimethylaminomethylcarbonyl).
[0177] Examples of tetracycline compounds of Formula (VII)
include:
##STR00066## ##STR00067## ##STR00068##
[0178] In another embodiment, the invention pertains to
tetracycline compounds of Formula (VIII):
##STR00069##
wherein [0179] R.sup.7 is fluoro substituted N-pyrrolidinylalkyl,
N-piperidinylalkylcarbonyl, dialkylaminoalkylaminocarbonyl,
aminoalkyl, N-pyrroyl alkyl, dialkylamino substituted pyridinyl,
substituted or unsubtituted phenyl substituted N-piperizinyl alkyl,
alkylaminoalkyl, alkoxy substituted pyrimidinyl,
1-H-pyrimidin-2-onyl, cyano substituted pyridinyl, substituted or
unsubstituted N-pyrrolidinyl alkyl, halogen substituted pyridinyl,
substituted or unsubstituted arylalkylamino alkyl,
alkoxyalkylaminoalkyl, N-imidizolylalkylcarbonyl,
N-dihydroimidizolylalkylcarbonyl, alkylaminoalkyl,
imidizopyrimidinyl, substituted or unsubstituted imidizopyridinyl,
or substituted or unsubstituted pyrizinyl substituted
alkylaminoalkyl, alkoxyalkylcarbonyl; and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0180] In one embodiment, the fluoro substituted
N-pyrrolidinylalkyl is difluoro substituted
N-pyrrolidinylmethyl.
[0181] In another embodiment, the aminoalkyl is aminomethyl.
[0182] In yet another embodiment, the N-pyrroyl alkyl is N-pyrroyl
methyl.
[0183] In another embodiment, the dialkylamino substituted
pyridinyl is dimethylamino substituted pyridinyl.
[0184] In a further embodiment, the substituted phenyl substituted
N-piperizinyl alkyl is para-fluorophenyl substituted phenyl
N-piperizinyl methyl.
[0185] In one embodiment, the alkoxy substituted pyrimidinyl is
methoxy substituted pyrimidinyl.
[0186] In another embodiment, the substituted N-pyrrolidinyl alkyl
is dimethyl substituted N-pyrrolidinyl methyl.
[0187] In yet another embodiment, the halogen substituted pyridiyl
is fluorine substituted pyridinyl.
[0188] In another embodiment, the arylalkylamino alkyl is
phenylmethylaminomethyl.
[0189] In one embodiment, the alkoxyalkylaminoalkyl is
methoxyalkylaminomethyl.
[0190] In another embodiment, the alkylaminoalkyl is
methylaminomethyl.
[0191] In yet another embodiment, the substituted arylalkylamino
alkyl is hydroxy substituted phenylmethylamino methyl.
[0192] In another embodiment, the substituted pyrizinyl substituted
amino alkyl is methyl pyrizinyl substituted methylaminomethyl.
[0193] In yet another embodiment, the substituted imidizopyridinyl
is halogen substituted imidizopyridinyl, for example, fluorine
substituted imidizopyridinyl.
[0194] In one embodiment, the alkoxyalkylcarbonyl is
methoxymethylcarbonyl.
[0195] Examples of tetracycline compounds of Formula (VIII)
include:
##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074##
[0196] In yet another embodiment, the invention pertains to
tetracycline compounds of Formula (IX):
##STR00075##
wherein [0197] R.sup.7 is dialkylaminomethyl, alkoxy substituted
phenyl, hydroxy, halogen substituted phenyl, halogenated alkyl
substituted phenyl, naphthyl; [0198] R.sup.9c is hydrogen,
fluorinated alkyl or unsubstituted alkyl and pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0199] In one embodiment, R.sup.9c is hydrogen. In a further
embodiment is dialkylaminomethyl (e.g., dimethylaminomethyl),
alkoxy substituted phenyl (e.g., para-trifluoromethoxy substituted
phenyl) or halogen substituted phenyl (e.g., chlorine substituted
phenyl or trifluoro substituted phenyl). In one embodiment, the
chlorine substituted phenyl is further substituted with
trifluoromethyl. In yet another embodiment, R.sup.7 is halogenated
alkyl substituted phenyl such as, for example, di-triflouoromethyl
substituted phenyl.
[0200] In another embodiment, R.sup.9c is fluorinated alkyl and
R.sup.7 is halogen substituted phenyl such as, for example,
difluoro substituted phenyl.
[0201] In yet another embodiment, R.sup.9c is unsubstituted alkyl
and R.sup.7 is hydroxy.
[0202] Examples of tetracycline compounds of Formula (IX)
include:
##STR00076## ##STR00077##
[0203] In another embodiment, the invention includes tetracycline
compounds of the Formula (X):
##STR00078##
wherein [0204] R.sup.1 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl,
arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl,
alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy,
thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, or
halogen, optionally linked to R.sup.2 to form a ring; [0205]
R.sup.2 is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl,
hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino,
alkylamino, heterocyclic, or absent, optionally linked to R.sup.1
to form a ring; [0206] R.sup.2', R.sup.2'', R.sup.4a, and R.sup.4b
are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0207]
R.sup.10 is hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug
moiety; [0208] R.sup.11b is hydroxyl, alkoxy, aryloxy, or
alkylamino; [0209] R.sup.4 and R.sup.4' are each independently
NR.sup.4aR.sup.4b, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or
hydrogen; [0210] R.sup.5 and R.sup.5' are each independently
hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl,
heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl
carbonyloxy, or aryl carbonyloxy; [0211] 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; [0212]
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.7a).sub.0-1C(.dbd.W')WR.sup.7l; [0213]
R.sup.8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.8c).sub.0-1C(=E')ER.sup.8a; [0214]
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.0-3(NR.sup.9f).sub.0-1C(.dbd.Z')ZR.sup.9a; [0215]
R.sup.7l, R.sup.7m, R.sup.7n, R.sup.7o, R.sup.7p, R.sup.7q,
R.sup.8a, R.sup.8b, R.sup.8c, R.sup.8d, R.sup.8e, R.sup.8f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, and R.sup.9f are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0216]
R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0217] E is CR.sup.8dR.sup.8e, S, NR.sup.b or O; [0218]
E' is O, NR.sup.8f, or S; [0219] Q is a double bond when R.sup.2 is
absent, Q is a single bond when R.sup.2 is hydrogen, alkyl,
halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, formyl,
alkoxy, amino, alkylamino, cyano, nitro, or heterocyclic; [0220] W
is CR.sup.7oR.sup.7p, S, NR.sup.7m or O; [0221] W' is O, NR.sup.7q,
or S; [0222] X is CHC(R.sup.13Y'Y), C.dbd.CR.sup.13Y,
CR.sup.6'R.sup.6, S, NR.sup.6, or O; [0223] Y' and Y are each
independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl,
amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, or an arylalkyl; [0224] Z is
CR.sup.9dR.sup.9e, S, NR.sup.9b or O; [0225] Z' is O, S, or
NR.sup.9f, and pharmaceutically acceptable salts, esters and
enantiomers thereof.
[0226] In a further embodiment, the tetracycline compound of
Formula (X) is:
##STR00079##
[0227] In another embodiment, the invention includes tetracycline
compounds of the Formula (XI):
##STR00080##
wherein [0228] R.sup.7r is substituted or unsubstituted
N-piperidinylalkyl, dialkylaminoalkyl and pharmaceutically
acceptable salts, esters and enantiomers thereof. [0229] In one
embodiment, dialkylaminoalkyl is dimethylaminomethyl. In another
embodiment, the substituted N-piperidinylalkyl is methyl
substituted N-piperidinylmethyl. [0230] Examples of the
tetracycline compounds of Formula (XI) are:
##STR00081##
[0231] In another embodiment, the invention includes tetracycline
compounds of the Formula (XII):
##STR00082##
wherein [0232] W is N or CH; and [0233] R.sup.7a is substituted or
unsubstituted alkyl, aryl, alkoxycarbonyl, alkylcarbonyl,
cycloalkyl, or aminocarbonyl; and pharmaceutically acceptable
salts, esters and enantiomers thereof.
[0234] In one embodiment, W is CH. In a further embodiment,
R.sup.7a is unsubstituted alkyl such as, for example, methyl.
[0235] In another embodiment, W is N. In a further embodiment, is
alkoxycarbonyl (e.g., ethoxycarbonyl), alkylcarbonyl (e.g., acyl),
cycloalkyl (e.g., cyclohexyl), aryl (e.g., phenyl), alkyl (e.g.,
isopropyl), or aminocarbonyl.
[0236] Examples of the tetracycline compounds of Formula (XII)
are:
##STR00083## ##STR00084## ##STR00085##
[0237] In another embodiment, the invention includes tetracycline
compounds of Formula XIII:
##STR00086##
wherein [0238] n is 0, 1 or 2; [0239] R.sup.7t' is hydrogen, alkyl,
alkenyl or cycloalkyl; [0240] R.sup.7t'' is unsubstituted alkyl,
dialkylaminoalkyl, halogenated alkyl, alkoxyalkyl, substituted or
unsubstituted arylalkyl, cycloalkyl, alkenylalkyl, heterocyclic,
cyano substituted alkyl, alkoxy substituted alkyl, heteroarylalkyl,
aminocarbonylalkyl, aryl, hydrogen, alkylcarbonyl, aminoalkyl or
alkoxycarbonyl; and pharmaceutically acceptable salts, esters and
enantiomers thereof.
[0241] In one embodiment, n is O. In a further embodiment,
R.sup.7t' is hydrogen. In yet another embodiment, R.sup.7'' is
dialkylaminoalkyl.
[0242] In another embodiment, n is 1. In a further embodiment,
R.sup.7t' is alkoxyalkyl, such as, for example, methoxyethyl. In
another embodiment, R.sup.7t'' is alkyl such as, for example,
isopropyl. In yet a further embodiment R.sup.7t' is alkyl such as,
for example, methyl.
[0243] In another embodiment, R.sup.7t' is alkenyl. In a further
embodiment, R.sup.7t'' is alkoxycarbonyl such as, for example,
methoxycarbonyl In another embodiment, R.sup.7t'' is alkylcarbonyl
such as, for example, acyl. Ina further embodiment, R.sup.7t' is
cycloalkyl, such as cyclpropyl.
