Title of Invention

7-SUBSTITUTED TETRACYCLINE COMPOUNDS

Abstract The present invention pertains, at least in part, to novel 7-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.
Full Text

7-SUBSTITUTED TETRACYCLINE COMPOUNDS
Related Applications
This application claims priority to U.S. Provisional Patent Application Serial No. 60/275,576, entitled "7-Substituted Tetracycline Compounds" filed March 13, 2001, and U.S. Provisional Patent Application Serial No. 60/216,760, entitled "7-Substituted Sancycline Compounds" filed on July 7,2000; the entire contents of each of these applications are hereby incorporated herein by reference.
Background of the Invention
The development of the tetracycline antibiotics was the direct result of a systematic screening of soil specimens collected fi:om 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 conipounds 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,
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. Patent 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; 4,01,889; 4,024,272; and 4,126,680, These patents are representative of the range of pharmaceutically active -tetracycline and tetracycline analogue compositions.
Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically agmnst rickettsiae; a number of gram-positiye 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 tetmcyclines 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 ar pathogenic (e.g., pneumococci and Sahnonella). The rise of tetracycline-resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline' analogue compositions as antibiotics of choice.

Where in
X is CHC(R13Y'Y), CR6 R6 C==CR6 R6 S,NR6 or D
R2 R2, R4, and R4 are each independently hydrogen, alkyl, alkenyl
alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,
heterocyclic, heterdaromatic or a prodmg moiety;
R4 is NR4'R4, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
R2, R3, R10, R11 and R12 are each hydrogen or a pro-drag moiety;
R5 is hydroxyl, hydrogen thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aliylsvilfinyl, alkylsulfonyl, alkylmnino, arylalkyl, alkyl carbonyloxy, or aryl carbohyloxy;
R6 and R6' are each independently hydrogen, methylene, absent, hydroxyl Halogen, thiol, alkyl, alkenyl,alkyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, fdkylamino, or an aryl alkyl;
R is hydrogen, nitro, alkyl, alkenyl, aryl heterocylclic alkoxy
alkylthio, alkylsulfinyl, alkylsulfonyl,arylalkyl,amino, amido, arylakenyl,arylkyn
or (CH2)0-3 NR7o C(W=)WR7a
R9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, amidb, arylalkenyl, arylalkynyl,
thionitroso(e.g.

R7A , R7B, R7C, R7D, R7C, R9A, R9B, R9C, R9D, AND R7C are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylalkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
o
R IS hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkyllMo, alkylsnlfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R13is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio alkylsnlfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and
Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsnlfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.
The invention also pertains to 7-substituted sancycline compounds of the

is a fused ring inmoiety of the formula I where Q is C or a heteroatom; an acylfiiranyl group; a tri-, tetra- or penta- halo substituted phenyl group; an aminomethylphenyl group; an acylaminomethyl group; an alkylesterphenyl group; an acylphenyl group; an acylalkynyl group; an iacylalkoxyphehyl group; a mefliylphoiyl group; a dimethylphenyl group; a carboxyphenyl a group carbbxyalkynyl group; a thiophene group; a halothiophene group; an alkoxycarbonylphenyl group; an alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoypyridyl group; an alkylenepyridine group; a cyclopentyl or cyclopentenyl group; a cyclohexylalkynyl group; a cyclohexenylalkynyl group; a cyclohexenylhaloalkenyl group; a hydroxycyclohexylalkynyl group; aphenylalkynyl group; aphenylalkenyl group; an aminoalkynyl group; a cyclobutylalkenyl group; apyridylalkynyl group pyridylalkenyl group; a mtrophenylalkynyl group; a nitrophenylalkenyl group; a cyanoaikynyl group; an alkynyl group; acyanoalkenyl group; a cyanophenyl group; a dialkylaniidoalkenyl group; a diallqrlamidophenyl group; an aminophenylesthyl group; an aminophenylethynyl group; a haloethenyl group; a halophenylalkynyl group; or an alkylester-substituted pentenyl group; and phannaceutically acceptable salts thereof.