[0244] In another embodiment, n is 1. In a further embodiment,
R.sup.7t' is hydrogen. In another embodiment, R.sup.7t'' is
halogenated alkyl (e.g., fluoroethyl, difluoroethyl or
trifluoroethyl), unsubstituted alkyl (e.g., methyl, ethyl,
t-butylmethyl, t-butyl or diethylmethyl), cycloalkyl (e.g.,
cyclohexyl, cyclopropyl, morpholino, cyclobutyl,
bicyclo[2.2.1]heptenyl, cyclopentyl), arylalkyl (e.g.,
phenylmethyl), alkenylalkyl, cyano substituted alkyl,
heteroarylalkyl (e.g., pyridinylmethyl, furanylmethyl or
N-methylpyrrolylmethyl), aminocarbonylalkyl (e.g.,
aminocarbonylmethyl), alkoxy substituted alkyl (e.g., methoxy
substituted alkyl), aryl (e.g., pyridinyl or phenyl), aminoalkyl
(e.g., aminomethyl) or substituted arylalkyl (e.g.,
difluorophenyl).
[0245] In yet another embodiment, n is 2. In a further embodiment,
R.sup.7t' is hydrogen. In yet a further embodiment, R.sup.7t'' is
alkyl, such as for example, methyl. In another embodiment,
R.sup.7t'' is alkylcarbonyl, such as, for example, acyl.
[0246] Examples of the tetracycline compounds of Formula (XIII)
are:
##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091##
##STR00092## ##STR00093## ##STR00094## ##STR00095##
[0247] In another embodiment, the invention includes tetracycline
compounds of Formula XIV:
##STR00096##
wherein [0248] R.sup.7u is substituted or unsubstituted
N-piperidinylalkyl, dialkylaminoalkyl, alkoxyaminoalkyl,
alkylaminoalkyl or dipiperidinium methyl; and pharmaceutically
acceptable salts, esters and enantiomers thereof.
[0249] In one embodiment, R.sup.u is substituted
N-piperidinylalkyl, such as, for example, methyl substituted
N-piperidinylalkyl or halogen substituted N-piperidinylalkyl.
[0250] In another embodiment, the halogen substituted
N-piperidinylalkyl is, includes, for example, fluorine substituted
N-piperidinylalkyl.
[0251] In yet another embodiment, R.sup.7u is dialkylaminoalkyl,
including, for example, dimethylaminomethyl.
[0252] In another embodiment, R.sup.7u is alkylaminomethyl is
methylaminomethyl.
[0253] In yet another embodiment, R.sup.7u is alkoxyaminoalkyl is
methoxyaminoalkyl.
[0254] Examples of the tetracycline compounds of Formula (XIV)
are:
##STR00097## ##STR00098##
[0255] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of formula (XV):
##STR00099##
wherein [0256] R.sup.7v is heteroaryl; and pharmaceutically
acceptable salts, esters and enantiomers thereof.
[0257] In one embodiment, the said heteroryl is imidizolyl, methyl
imidizolyl, imidizolidinyl or methyl imidizolidinyl.
[0258] Examples of tetracycline compounds of formula (XV) are:
##STR00100##
[0259] In another embodiment, the invention pertains, at least in
part, to tetracycline compounds of formula (XVI):
##STR00101##
wherein: [0260] R.sup.2', R.sup.2'', R.sup.4a, and R.sup.4b are
each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0261]
R.sup.10, R.sup.11 and R.sup.12 are each independently hydrogen,
alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; [0262]
R.sup.3' is hydroxyl, hydrogen, or a pro-drug moiety; [0263]
R.sup.4 is NR.sup.4aR.sup.4b, alkyl, alkenyl, alkynyl, hydroxyl,
halogen, or hydrogen; [0264] R.sup.5 and R.sup.5' are each
independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl,
aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl
carbonyloxy, or aryl carbonyloxy; [0265] 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; [0266]
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; [0267]
R.sup.8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.8c).sub.0-1C(=E')ER.sup.8a; [0268]
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.0-3(NR.sup.9c).sub.0-1C(.dbd.Z')ZR.sup.9a; [0269]
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.8a, R.sup.8b, R.sup.8c, R.sup.8d, R.sup.8e, R.sup.8f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, and R.sup.9f are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0270]
R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0271] E is CR.sup.8dR.sup.8e; S, NR.sup.8b or O; [0272]
E' is O, NR.sup.8f, or S; [0273] W is CR.sup.7dR.sup.7e, S,
NR.sup.7b or O; [0274] W' is O, NR.sup.7f, or S; [0275] X is
CHC(R.sup.13Y'Y), C.dbd.CR.sup.13Y, CR.sup.6'R.sup.6, S, NR.sup.6,
or O; [0276] Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0277] Z is CR.sup.9dR.sup.9c, S, NR.sup.9b or O; [0278]
Z' is O, S, or NR.sup.9f, and pharmaceutically acceptable salts,
esters and enantiomers thereof.
[0279] In a further embodiment, R.sup.2', R.sup.3, R.sup.10,
R.sup.11, and R.sup.12 are each hydrogen or a prodrug moiety; X is
CR.sup.6R.sup.6'; and R.sup.2'', R.sup.5, R.sup.5', R.sup.6, and
R.sup.6' are each hydrogen.
[0280] Alternatively, R.sup.5 and R.sup.5' are hydrogen and X is
CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydroxy. Alternatively, when R.sup.5 is hydroxyl; X is
CR.sup.6R.sup.6'; R.sup.6 is methyl; and R.sup.5' and R.sup.6' are
hydrogen. In yet another embodiment, X is CR.sup.6R.sup.6';
R.sup.5, R.sup.5', R.sup.6 and R.sup.6' are hydrogen atoms and
R.sup.7 is dimethylamino.
[0281] In one embodiment, R.sup.9 is hydrogen. In another
embodiment, R.sup.9 is substituted or unsubstituted aryl (e.g.,
phenyl or heteroaryl). In another embodiment, R.sup.9 is
substituted or unsubstituted alkyl. In a further embodiment,
R.sup.9 is aminoalkyl, e.g., aminomethyl (e.g.,
--CH.sub.2--N.sup.9nR.sup.9m, wherein R.sup.9n is hydrogen or a
prodrug and R.sup.9m is hydrogen or lower alkyl).
[0282] In another embodiment, R.sup.7 is hydrogen. In yet another
embodiment, R.sup.7 is substituted or unsubstituted aryl, e.g.,
phenyl or heteroaryl (e.g., pyridinyl, pyrrolyl, pyrazinyl, etc.).
In another embodiment, R.sup.7 is substituted or unsubstituted
amino (e.g., dimethylamino), nitro or halogen. In another
embodiment, R.sup.8 is hydrogen. In another further embodiment,
R.sup.11 is hydrogen.
[0283] In a further embodiment, the tetracycline compound is:
##STR00102##
[0284] In another embodiment, the invention pertains to
tetracycline compounds substituted at the 2 position such as
compounds of formula (XVII):
##STR00103##
wherein: [0285] R.sup.2a is alkyl or aryl; [0286] R.sup.4a and
R.sup.4b are each independently hydrogen, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,
arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
[0287] R.sup.10, R.sup.11 and R.sup.12 are each independently
hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety;
[0288] R.sup.3' is hydroxyl, hydrogen, or a pro-drug moiety; [0289]
R.sup.4 is NR.sup.4aR.sup.4b, alkyl, alkenyl, alkynyl, hydroxyl,
halogen, or hydrogen; [0290] R.sup.5 and R.sup.5' are each
independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl,
aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl
carbonyloxy, or aryl carbonyloxy; [0291] 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; [0292]
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; [0293]
R.sup.8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl,
alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl,
aminoalkyl, heterocyclic, thionitroso, or
--(CH.sub.2).sub.0-3(NR.sup.7c).sub.0-1C(=E')ER.sup.8a; [0294]
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.0-3(NR.sup.7').sub.0-1C(.dbd.Z')ZR.sup.9a; [0295]
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.8a, R.sup.8b, R.sup.8c, R.sup.8d, R.sup.8e, R.sup.8f,
R.sup.9a, R.sup.9b, R.sup.9c, R.sup.9d, R.sup.9e, and R.sup.9f are
each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl,
aryl, heterocyclic, heteroaromatic or a prodrug moiety; [0296]
R.sup.13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0297] E is CR.sup.8dR.sup.8e, S, NR.sup.8b or O; [0298]
E' is O, NR.sup.8f, or S; [0299] W is CR.sup.7dR.sup.7e, S,
NR.sup.7b or O; [0300] W' is O, NR.sup.7f, or S; [0301] X is
CHC(R.sup.13Y'Y), C.dbd.CR.sup.13Y, CR.sup.6'R.sup.6, S, NR.sup.6,
or O; [0302] Y' and Y are each independently hydrogen, halogen,
hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an
arylalkyl; [0303] Z is CR.sup.9dR.sup.9e, S, NR.sup.9b or O; [0304]
Z' is O, S, or NR.sup.9f, and pharmaceutically acceptable salts,
esters and enantiomers thereof.
[0305] In a further embodiment, R.sup.3, R.sup.10, R.sup.11 and
R.sup.12 are each hydrogen or a prodrug moiety; X is
CR.sup.6R.sup.6'; and R.sup.5, R.sup.5', R.sup.6, and R.sup.6' are
each hydrogen.
[0306] Alternatively, R.sup.5 and R.sup.5' are hydrogen and X is
CR.sup.6R.sup.6', wherein R.sup.6 is methyl and R.sup.6' is
hydroxy. Alternatively, when R.sup.5 is hydroxyl; X is
CR.sup.6R.sup.6'; R.sup.6 is methyl; and R.sup.5' and R.sup.6' are
hydrogen. In yet another embodiment, X is CR.sup.6R.sup.6';
R.sup.5, R.sup.5', R.sup.6 and R.sup.6' are hydrogen atoms and
R.sup.7 is dimethylamino.
[0307] In one embodiment, R.sup.9 is hydrogen. In another
embodiment, R.sup.9 is substituted or unsubstituted aryl (e.g.,
phenyl or heteroaryl). In another embodiment, R.sup.9 is
substituted or unsubstituted alkyl. In a further embodiment,
R.sup.9 is aminoalkyl, e.g., aminomethyl (e.g.,
--CH.sub.2--N.sup.9nR.sup.9m, wherein R.sup.9n is hydrogen or a
prodrug and R.sup.9m is hydrogen or lower alkyl).
[0308] In another embodiment, R.sup.7 is hydrogen. In yet another
embodiment, R.sup.7 is substituted or unsubstituted aryl, e.g.,
phenyl or heteroaryl (e.g., pyridinyl, pyrrolyl, pyrazinyl, etc.).
In another embodiment, R.sup.7 is substituted or unsubstituted
amino (e.g., dimethylamino), nitro or halogen. In another
embodiment, R.sup.8 is hydrogen.
[0309] In a further embodiment, R.sup.2a is alkyl, e.g., methyl,
ethyl or propyl.
[0310] In another further embodiment, the tetracycline compound
is:
##STR00104##
[0311] In one embodiment, the tetracycline compounds of the
invention do not include those described in U.S. Ser. Nos.
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.
Methods for Synthesizing Tetracycline Compounds of the
Invention
[0312] 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.
[0313] 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.
[0314] 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 (11)).
##STR00105##
[0315] 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.
##STR00106##
[0316] 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).
##STR00107##
[0317] 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.
##STR00108##
[0318] 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 (MS) 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
##STR00109##
[0319] 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.
[0320] 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.
##STR00110##
[0321] 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).
##STR00111##
[0322] 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).
##STR00112##
[0323] As shown in Scheme 9 below, 7 and 9-aminomethyl
tetracyclines may be synthesized using reagents such as
hydroxymethyl-carbamic acid benzyl ester.
##STR00113##
[0324] 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.
[0325] 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.
[0326] 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).
[0327] 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.
[0328] 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.
[0329] 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.
[0330] 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.
[0331] 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.
[0332] 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.
[0333] 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.
[0334] 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.
[0335] 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.
[0336] 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.
[0337] 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.
[0338] 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.
[0339] 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.
[0340] 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).
[0341] 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.
[0342] The term "thiocarbonyl" or "thiocarboxy" includes compounds
and moieties which contain a carbon connected with a double bond to
a sulfur atom.
[0343] 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.
[0344] 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.
[0345] 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.
[0346] The term "hydroxy" or "hydroxyl" includes groups with an
--OH or --O.sup.-.
[0347] 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.
[0348] 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.
[0349] The term "heteroatom" includes atoms of any element other
than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorus.
[0350] 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.
[0351] 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.
Methods for Treating Tetracycline Responsive States
[0352] 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, VI, VII,
VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII or otherwise
described herein), such that the tetracycline responsive state is
treated.
[0353] 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.
[0354] 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. Tetracycline compound
responsive states include bacterial, viral, and fungal infections
(including those which are resistant to other tetracycline
compounds), cancer (e.g., prostate, breast, colon, lung melanoma
and lymph cancers and other disorders characterized by unwanted
cellular proliferation, including, but not limited to, those
described in U.S. Pat. No. 6,100,248), arthritis, osteoporosis,
diabetes, 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).
[0355] 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.
[0356] 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.
[0357] 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.
[0358] 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. 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.
[0359] 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.
[0360] The term "inflammatory process associated state" also
includes, in one embodiment, matrix metalloproteinase associated
states (MMPAS). MMPAS include states characterized 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.
[0361] 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.
[0362] 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.
[0363] 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.
[0364] 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.
[0365] Other examples of tetracycline compound responsive states
are described in WO 03/005971A2 and U.S. Patent Application
Publication No. 20040214800, each of which is incorporated herein
by reference.
[0366] 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. Nos. 6,100,248; 5,843,925;
5,837,696; or 5,668,122, incorporated herein by reference in their
entirety.
[0367] 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.
[0368] 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.
[0369] 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.
[0370] The invention also pertains to a method for treating acute
lung injury by administering a substituted tetracycline compound of
the invention.
[0371] 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.
[0372] 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. Nos. 6,231,894;
5,773,430; 5,919,775 or 5,789,395, incorporated herein by
reference.
[0373] 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.
[0374] 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.
[0375] 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).
[0376] 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.
[0377] 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.
[0378] 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.
[0379] 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.
Pharmaceutical Compositions of the Invention
[0380] 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, VI, VII,
VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII or any other
compound described herein) and, optionally, a pharmaceutically
acceptable carrier.
[0381] 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.
[0382] The tetracycline compounds of the invention that are basic
in nature are capable of forming a wide variety of salts with
various inorganic and organic acids. The acids that may be used to
prepare pharmaceutically acceptable acid addition salts of the
tetracycline compounds of the invention that are basic in nature
are those that form non-toxic acid addition salts, i.e., salts
containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and palmoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such
salts must be pharmaceutically acceptable for administration to a
subject, e.g., a mammal, it is often desirable in practice to
initially isolate a tetracycline compound of the invention from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent and subsequently convert the
latter free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of this
invention are readily prepared by treating the base compound with a
substantially equivalent amount of the chosen mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salt is readily obtained. 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.
[0383] 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.
[0384] 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.
[0385] 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.
[0386] 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.
[0387] 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.
[0388] 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.
[0389] 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.
[0390] 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.
[0391] 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.
[0392] 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.
[0393] 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.
[0394] 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.
[0395] 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.
[0396] 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.
[0397] Furthermore, the invention also pertains to the use of a
tetracycline compound of formula I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII, XIII, XIV, XV, XVI or XVII 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
Preparation of 7-(1,2,3,6-tetrahydro-pyridin-4-yl)-sancycline
##STR00114##
[0399] In a 500 mL two-neck round bottom flask, 7-iodo-sancycline
TFA salt (654 mg, 1 mmol) and Pd(OAc).sub.2 (22 mg, 0.1 mmol) were
taken in 100 mL of MeOH. The reaction mixture was then heated to
70.degree. C. under argon. After 5 minutes, Na.sub.2CO.sub.3 (420
mg, 4 mmol, a saturated solution in 10 mL of water) was added. A
yellow precipitate was obtained which was further heated at
70.degree. C. for 10 minutes. To this solution,
4-N,N-dimethylamino-3-pyridinyl-boronic acid (248 mg, 1.5 mmol,
dissolved in 10 mL of DMF) was added and the reaction mixture was
heated for another 2 hours. Progress of the reaction was monitored
by HPLC and LC/MS. The reaction was completed in 2 hours. Reaction
mixture was filtered through celite to remove the catalyst. Solvent
was then evaporated to dryness and the crude material was
precipitated using MeOH/diethyl ether (20/200 mL). Brown-yellow
precipitate was filtered and dried under vacuum. The solid obtained
was taken in 20 mL of TFA and stirred at room temperature for 5
minutes. TFA was removed and purification was done on a C-18 Luna
column using a 5-25% organic gradient (CH.sub.3CN/0.1% TFA and
Water/0.1% TFA). Fractions collected were dried in vacuo and the
solid obtained was converted to its HCl salt using a saturated
solution of methanol-HCl (20 mL). Compound was dried overnight over
P.sub.2O.sub.5 to yield the product as a yellow powder. MS: (m/z)
496.2391. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.32 (d, 1H),
6.75 (d, 1H), 5.51 (s, 1H), 3.95 (s, 1H), 3.71 (s, 2H), 3.35 (m,
2H), 2.94-2.76 (m, 8H), 2.52-2.39 (m, 1H), 2.36-2.31 (m, 1H), 2.05
(m, 1H), 1.48-1.47 (m, 1H).
Example 2
Preparation of
7(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-sancycline
##STR00115##
[0401] In 40 mL glass vial, 7-(1,2,3,6-tetrahydro-pyridin-4
yl)-sancycline (495 mg, 1 mmol) and InCl.sub.3 (11 mg, 0.1 mmol)
were taken in DMF (20 mL) under an argon atmosphere.
Isobutyraldehyde (144 .mu.L, 2 mmol) was added to the reaction
mixture and it was further stirred at room temperature for 20
minutes. To this sodium cyanoborohydride (186 mg, 3 mmol) was
added, and the reaction solution was stirred at room temperature
for another 4 hours. Completion of the reaction was confirmed by
HPLC and LC-MS. Solvent was then evaporated to dryness, redissolved
in water/0.1% TFA and purified using a C-18 Luna column using a
7-35% organic gradient (CH.sub.3CN/0.1% TFA and water/0.1% TFA).
The Fractions collected were dried in vacuo and the solid obtained
was converted to its HCl salt using a saturated solution of
Methanol-HCl (20 mL). The compound was then dried overnight over
P.sub.2O.sub.5 to yield the product as a yellow powder. MS: (m/z)
552.3212. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.26-7.23 (m,
1H), 6.74-6.72 (m, 1H), 5.50-5.46 (m, 1H), 4.02 (s, 1H), 3.92-3.88
(m, 1H), 3.65-3.60 (m, 2H), 3.03-2.76 (m, 11H), 2.33-2.28 (m, 1H),
2.20-2.15 (m, 3H), 1.18-1.04 (m, 1H), 1.04-0.99 (m, 611).
Example 3
Preparation of 7-imidazo-[1,2-a]-pyrimidin-2-yl-sancycline
##STR00116##
[0403] In a 40 mL glass vial, 7-acetyl sancycline (1 g, 2.19 mmol)
and Na.sub.2SO.sub.3 (200 mg, to prevent oxidation of products)
were taken in acetic acid (4 mL) and water (1 mL). The reaction
mixture was stirred until contents dissolved (5 minutes) under
argon atmosphere. To this solution, HBr (33 wt % solution in HOAc,
3 mL, 0.02 mmol) was slowly added. Dropwise addition of bromine
(0.15 mL, 1.21 mmol) gave an exothermic reaction. The reaction was
monitored by HPLC and LC-MS and completion of the reaction was
observed within 15 minutes. HPLC/LC-MS indicates the formation of
mono and bis-bromo-substituted products. An amount of 200 mL of
diethyl ether was added to the reaction mixture to form a
precipitate. The ether was decanted, and 200 mL fresh ether added,
and decanted once again. The yellow precipitate was filtered and
dried under vacuum for 5 minutes and was used for the next step
without any purification. Crude 2'-bromo-7-acetyl-sancycline was
dissolved in NMP (10 mL) and Na.sub.2SO.sub.3 (200 mg) was added to
prevent oxidation of products. K.sub.2CO.sub.3 (1 g, 7.25 mmol) was
added to the reaction solution, followed by addition of
2-amino-pyrimidine (1 g, 10.52 mmol). The reaction was monitored by
HPLC and LC-MS. Starting material was consumed after 30 minutes.