The invention also pertains to a method for%eating a tetracycline responsive state in a subject, by administering to the subject a 7-substituted tetracycline compound of the invention (e.g., of Formula I or II), such that Hxc tetmcycline responsive state is treated
The invention also includes pharmaceutical compositions comprising an effective amount of a 7-substituted tetracycline compound of the invention and, optionally, a pharmacejitically acceptable carrier.
Detailed Description of the Inventioa:
The present invention pertains, at least in part, to novel 7-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 appUcations for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.
The term "tetracycline compound" includes many compounds with a sinwlar ring structure to tetracycline. Examples of tetracycline compounds include: tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, and minocycline. Other derivatives and analogues comprising a similar four ring structure are also included. Table 1 depicts tetracycline and several known tetracycline derivatives.

The term "Jrsubstituted tetracycline compoxmds" includes tetracycline compounds with substitution at the 7 position. In one enibodiment, the substitution at the 7- position enhances Ihe ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states. In an embodiment, the 7-substituted

tetracycline compound is 7-substituted tetracycline (e.g., wherein R4 is NR4 R4, R'4 and R"4" are methyl, R4 is hydrogen andX is CR4R4', wherein R4 is methyl and R4' is hydroxy); 7-substituted doxycycline (e.g., wherein R4 is NR'4 R'4, R'4 and R'4 are methyl, R4 is hydroxyl and X is CR4R4', wherein R4 is methyl and R4' is hydrogen); 7-substituted tetracycline compovind, wherein X is CR4R4 , R'4, R4, R4 , and R4 are hydrogen; or 7- substituted sancycline (wherein R4 is NR'4 R'4", R'4 and R'4are methyl; R4 is hydrogen and X is CR4R4 wherein R4 and R4 are hydrogen atoms.
The invention pertains, at least in part, to 7-substituted tetracycline

wherein:
X is CHC(R13Y'Y), CR6R4, C=CR4'R4 S, I4 or O;
R4R4R'44,andR4' are each independently hydtbgen, allg4l, alkenyl, alkynyl, alkoxy, aUg4lthio, alkylsulfinyl, alkylsulfonyl, alkylaminb, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R'4 is NR'4'R'4", alkyl, alkenyl, alkynylj hydroxyl, halogen4 or hydrogen;
R4, R4, R44, R4 4 and R44 are each hydrogen or a pro-drag moiety;
R4 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaroriiatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyljmflino, arylallQ4l, alkyl c4
R4andR4' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkbjQ4i alkylthio, alkylsulfinyl, allQ4lsulfonyl, Mkylainino, arylalkyl, or, when taken together, I
R4 is iiiteo, all ' ZisCR44,S,NR4VO; '
Z4isO,S,orNR44
W is CR'44 S, NR44r O;
W'isO,NR'4S;

R4 R44 R4 R'44 R4", K4\ R4\ R4\ R4\ and R44 are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkyl&io, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R4 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and
Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, alkylthio4 alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof. In certain embodiment, R4 is not nitro or amino.
In an embodiment, X is CR4R4'; R4 R4', R4 R4', R4 R4 R44 R44 and R44 are each hydrogen; R"4 is NR"4 R"4; R"4 and R"4 are lower alkyl (e.g., methyl); and R4 is hydroxy or hydrogen.
In an embodiment, R is aryl. Examples of aryl R groups include substituted or unsubstituted phenyl. The phenyl R4 group can be substituted with any substituent which allow the tetracycline compound to perform its intended function. Examples of substituents include, but are not limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkylqxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbpnyl, alkenylcarbonyl, alkoxycarbonyl, sUyl, aminocarbonyl4 alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phpsphinatp, cyano, amino, acylamino, amido, imin alkylthio, stdfate, arylthio, thiocarbpxylate, alkylsulfinyl, sulfonato, sidfemoyl, sulfonamido, nitro, cyano, azidp, heterocyclyl, alkylaryl, aryl and heteroaryl.
In a further embodiment, the phenyl R group is substituted with substituted or unsubstituted allc4L Examples of substituents of the alkyl include heterocycles such as, motpholine, piperdine, and pyrrolidine. In another further embodiment, the phenyl R group is substituted with an amino group. The amino group
also may be further substituted e.g., with an alkyl, alkenyl, alkynyl, carbonyl, alkoxy or aryl (e.g., substituted or iinsubstituted, heteroaryl, phenyl, ete,) group. The phenyl
amino substituent may be substituted with any substituent or combination of substituents
which allow it to perform its intended function. Examples of sudi substituents include halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), amino (e.g., which can in turn be substituted with an alkyl, carbonyl, alkenyl, alkynyl, or aryl moiety), and arylamino (e.g., phenylamino).