Crude material was precipitated in diethyl ether (200 mL); the
precipitate was filtered through a sintered glass funnel, and
washed with fresh ether. A dark yellow solid of crude material
(0.95 g) remained. The crude material was purified on a C-18 Luna
column using a 10-30% organic gradient (CH.sub.3CN with 0.1% TFA
and Water with 0.1% TFA). The purified compound was dried in vacuo
and redissolved in methanol (20 mL) saturated with HCl to exchange
the salt. The compound was dried overnight over P.sub.2O.sub.5 to
yield the product as a yellow powder. MS: (m/z) 532.2317. .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 9.22 (d, 1H), 9.03 (d, 1H), 8.24
(s, 1H), 0.7.72-7.62 (m, 2H), 7.04 (d, 1H), 4.13 (s, 1H), 3.18-2.94
(m, 9H), 2.18 (t, 1H), 1.59 (d, 1H), 1.26 (q, 1H).
Example 4
Preparation of
7-{3'-[ethyl-methyl-amino)-methyl]-phenyl}-sancycline
##STR00117##
[0405] A mixture of 7-(3'-formyl-phenyl)-sancycline (389 mg, 0.75
mmol), N-methyl-N-ethylamine (644 .mu.L, 7.5 mmol) and
triethylamine in 1,2-dichloroethane was stirred overnight. Sodium
triacetoxyborohydride (477 mg, 2.25 mmol) was added and stirred for
5 hours. Excess sodium triacetoxyborohydride (318 mg, 1.5 mmol) was
added and stirred for additional 2.5 hours. The solvent was
evaporated and purified by prep-HPLC (10-40% acetonitrile in
water). This was converted to hydrochloride salt to give a yellow
solid: MS (Mz+1=562); .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.56-7.38 (5H), 6.90 (m, 1H), 4.46 (m, 1H), 4.25 (m, 1H), 4.03 (d,
J=1.0 Hz), 3.31 (m, 1H), 3.19-2.72 (13H), 2.51 (m, 1H), 2.00 (m,
1H), 1.50 (m, 1H), 1.37 (t, 3H, J=7.3 Hz).
Example 5
Preparation of
7-{[3'-(2-methoxy-ethylamino)-methyl]-furan-2'-yl-methyl}-sancycline
##STR00118##
[0407] A mixture of 7-(3'-formyl-furan-2'yl)-sancycline (1.02 g, 2
mmol) and 2-methoxyethylamine (348 .mu.L, 4 mmol) in
1,2-dichloroethane (60 mL) was stirred for 1 hour. Sodium
triacetoxyborohydride (1.272 g, 6 mmol) was added and stirred for 7
hours. The solvent was evaporated and purified by prep-HPLC to give
a yellow solid: MS (Mz+1=568); .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.67 (m, 1H), 7.50 (m, 1H), 6.96 (m, 1H), 7.77 (m, 1H),
4.09-3.98 (3H), 3.59 (m, 2H), 3.33 (s, 3H), 3.16-2.93 (m, 10H),
2.69 (m, 1H), 2.46 (m, 1H), 2.14 (m, 1H), 1.55 (m, 1H).
Example 6
Preparation of
7-(5'-dimethylaminomethyl-1H-pyrrol-2-yl)-sancycline
##STR00119##
[0409] A mixture of 7-(1'-Boc-5'-formyl-pyrrol-2'-yl)-sancycline
(262.2 mg, 0.36 mmol), dimethylamine hydrochloride (148 mg, 1.8
mmol), and triethylamine (254 .mu.L, 1.8 mmol) in
1,2-dichloroethane (17 mL) was stirred for 1 hour. Sodium
triacetoxyborohydride was added and stirred overnight, after which
LC-MS showed the completion of the reaction. The solvent was
evaporated and purified by prep-HPLC (12-40% acetonitrile in
buffer). The resulting residue (85 mg) was stirred in 5 mL
trifluoroacetic acid for 2 hour. Trifluoroacetic acid was
evaporated and purified by prep-HPLC (10-40% acetonitrile in
water). The solvent was evaporated to give a yellow solid: MS
(Mz+1=537); .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 10.89 (s,
1H), 7.50 (m, 1H), 6.87 (m, 1H), 6.39 (brt, 1H), 6.14 (brd, 1H),
4.27 (s, 2H), 4.00 (s, 1H), 3.13-2.84 (9H), 2.81 (s, 6H), 2.49 (m,
1H), 2.00 (m, 1H), 1.55 (m, 1H).
Example 7
Preparation of
7-[2-(4-methyl-piperidin-1-yl)-acetyl]-sancycline
##STR00120##
[0411] 7-acetyl sancycline (1 g, 2.19 mmol) was combined with
acetic acid (4 mL), water (1 mL) and HBr (33 wt % solution in AcOH,
2 mL, 0.01 mmol) in a 40 mL glass vial. The reaction mixture was
stirred under argon until the contents were dissolved (5 minutes).
Bromine (0.15 mL, 1.21 umol) was added dropwise to the solution (an
exothermic reaction). Reaction was monitored by HPLC and LC-MS, and
the starting material was consumed within 15 minutes. Mono and
bis-substituted bromine products were both detected. An amount of
400 mL of diethylether was added to the reaction solution and a
bright yellow solid precipitate was formed. The ether was decanted,
400 mL fresh ether was added, and then decanted once again.
Acetonitrile (300 mL) was added to the resulting yellow precipitate
and the mixture was filtered through filter paper. The filtrate was
dried in vacuo to yield a dark yellow solid. The crude bromo acetyl
sancycline was dissolved in DMF (20 mL) in a 100 mL round bottom
flask. Argon line was attached to the reaction. TEA (1 mL, 7.19
mmol) was added, followed by 4-methylpiperidine (1 mL, 8.1 mmol).
The reaction was monitored by HPLC and LC-MS and the starting
material was consumed after 30 minutes. Methanol (50 mL) was added
to quench the reaction, and the solvent was dried in vacuo. The
crude material was purified on a C-18 Luna column using a 10-30%
organic gradient (CH.sub.3CN with 0.1% TFA and water with 0.1%
TFA). The purified compound was dried in vacuo and redissolved in
HCl saturated methanol to exchange the salt. The compound was dried
overnight over P.sub.2O.sub.5 to yield the product as a yellow
powder. MS: (m/z) 553. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.99 (m, 1H), 6.93 (m, 1H), 4.89 (m, 1H), 4.61 (m, 1H), 4.07 (s,
1H), 3.68 (m, 1H), 3.56 (m, 1H), 3.30 (m, 1H), 3.11 (m, 2H), 3.01
(m, 7H), 2.47 (m, 1H), 2.15 (m, 1H), 1.89 (m, 2H), 1.55 (m, 4H),
0.96 (d, J=9 Hz, 3H).
Example 8
Preparation of 7-[2-(1-methyl-1H-pyrrole-2-yl methyl
amino)-acetyl]-sancycline
##STR00121##
[0413] 7-acetyl sancycline (1 g, 2.19 mmol) was combined with
acetic acid (4 mL), water (1 mL) and HBr (33 wt % solution in AcOH,
3 mL, 0.02 mmol) in a 40 mL glass vial. Na.sub.2SO.sub.3 (200 mg)
was added to prevent oxidation of products. The reaction mixture
was stirred under argon until contents were dissolved (5 minutes).
Bromine (0.15 mL, 1.21 umol) was added dropwise to the reaction
solution (an exothermic reaction). The reaction was monitored by
HPLC and LC-MS, and the starting material was consumed within 15
minutes. Mono and bis-substituted bromine products were both
detected. An amount of 400 mL of diethylether was added to the
reaction solution and a bright yellow solid precipitate was formed.
The ether was decanted, 400 mL fresh ether added, and then decanted
once again. Acetonitrile (300 mL) was added to the yellow
precipitate, and the mixture was filtered through filter paper. The
filtrate was dried in vacuo to yield a dark yellow solid. The crude
bromo acetyl sancycline was dissolved in NMP (12 mL).
Na.sub.2SO.sub.3 (200 mg) was added to prevent oxidation of
products. K.sub.2CO.sub.3 (1 g, 7.25 mmol) was added to the
reaction solution, followed by
(1-methyl-1H-pyrrole-2-yl)-methylamine (1 mL, 7.25 mmol). The
reaction was monitored by HPLC and LC-MS and the starting material
was consumed after 30 minutes. The crude material was precipitated
in diethyl ether (500 mL), filtered through a sintered glass
funnel, and washed with fresh ether. A dark yellow solid of crude
material remained. The crude material was purified on a C-18 Luna
column using a 10-30% organic gradient (CH.sub.3CN with 0.1% TFA
and water with 0.1% TFA). Purified compound was dried in vacuo and
redissolved in HCl saturated methanol to exchange the salt. The
compound was dried overnight over P.sub.2O.sub.5 to yield the
product as a yellow powder. MS: (m/z) 564. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.93 (m, 1H), 6.91 (m, 1H), 6.74 (m, 1H), 6.27
(m, 1H), 5.99 (m, 1H), 4.71 (m, 1H), 4.44 (m, 1H), 4.27 (m, 2H),
4.07 (s, 1H), 3.71 (s, 3H), 3.58 (m, 1H), 3.28 (s, 1H), 3.15 (s,
1H), 2.95 (m, 7H), 2.38 (m, 1H), 2.11 (m, 1H), 1.55 (m, 1H).
Example 9
Preparation of 7-(3'-dimethylamino-propenyl)-sancycline
##STR00122##
[0415] A solution of propionaldehyde diethyl acetal I (12.9 mL, 90
mmol) in 60 mL THF was cooled in an ice-bath and BH.sub.3/THF was
added dropwise and stirred. A mixture of 7-iodosancycline
trifluoroacetate (5.889 g, 9 mmol), Pd(PPh.sub.3).sub.4, and
Palladium (II) acetate in methanol (160 mL) was purged with argon.
A solution of sodium carbonate (3.82 g, 36 mmol) in water (40 mL)
was added and purged for additional 5 minutes. To this mixture was
added DMF (40 mL) and reaction mixture I and further purged with
argon. The reaction mixture was heated to 44.degree. C. and stirred
at this temperature for 3 hour. This intermediate (MS, Mz+1=469)
was purified by short DVB column followed by prep-HPLC. To a
stirred solution of the intermediate (250 mg, 0.43 mmol),
dimethylamine hydrochloride (70 mg, 0.86 mmol), and triethylamine
(120 .mu.L, 0.86 mmol) in 1,2-dichloroethane (25 mL) was added
sodium triacetoxyborohydride (182 mg, 0.86 mmol) and the reaction
mixture was stirred for 1 hour. The solvent and excess reagent was
evaporated. The product was purified by prep-HPLC (5-25%
acetonitrile in water) to give a yellow solid: MS (Mz+1=562); NMR
(300 MHz, CD.sub.3OD) 57.79 (d, J=8.8 Hz, 1H), 7.43 (d, J=15.5 Hz,
1H), 6.91 (d, J=8.8 Hz, 1H), 6.14 (dt, J=15.5 Hz, 7.7 Hz, 1H), 4.10
(s, 1H), 3.94 (d, J=7.4 Hz, 2H), 3.28-2.89 (15H), 2.42 (m, 1H),
2.20 (m, 1H), 1.67 (m, 1H).
Example 10
Preparation of 7-(4-methyl-piperidin-1-ylmethyl)-sancycline
##STR00123##
[0417] 7-iodo sancycline (6 g, 9.17 mmol) was combined with NaOAc
(0.75 g, 9.17 mmol) and DMF (100 mL) in an oven-dried 500 mL 2-neck
round bottom flask. The reaction mixture was stirred at ambient
temperature for 1 hour under argon. An amount of
Pd(PPh.sub.3).sub.4 (1.06 g, 0.917 mmol) was added, and the
reaction mixture was purged with CO for 20 minutes. The reaction
mixture was placed in a 70.degree. C. pre-heated oil bath, and
stirred under CO atmosphere for 1 hour. An amount SnBu.sub.3H (3.2
g, 1.1 mmol) was added via syringe pump over 2 hours. The reaction
was monitored by HPLC and LC-MS, and the starting material was
consumed 2 hours post tin addition. The reaction was quenched with
CH.sub.3CN (50 mL), and the solvent was evacuated in vacuo. Water
(1 L with 0.1% TFA) was added, and a heterogeneous mixture was
formed. After filtration through celite to remove unwanted
precipitate, the aqueous layer was loaded onto a prepared DVB
column. The product was eluted with 30% organic gradient
(CH.sub.3CN with 0.1% TFA and water with 0.1% TFA). The solvent was
evaporated to yield 7-formyl sancycline product as a yellow solid.
The 7-formyl sancycline (0.5 g, 1.13 mmol) was combined with
InCl.sub.3 (0.025 g, 0.13 mmol), 4-methylpiperidine (0.267 mL, 2.26
mmol) and DMF (10 mL) in a glass vial. The reaction mixture was
stirred at ambient temperature for 30 minutes under argon. An
amount of NaCNBH.sub.3 (0.1 g, 1.58 mmol) was added to the reaction
mixture, and the progress of the reaction was monitored by HPLC and
LC-MS. After stirring overnight at ambient temperature, the
starting material was consumed. Methanol (10 mL) was added to
quench the reaction and the solvent was evacuated in vacuo. The
crude material was purified on a C-18 Luna column using a 10-30%
organic gradient (CH.sub.3CN with 0.1% TFA and water with 0.1%
TFA). The purified material was concentrated, and redissolved in
HCl saturated methanol (20 mL) to exchange the salt. After drying
overnight under high vacuum the product was obtained as a yellow
powder. MS: (m/z) 525. NMR (300 MHz, CD.sub.3OD) .delta. 7.54 (m,
1H), 6.86 (m, 1H), 4.22 (m, 2H), 4.03 (s, 1H), 3.44 (m, 1H), 3.27
(m, 1H), 3.15 (m, 1H), 2.94 (m, 9H), 2.31 (m, 2H), 1.61 (m, 6H),
0.90 (d, J=7 Hz, 3H).
Example 11
Preparation of 7-(4-dimethylamino-pyridin-3-yl)-sancycline
##STR00124##
[0419] In a 500 mL two-neck round bottom flask, 7-iodo-sancycline
TFA salt (654 mg, 1 mmol) and Pd(OAc).sub.2 (22 mg, 0.1 mmol) were
taken in 100 mL of MeOH. The reaction mixture was then heated to
70.degree. C. while purging with argon. After 5 minutes,
Na.sub.2CO.sub.3 (420 mg, 4 mmol, a saturated solution in 10 mL of
water) was added to the reaction mixture. A yellow precipitate was
obtained which was further heated at 70.degree. C. for 10 minutes.
To this, 4-dimethylamino-pyridin-3-yl-boronic acid (248 mg, 1.5
mmol, dissolved in 10 mL of DMF) was added and the reaction was
continued for another 3 hours. The progress of the reaction was
monitored by HPLC and LC/MS. The reaction was completed in 3 hours.
It was then filtered through celite to remove the catalyst. The
solvent was evaporated to dryness and the crude material obtained
was purified using preparative HPLC using a C-18 Luna column with a
10-40% organic gradient (CH.sub.3CN/0.1% TFA and Water/0.1% TFA).
The fractions collected were dried in vacuo and the solid obtained
was converted to its HCl salt using a saturated solution of
methanol-HCl (20 mL). The compound was dried overnight over
P.sub.2O.sub.5 to yield the product as a yellow powder. MS: (m/z)
535.2242. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 8.10 (d, 1H),
7.85 (s, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 6.86 (d, 1H), 3.98 (s,
1H), 3.20 (s, 6H), 3.08-2.82 (m, 8H), 2.49 (m, 1H), 2.45 (t, 1H),
1.84-1.47 (m, 1H), 1.44-1.19 (m, 1H).
Example 12
Preparation of 7-(4'-hydroxy-phenyl)-sancycline
##STR00125##
[0421] A solution of 7-iodosanscycline trifluoroacetate (654.43 mg,
1 mmol), Pd(PPh.sub.3).sub.4 (115.6 mg, 0.1 mmol), and palladium
(II) acetate (22.5, 0.1 mmol) in 20 mL methanol was purged with
argon for 10 minutes. A solution of sodium carbonate (424 mg, 4
mmol) in 5 mL water was added and the mixture was purged for
additional 5 minutes. A solution of 4-hydroxyphenyl boronic acid
pinacol ester in DMF (5 mL) was purged with argon and added to the
mixture. The reaction mixture was heated to 65.degree. C. and
stirred at the same temperature for 3 h. The reaction mixture was
cooled and filtered through celite pad. The filtrate was taken,
solvent evaporated and the crude product was precipitated from
ether. It was further purified by prep-HPLC (20-40% acetonitrile in
water) to give a yellow solid: MS (Mz+1, 507); .sup.1H NMR (300
MHz, CD.sub.3OD) 7.39 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H),
6.84 (m, 1H), 4.04 (s, 1H), 3.00-2.85 (9H), 2.44 (m, 1H), 2.05 (m,
1H), 1.55 (m, 1H).
Example 13
Preparation of minocycline-2-acetyl amide
##STR00126##
[0423] To a suspension of minocycline (0.1 g, 0.19 mmol) in
pyridine was added acetic anhydride with stirring. The suspension
became a clear solution. The reaction mixture was stirred at room
temperature overnight. The product was obtained after HPLC
purification as a yellow powder. MS: (M+1=500); .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.87 (d, J=8.8 Hz, 1H), 7.14 (d, J=9 Hz,
1H), 4.83 (d, J=3 Hz, 1H), 3.98 (m, 1H), 3.49-3.10 (15H), 2.60 (m,
1H), 2.40 (s, 3H), 19 (m, 1H).
Example 14
Preparation of 7-(3,4,5-trifluorophenyl)-9-aminomethyl
minocycline
##STR00127##
[0425] 7-iodo sancycline in methanesulfonic acid/TFA was treated
with excess hydroxymethylbenzyl carbamate (.about.5 equivalents).
The resulting reaction mixture was stirred for several hours. The
solvent was evaporated and to the residue was added to
methanol/water. The insoluble material was filtered and the
filterate was dried to yield the crude product. The desired
intermediate was obtained by preparative HPLC. To a solution of
7-iodo-9-aminomethylsanscycline trifluoroacetate in methanol was
added 0.2 equiv of tetrakis(triphenylphosphine)Palladium (0) and
the resulting solution was stirred under argon for 5 minutes. An
amount of 3 equivalents of sodium carbonate in water was added
followed by substituted phenylboronic acid. The resulting solution
was heated at 70.degree. C. for several hours. The catalyst was
filtered through celite, and the filtrate was dried to yield the
crude reaction product. The desired material was isolated via
reverse-phase preparative HPLC as a yellow solid. MS: M+1=574;
.sup.1H NMR (300 MHz, CD.sub.3OD), .delta. d 7.54 (s, 1H), 7.15 (t,
2H), 4.2 (s, 2H), 4.08 (s, 1H), 2.98-2.50 (m, 10H), 2.1 (bd, 1H),
1.6 (m, 1H).
Example 15
Preparation of
9-[(2-dimethylamino-acetylamino)-methyl]-doxycycline
##STR00128##
[0427] An amount of 5 g of doxycycline in 50 ml of TFA was treated
with excess hydroxymethylbenzyl carbamate (HMBC) (.about.5
equivalents). Several drops of sulfuric acid were then added and
the resulting reaction mixture was stirred for several hours. The
solvent was evaporated and to the residue was added methanol/water.
The insoluble material was filtered and the filterate was dried to
yield the crude product. The intermediate (9-aminomethyl
doxycycline) was obtained by preparative HPLC.
[0428] An amount of 800 mg of 9-aminomethyl-doxycycline was reacted
with 3 equivalents of N,N-dimethylglycinyl chloride in the presence
of diisopropylethylamine (3 equivalents) in DMF. The reaction
mixture was stirred at room temperature for several hours. The
product was obtained by preparative HPLC as a yellow solid. MS:
M+1=559; .sup.1HNMR (300 MHz, CD.sub.3OD) .delta. d 7.54 (d, 1H),
6.96 (d, 1H), 4.47 (s, 2H), 4.44 (s, 1H), 3.98 (s, 2H), 3.56 (q,
1H), 3.34 (s, 1H), 2.99-2.75 (m, 14H), 2.59 (q, 1H), 1.55 (d,
3H).
Example 16
Preparation of 7-hydroxy-9-[(2,2-dimethyl
propylamino)-methyl]-sancycline
##STR00129##
[0430] An amount of 9-[(2,2-dimethyl
propylamino)-methyl]-minocycline (2.0 g, 3.5 mmol) was added to DDI
water (40 mL) and pH adjusted to pH 11 using a 1.0 N solution of
sodium hydroxide. Subsequently, sodium metaperiodate (700 mg, 3.29
mmol) was added to the above solution and allowed to stir at room
temp for 40 seconds. Subsequently, a pre-dissolved aqueous solution
of ascorbic acid (5.0 g, 28 mmol) in DDI water (80 mL) was added to
quench the above reaction. The reaction was added to DDI water (1.0
L) and the pH was lowered to pH 2 using trifluoroacetic acid. The
solution was then filtered and concentrated onto a plug of divinyl
benzene (DVB) resin, eluted from the resin with acetonitrile and
concentrated via rotary evaporation to 800 mg crude product. The
crude product was purified by HPLC using a C-18 column,
triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as
the organic phase. The fractions containing the desired compound
were loaded onto a DVB plug, washed with aqueous 0.05 N HCl (1.0 L)
and eluted with acetonitrile to give the HCl salt of the product as
a yellow powder. MS: M+1=530; .sup.1H-NMR (300 MHz, CD.sub.3OD)
.delta. 7.1-7.3 (s, 1H), 4.2-4.3 (s, 2H), 4.0-4.1 (s, 1H), 2.9-3.2
(m, 8H), 2.8-2.9 (m, 2H), 2.1-2.3 (m, 2H), 1.6-1.9 (m, 1H), 1.0-1.1
(s, 9H).
Example 17
Preparation of 9-methyl minocycline
##STR00130##
[0432] A 1000 mL 2 or 3 neck round-bottomed flask with reflux
condenser was charged with anhydrous InCl.sub.3 (12.1 g, 40.5 mmol)
and dried under vacuum with a heat gun. After flask was cooled to
ambient temperature and flushed with argon, anhydrous THF (240 mL)
was added. The solution was cooled to -78.degree. C. and methyl
MgBr(Cl) (122 mmol) as solution in THF was added. After 15 minutes,
the solution was allowed to slowly warm to room temperature to form
a clear heterogeneous solution. To the reaction flask was added
9-iodominocycline (21.0 g, 36 mmol) and Pd(t-Bu.sub.3P).sub.2
(0.920 g, 1.80 mmol). The solution was heated to reflux under argon
until the reaction was complete. After cooling to ambient
temperature, the solution was quenched with MeOH (1 mL) and poured
into a stirring cold solution of 1M HCl (3 L). After 1 h, the
solution was filtered through a pad of celite rinsing with water.
The water solution was loaded onto a large fritted funnel
containing a bed of prepared DVB resin. At first, cold water (500
mL) was eluted then a gradient of cold acetonitrile/water was
eluted in (500 mL) fractions. The fractions containing product were
concentrated under reduced pressure and then dried under high
vacuum overnight to afford desired product as a dark yellow solid.
MS: M+1=472; .sup.1H NMR (300 MHz, CD.sub.3OD) S 7.26 (s, 1H), 4.22
(s, 1H), 3.41-3.35 (m, 1H), 2.90-2.52 (m, 15H), 2.21-2.00 (m, 4H),
1.68-1.55 (m, 1H).
Example 18
Preparation 9-(4-pyrazol)-minocycline
##STR00131##
[0434] To a solution of anhydrous 9-iodominocycline freebase (2.04
g, 3.5 mmol), pyrazolyl boronic acid (4.38 mmol) and
Cl.sub.2Pd(dppf) (0.143 g, 0.175 mmol) in NMP (10 mL) was added (10
mL) of 2M K.sub.3PO.sub.4 in a 20 mL Biotage microwave vial. The
secured vial was placed into a Biotage microwave reactor with a
temperature setting of 100.degree. C. for 10 minutes. The reaction
was cooled to rt and poured into a solution of 1% TFA/H.sub.2O (150
mL). The solution was loaded onto a previously prepared funnel of
DVB resin (3.times.10 cm packed DVB column). After loading, water
(100 mL) was eluted and finally 1% TFA/CH.sub.3CN to elute the
desired product. The yellow solution was concentrated under reduced
pressure and further purified by preparatory chromatography. The
product was obtained as a brown solid. MS: M+1=524; .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.69 (s, 1H), 8.32 (s, 1H), 4.18 (s,
1H), 3.41-2.94 (m, 15H), 2.60-2.49 (m, 1H), 2.35-2.29 (m, 1H),
1.73-1.61 (m, 1H).
Example 19
Preparation of 9-(thiazol-2-yl)-minocycline
##STR00132##
[0436] To a solution of anhydrous 9-iodominocycline freebase (2.04
g, 3.5 mmol), thiazol-2-yl stannane (4.38 mmol), CuI (0.067 g,
0.350 mmol), P(2-furyl).sub.3 (0.163 g, 0.700 mmol) and
Pd.sub.2(dba).sub.3 (0.081 g, 0.088 mmol) in DMF (20 mL) in a 20 mL
Biotage microwave vial. The secured vial was placed into a Biotage
microwave reactor with a temperature setting of 100.degree. C. for
10 minutes. The reaction was poured into a solution of 1%
TFA/H.sub.2O (150 mL). The solution was filtered through a plug of
Celite rinsing with 1% TFA water solution. The solution was loaded
onto a previously prepared funnel of DVB resin (3.times.10 cm
packed DVB column). After loading, water (100 mL) was eluted and
finally CH.sub.3CN to elute the desired product. The yellow
solution was concentrated under reduced pressure and further
purified by preparatory chromatography. The product was obtained as
an orange-yellow solid. MS: M+1=541; .sup.1H NMR (300 MHz,
CD.sub.3OD) S 8.88 (s, 1H), 8.12 (d, J=3 Hz, 1H), 7.98 (d, J=3 Hz,
1H), 4.19 (s, 1H), 3.50-2.92 (m, 15H), 2.65-2.53 (m, 1H), 2.40-2.22
(m, 1H), 1.76-1.61 (m, 1H).
Example 20
Preparation of 9-(3-methoxy-pro-1-ynyl)-minocycline
##STR00133##
[0438] An amount of 9-iodo-minocycline (free-base) (5.00 g, 8.57
mmol), trans-dichlorobis-(triphenylphosphine)palladium(II) (152 mg,
0.22 mmol), palladium(II)acetate (55 mg, 0.24 mmol),
copper(I)iodide (92 mg, 0.48 mmol) were loaded in anhydrous
acetonitrile (86 mL) in a flame-dried 100 mL round bottom flask
equipped with a magnetic stirring bar. The mixture was degassed by
bubbling argon through for 10 minutes, and diisopropylethylamine
(4.5 mL, 25.83 mmol) was added, followed by 3-methoxy-propyne (1.5
mL, 17.76 mmol). The reaction mixture was then stirred at room
temperature for 18 hours while being monitored by LC/MS. After
filtration through a pad of celite, the solution was poured into a
1% TFA in water solution (1 L) and purified on a DVB column by
eluting with a gradient of 1% TFA in water solution and a 50/50
mixture of methanol and acetonitrile. The major peak was isolated,
and all solvents were evaporated. The residue was then purified by
preparative HPLC (C18 Lumina). A salt exchange with a 0.2N HCl
solution on a DVB column followed by evaporation to dryness then
yielded the desired product as a yellow solid. MS: M+1=526.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .quadrature. 8.03 (s, 1H), 4.38
(s, 2H), 4.15 (d, 1H), 3.45 (s, 3H), 3.33-3.36 (m, 1H), 3.24 (s,
6H), 3.06-3.24 (m, 1H), 2.94-3.04 (m, 7H), 2.54 (m, 1H), 2.31 (m,
1H), 1.68 (m, 1H).
Example 21
Preparation of 9-cyano minocycline
##STR00134##
[0440] An amount of 9-iodo-minocycline (2.00 g, 3.43 mmol),
tetrakis(triphenylphosphine) palladium (0) (97 mg, 0.34 mmol), zinc
cyanide (500 mg, 4.17 mmol) were loaded in anhydrous DMF (20 mL) in
a dry 20 mL microwave reaction vessel equipped with a magnetic
stirring bar. Argon was bubbled through for 10 minutes, and the
vessel was sealed. The reaction mixture was then subjected to the
microwave irradiation for 10 minutes at 100.degree. C. with the
"heating while cooling" feature and is monitored by LC/MS. The
reaction mixture was poured into a 0.1M solution of sodium acetate.
The mixture was then filtered through a pad of celite, and washed
several times with the 0.1M sodium acetate solution. The resulting
aqueous solution was purified on a DVB column (gradient of water
and acetonitrile). After evaporation of the organic solvent, the
resulting residue is then purified by preparative HPLC (C18
Lumina). A salt exchange with a 0.2N HCl solution on a DVB column
followed by evaporation to dryness then yielded the desired product
as a yellow solid. MS: M+1=483. .sup.1H-NMR (300 MHz, CD.sub.3OD):
.quadrature. 8.13 (s, 1H), 4.13 (s, 1H), 3.40 (m, 1H), 2.90-3.16
(m, 14H), 2.52 (m, 1H), 2.28 (m, 1H), 1.65 (m, 1H).
Example 22
Preparation of 9-[5-(2-methoxy-ethylamino)-methyl
furan-2-yl]-minocycline
##STR00135##
[0442] An amount of 9-2-formyl-furany-2-yl minocycline (0.5 g, 0.91
mmol) was combined with 2-methoxyethylamine (0.157 mL, 1.81 mmol)
and 1,2-DCE (20 mL) in a glass vial. The reaction mixture was
stirred at ambient temperature for 10 minutes under argon.
NaCNBH.sub.3 (0.086 g, 1.36 mmol) was added to the reaction
mixture, and was stirred for 1 hour. Reaction was monitored by HPLC
and LC-MS, and the starting material was consumed after 1 hour.
Methanol (50 mL) was added to quench the reaction, and the solvent
was evacuated in vacuo. The crude material was purified on a C-18
Luna column using a 5-30% organic gradient (CH.sub.3CN with 0.1%
TFA and water with 0.1% TFA). Solvent was evacuated and, the
product was redissolved in HCl saturated methanol (20 mL) to
exchange the salt. After drying overnight under high vacuum the
product was obtained as a yellow powder. MS: (m/z) 610. .sup.1H NMR
(300 MHz, CD.sub.3OD) S 8.49 (s, 1H), 7.16 (d, J=3 Hz, 1H), 6.75
(d, J=3 Hz, 1H), 4.37 (s, 2H), 4.12 (s, 1H), 3.67 (m, 2H), 3.37 (s,
4H), 3.31 (m, 7H), 2.98 (m, 7H), 2.51 (m, 1H), 2.32 (m, 1H), 1.67
(m, 1H).
Example 23
Preparation of
9-[(4-methylphenyl)-thiocarboxylacyl]-minocycline
##STR00136##
[0444] To solution of 4-methylbenzenethiol sodium salt (20.0 g, 137
mmol) in anhydrous DMF (500 mL) under argon was added Bu.sub.3SnCl
(36.9 mL, 137 mmol) drop wise. After 12 hours, the solution was
poured into a 1:1 solution of hexane/water (1000 mL), and then the
layers were separated. The water layer was back extracted with
hexane (250 mL). The combined organic layers were dried over
anhydrous MgSO.sub.4, filtered rinsing with hexane, and then
concentrated under reduced pressure to afford 4-methylbenzenethil
tributyltin (56.5 g) as colorless oil in 99% yield. To a solution
of anhydrous 9-iodominocycline freebase (20.4 g, 35.0 mmol),
4-methylphenylthiotributyltin (15.9 g, 38.5 mmol) and
Pd(PPh.sub.3).sub.4 (2.02 g, 1.75 mmol) in anhydrous DMF (175 mL)
was bubbled CO for 15 minutes, then heated to 70.degree. C. with a
large balloon of CO affixed to the flask to maintain a positive
pressure of CO. After 12 hours, the reaction was cooled to room
temperature and poured into a cold 1:1 solution of 1% TFA/H.sub.2O
(500 mL) and MTBE (500 mL). After separating layers, the organic
layer was back extracted with 1% TFA/H.sub.2O (500 mL). The
combined water layers were loaded onto a previously prepared funnel
of DVB resin (7.times.15 cm packed DVB column). After loading, a
cold solution of 1M NaOAc was eluted until the eluent became basic
(approx. 300 mL), then water (400 mL) and finally 1:1
CH.sub.3CN/THF to elute the desired product. The yellow solution
was concentrated under reduced pressure and further dried under
high vacuum overnight to afford 18.5 g as an orange-yellow solid in
87% yield. MS: M+1=608; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
8.00 (s, 1H), 7.38-7.26 (m, 1H), 4.07 (s, 1H), 3.42-2.76 (m, 15H),
2.37 (s, 3H), 2.32-2.67 (m, 1H), 2.25-2.06 (m, 1H), 1.72-1.60 (m,
1H).
Example 24
Preparation of 9-propionyl minocycline
##STR00137##
[0446] A 1000 mL 2 neck round-bottomed flask with reflux condenser
was charged with anhydrous InCl.sub.3 (12.1 g, 40.5 mmol) and dried
under vacuum with a heat gun. After flask was cooled to ambient
temperature and flushed with argon, anhydrous THF (240 mL) was
added. The solution was cooled to -78.degree. C. and
CH.sub.3CH.sub.2MgBr(Cl) (122 mL, 122 mmol) as a solution in THF
was added. After 15 minutes, the solution was allowed to slowly
warm to room temperature to form (CH.sub.3CH.sub.2).sub.3In as a
clear heterogeneous solution. To a solution of
9-[(4-methylphenyl)-thiocarboxyl acyl]-minocycline (1.70 g, 2.80
mmol), Cu(I)-thiophenecarboxylate (0.801 g, 4.20 mmol),
Pd.sub.2(dba).sub.3 (0.064 g, 0.070 mmol) and P(2-furyl).sub.3
(0.130 g, 0.560 mmol) in anhydrous THF (5 mL) under argon was added
a 0.1M solution of previously prepared (CH.sub.3CH.sub.2).sub.3In
(56.0 mL, 5.60 mmol), then the solution was heated to reflux until
reaction was complete. After cooling to room temperature, the
solution was poured into cold 0.1M HCl (mL) and stirred for 1 hour.
The solution was added to celite and then filtered through a large
plug of Celite rinsing with cold water. The cold solution was
loaded onto a prepared column of DVB resin (3.times.10 cm packed
DVB column). When the loading was complete, water (300 mL) was
eluted, and then CH.sub.3CN was eluted until the eluent became
colorless. The yellow solution was concentrated under reduced
pressure, the further purified by preparatory chromatography. The
product was obtained as a yellow solid. MS: M+1=514; .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.28 (s, 1H), 4.13 (s, 1H), 3.42-2.91
(m, 17H), 2.63-2.47 (m, 1H), 2.32-2.15 (m, 1H), 1.70-1.54 (m, 1H),
1.14 (t, J=7 Hz, 3H).
Example 25
Preparation of 9-{1-[(E)-methoxyimino]-ethyl}-minocycline
##STR00138##
[0448] 9-acetyl-minocycline (3.00 g, 5.24 mmol) was dissolved in
methanol (50 mL) at room temperature in a dry 100 mL round bottom
flask equipped with a magnetic stirring bar. Methoxylamine
hydrochloride (2.23 g, 26.17 mmol) was then loaded in one portion,
and the mixture was stirred at room temperature for 3 hours while
being monitored by LC/MS. The solvent was evaporated to dryness,
and a 1% TFA in water solution was added in order to purify the
product on a DVB column. The product was eluted with a gradient of
1% TFA in water solution and a 50/50 mixture of methanol and
acetonitrile. All solvents were evaporated and the residue was
purified by preparative HPLC (C18 Lumina). After evaporating the
volatiles, the aqueous solution was then loaded on a DVB column and
washed with water to yield the product (a free base) as a yellow
solid. MS: M+1=529. .sup.1H-NMR (300 MHz, CD.sub.3OD): .quadrature.
7.35 (s, 1H), 3.94 (s, 3H), 3.76 (t, 1H), 3.39 (dd, 1H), 2.89 (m,
1H), 2.73 (s, br, 61-1), 2.66 (m, 1H), 2.61 (s, 6H), 2.22 (m, 1H),
2.21 (s, 3H), 2.12 (m, 1H), 1.65 (m, 1H).
Example 26
Preparation of 9-methoxyethylester minocycline
##STR00139##
[0450] To a bomb was added 9-iodominocycline free base (4.00 g,
6.86 mmol), 2-methoxy ethanol (50 mL),
tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.29 mmol),
triethylamine (1.5 mL, 2.7 g, 20 mmol). The bomb was closed and
charged with carbon monoxide (500 psi), heated to 70.degree. C. and
allowed to stir for 3 hours. The reaction was added to water (1.0
L) and the pH was lowered to 2 using trifluoroacetic acid. The
solution was then filtered through celite to remove the catalyst,
concentrated onto a plug of divinyl benzene (DVB) resin, eluted
from the resin with acetonitrile and concentrated via rotary
evaporation to give the crude product (4.5 g). The crude product
was purified by HPLC using a C-18 column, triethanolamine (0.002 M)
pH 7.4 aqueous buffer and acetonitrile as the organic phase. The
fractions containing the desired compound were loaded onto a DVB
plug, washed with aqueous 0.05 NaOAc (1.0 L) and eluted with
acetonitrile to give the free base of 9-methoxyethylester
minocycline as a dark red solid. MS: M+1=560; .sup.1H-NMR (300 MHz,
CD.sub.3OD) .delta. 8.7-7.9 (m, 1H), 4.3-4.5 (m, 3H), 3.7-3.8 (m,
2H), 3.4-3.6 (m, 3H), 2.9-3.0 (m, 3H), 2.5-2.8 (m, 12H), 2.2-2.4
(m, 1H), 2.0-2.2 (m, 1H), 1.6-1.9 (m, 1H).
Example 27
Preparation of 9-carboxylic acid minocycline
##STR00140##
[0452] To a 1.0 L round bottom flask was added 9-iodo minocycline
free base (30.0 g, 51.6 mmol),
[1,1'-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
complex with dichloro methane 1:1 (5.0 g, 6.13 mmol), DMF (500 mL)
and carbon monoxide (1 atm) was heated to 60.degree. C. for 1 hour.
Subsequently, a 1:1 solution of aqueous saturated sodium
bicarbonate and DMF (300 mL) was slowly added to the reaction. The
reaction was allowed to stir overnight then reduced to half the
volume using rotory evaporation (5 mm Hg, 60.degree. C.). The
reaction was added to water (4.0 L) and the pH was lowered to 3
using trifluoroacetic acid. The solution was then filtered through
celite to remove the catalyst, concentrated onto a plug of divinyl
benzene (DVB) resin, eluted from the resin using a 5-25% gradient
of acetonitrile in water buffered with an overall concentration of
0.1% TFA. The fractions containing compound were concentrated via
rotary evaporation to 11.0 g crude product. Some of the crude
product (1.0 g) was purified using HPLC using a C-18 column,
triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as
the organic phase. The fractions containing the desired compound
were loaded onto a DVB plug, washed with aqueous 0.05 N HCl (1.0 L)
and eluted with acetonitrile to give the HCl salt of the 9-carboxy
minocycline as a dark yellow solid. MS: M+1=502; .sup.1H-NMR (300
MHz, CD.sub.3OD) .delta. 8.5 (s 1H), 4.2 (s, 1H), 3.4-3.6 (m, 6H),
2.9-3.2 (m, 8H), 2.5-2.7 (m, 1H), 2.3-2.5 (m, 1H), 1.6-1.9 (m,
1H).
Example 28
Preparation of 9-(alpha-keto acid)-minocycline
##STR00141##
[0454] To a bomb was added 9-iodo minocycline free base (4.00 g,
6.86 mmol), DMF (50 mL), Pd(0) (1.59 g, 1.37 mmol), triethylamine
(2.0 mL, 2.8 g, 2.7 mmol) and piperidine (7.88 g, 6.78 mL, 6.8
mmol). The bomb was closed and charged with carbon monoxide (400
psi), heated to 70.degree. C. and allowed to stir for 3 h until the
9-piperidine amide dicarbonyl minocycline intermediate was seen
(M+1=597). The intermediate was then hydrolyzed to the product by
adding the reaction to water (1.0 L). The pH was lowered to 2 using
trifluoroacetic acid and the solution was then filtered through
celite to remove the catalyst, concentrated onto a plug of divinyl
benzene (DVB) resin, eluted from the resin with acetonitrile and
concentrated via rotary evaporation to 4 g crude product. The crude
product was purified by HPLC using a C-18 column, triethanolamine
(0.002 M) pH 7.4 aqueous buffer and acetonitrile as the organic.
The fractions containing the desired compound were loaded onto DVB
plug, washed with aqueous 0.05 HCl (1.0 L) and eluted with
acetonitrile to give the free base of 9-alpha-keto acid minocycline
as a yellow solid. MS: M+1=530; .sup.1H-NMR (300 MHz, CD.sub.3OD)
.delta. 8.1-8.3 (m 1H), 4.1 (s, 1H), 3.4-3.6 (m, 9H), 2.9-3.2 (m,
11H), 2.5-2.8 (m, 1H), 2.3-2.5 (m, 1H), 1.6-1.9 (m, 1H).
Example 29
Preparation of 9-carboxylic acid amide minocycline
##STR00142##
[0456] To 2 L flask was added (2.50 g, 4.30 mmol) 9-iodo
minocycline free base, NMP (16.5 mL), N-hydroxysuccinimide (2.50 g,
221 mmol). To remove residual water from the above reactants
toluene was added (500 mL), the flask was placed on the rotary
evaporator (35 mm Hg, 45.degree. C.) until all the toluene was
evaporated. The flask was backfilled with argon and the contents
were then transferred via cannula to a dry 50 mL flask. To the 50
mL flask was added tetrakis-(triphenylphosphine)palladium(0) (0.50
g, 0.40 m mol) and DIEA (3.0 mL, 174 m mol). The flask was placed
under vacuum (20 mm Hg) and purged with carbon monoxide three
times. The flask was then heated to 60.degree. C. under 1.0 ATM of
carbon monoxide and let stir for 3 h until all 9-iodo minocycline
was consumed and a peak for the corresponding
N-hydroxysuccinimide-ester intermediate (M+1=599) was formed as
determined via LC/MS. Subsequently, 37% aqueous ammonia hydroxide
(3.0 mL) was added and the reaction was allowed to stir for 5 min.
The reaction was added to water (1.0 L) and the pH was lowered to 2
using trifluoroacetic acid. The solution was then filtered through
celite to remove the catalyst, concentrated onto a plug of divinyl
benzene (DVB) resin, eluted from the resin with acetonitrile and
concentrated via rotary evaporation to 800 mg crude product. The
crude product was purified by HPLC using a C-18 column,
triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as
the organic phase. The fractions containing the desired compound
were loaded onto DVB plug, washed with aqueous 0.05 N HCl (1.0 L)
and eluted with acetonitrile to give the HCl salt of 9-carboxamide
minocycline as a beige colored solid. MS: M+1=501; .sup.1H-NMR (300
MHz, CD.sub.3OD) .delta. 8.4 (s 1H), 4.5 (s, 1H), 2.9-3.5 (m, 15H),
2.5-2.7 (m, 1H), 2.2-2.4 (m, 1H), 1.6-1.9 (m, 1H).
Example 30
In vitro Minimum Inhibitory Concentration (MIC) Assay
[0457] 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:
TABLE-US-00002 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 S. pseumoniae 3 .times. 10.sup.8 CFU/mL
[0458] 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 hour. 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.
[0459] The compounds shown in Table 2 below were determined to have
no measurable antibacterial activity.
[0460] Table 3 gives the MIC (.mu.g/mL) of selected substituted
tetracycline compounds against S. aureus, S. pseumoniae, and E.
coli. Compounds which showed superior inhibition of S. aureus, S.
pseumoniae and E. coli are indicated by "***," and compounds which
showed very good or good inhibition of S. aureus, S. pseumoniae and
E. coli are indicated by "**" or "*" respectively. The designation
"ND" indicates that no value was obtained.
TABLE-US-00003 TABLE 2 ##STR00143## ##STR00144## ##STR00145##
##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150##
##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155##
##STR00156## ##STR00157## ##STR00158## ##STR00159##
##STR00160##
Example 31
Assessment of Antimalarial Activity In Vivo
[0461] The assessment is performed with P. vinckei, a murine
parasite that consistently causes a rapidly fatal malaria, and is
an excellent model for drug efficacy. However, other murine
parasites which are available (e.g. P. berghei) can also be studied
using similar methodology.
[0462] 20 gm Swiss Webster mice are inoculated intraperitoneally
with 10.sup.6 P. vinckei-infected erythrocytes obtained from
another infected mouse. Twelve hours after infection, treatment is
initiated by the intraperitoneal injection of test compounds.
Treatment is continued twice-a-day (BID) for four days. The
progress of malaria infections in experimental and control
(injected with diluent only) mice is followed by daily examinations
of blood smears obtained from tail veins. The pharmacological
endpoint is parasitemia>50%. Uninfected animals are followed for
6 weeks, and the animals that remain uninfected through this period
are considered long-term cures.
[0463] The test compounds are injected into the stomach of the test
mice by gavage. A number of variations of standard in vivo protocol
may be utilized for specific purposes. For example, dosing
intervals may be altered based on the known pharmacokinetics or
observed initial efficacy data for a compound. Protocols may also
be altered to more closely mimic true treatment (with delay of
therapy after inoculation of parasites) or chemoprophylaxis (with
treatment before the inoculation of parasites) conditions.
[0464] For all in vivo experiments, the mice are monitored daily,
for at least the first two weeks of an experiment, with blood
smears. Counts per 1000 erythrocytes provide parasitemias, and the
parasitemias are then plotted over time, and results for control
and experimental animals are compared.
Example 32
Mammalian Cytotoxicity Assay
[0465] COS-1 and CHO-K1 cell suspensions were prepared, seeded into
96-well tissue culture treated black-walled microtiter plates
(density determined by cell line), and incubated overnight at
37.degree. C., in 5% CO.sub.2 and approximately 95% humidity. The
following day, serial dilutions of drug were prepared under sterile
conditions and transferred to cell plates. Cell/Drug plates were
incubated under the above conditions for 24 hours. Following the
incubation period, media/drug was aspirated and 50 .mu.l of
Resazurin (0.042 mg/ml in PBS w/Ca and Mg) was added. The plates
were then incubated under the above conditions for 2 hours and then
in the dark at room temperature for an additional 30 minutes.
Fluorescence measurements were taken (excitation 535 nm, emission
590 nm). The IC.sub.50 (concentration of drug causing 50% growth
inhibition) was then calculated. The cytotoxicity of both
unsubstituted minocycline and doxycycline were found to be greater
than 25. Table 3 shows the results of this assay. Compounds which
showed superior cytotoxicity are indicated by "***," and compounds
which showed very good or good cytotoxicity are indicated by "**"
or "*" respectively. The designation "ND" indicates that no value
was obtained.
TABLE-US-00004 TABLE 3 Median Median Median MIC for MIC for MIC for
Cytotoxicity Cytotoxicity S. aureus S. pneumoniae E. coli COS CHO
MOLECULAR RN450 157E MG 1655 Tox50 Tox50 STRUCTURE (mg/mL) (mg/mL)
(mg/mL) (mL) (mL) ##STR00161## *** *** * ** ** ##STR00162## *** **
* ** ** ##STR00163## * * * * * ##STR00164## *** *** * *** ***
##STR00165## ** ** * ** ** ##STR00166## * * * * * ##STR00167## * *
* * * ##STR00168## *** *** * ** ** ##STR00169## * * * * *
##STR00170## ** ** * * * ##STR00171## *** *** * * * ##STR00172##
*** ** * * * ##STR00173## *** *** * * * ##STR00174## *** *** ** **
** ##STR00175## *** *** * * * ##STR00176## *** *** * *** ***
##STR00177## *** *** * *** *** ##STR00178## *** *** * * *
##STR00179## *** *** * ** ** ##STR00180## * * * *** ***
##STR00181## *** *** * *** *** ##STR00182## * * * * * ##STR00183##
*** *** * ** ** ##STR00184## *** ** * * * ##STR00185## *** *** * *
* ##STR00186## *** ** * *** *** ##STR00187## * * * ** **
##STR00188## * * * * * ##STR00189## *** *** * *** *** ##STR00190##
* * * * * ##STR00191## * * * * * ##STR00192## ** * * * *
##STR00193## ** * * * * ##STR00194## * * * * * ##STR00195## * * * *
* ##STR00196## * * * * * ##STR00197## * * * * * ##STR00198## * * *
* * ##STR00199## *** *** * *** *** ##STR00200## * *** * * *
##STR00201## * *** * * * ##STR00202## * * * * * ##STR00203## ***
*** * *** *** ##STR00204## * ** * *** *** ##STR00205## ** ** * * *
##STR00206## * * * * * ##STR00207## *** ** * ** ** ##STR00208## * *
* * * ##STR00209## * * * * * ##STR00210## * * * ** **
EQUIVALENTS
[0466] 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.
* * * * *