In a futher embodiment, the alkenyl, R. group is subsuted with a
substituted or unsubstituted phenyl. The phenyl can be substituted with any substituent which allows it to perform its intended function. Examples of substituents include those listed supra for other phenyl moieties. Other examples of substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alfcoxy (e.g., methoxy, ethoxy, propoxy, perfluoromethyl, perchloromethyl, etc.), hydroxy, or alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.) groups.
Another example of R include substituted and unsubstituted alkynyls. The alkynyl moieties can be substituted with any substituent or combination of substituents which allow the tetracycline compound of the invention to perform its intended function. Examples of the substituents include, but are not limited to alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,4 alkyloxycarbonyi, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxyearbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl moieties.
In an embodiment, the alkynyl R7 moiety is substituted with an aryl, e.g., substituted or unsubstituted heteroaryl, phenyl, etc. This aryl moiety may be substituted with any substituent or combuiations of substituents listed supra for the alkynyl R moiety. Examples of advantageous substituents include, but are not limited to, carbonylamino (e.g., alkylcarbonylamino, dialkylcarbonylamino, arylcarbonylamino, etc.) and sulphonamido groups.
In another embodiment, the alkynyl R7 group is substituted with a tetracycline moiety. The term "tetracycline moiety4' includes a four ring tetracycline ring system as described above. This may be connected to the alkynyl R group through a linker of 1-20 atoms. The linker may be attached to the tetracycline moiety at any position on that ring system which is convement or allows the compound to perform its intended function. In a certain embodiment, the tetracycline moiety is attached to the linker at its 7 position.
Other examples of R7 moieties include substituted and unsubstituted alkylcarbonyl amino, sulfonamido, imino and carbonyl moieties. The carbonyl moieties may be substituted with a substituted or unsubstituted alkyl group. Examples of possible substituents of the alkyl group) include, but are not limited to, aryl mpieties such as phenyl and heteroaryls (e.g., pyridinyl, etc.). Examples of substituents of the imino group include, but are not limited to, hydroxy and alkoxy groups.

In another embodiment, R"4 is NR44(C=W')WR44 Examples of tetracycline compounds of the invention include compounds wherein R444 is hydrogen, W is oxygen and W is oxygen. In certahi embodiments, R444 is substituted or unsubstituted phenyl. Examples of substituents include, but are not limited to, alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, alkylcarbonylamino, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxyc4rbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyU alkenylcarbonyU alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, araikyl, phosphonato, phosphinato, cyano, anuno, acylamino, amido, knino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfihyl, sulfonate, sulfamoyl, sulfonamido, nitro, cyano, asado, heterocyclyl, alkylaryl, aryl and heteroaryL In a further embodiment, R44 is substituted or unsubstituted alkyl.

heteroatom; an acylfuranyl group; a tri-, tetra- of penta-hialo substituted phenyl group;-Em aminomethylphehyl groi4; an acylaminomethyl group; an allQ4lesteiphenyl group; an acylphenyl group; an acylalkynyl group; mi acylalkoxyphehyl group; ainethylphenyl '■' group; a dimethylphenyl group; a carboxyphenyl group; a carboxyalkynyl group; a tiuophene group; ahalothiophene group; an alkoxycarbonylphenyl group; an alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoxypyridyl group; an alkylenepyridine group; a cyclopentyl or cyclopenteiiyl group; a cyclohexylalkynyl group; a cyclohexenylalkynyl group; a cyclohexenylhaloalkenyl group; a hydroxycyclohexylalkynyl group; aphenylalkynyl group; aphenylalkenyl group; an aminoalkynyl group; a cyclobutylalkenyl group; a pyridylallqmyl group; a pyridylalkenyl group; a nitrophenylalkynyl group; a nitrophenylalkenyt group; a

cyanoalkynyl group; an alkynyl group; a cyanoalkenyl group; a cyanophenyl group; a dialkylamidoalkenyl group; a dialkylamidophenyl group; an aminophenylethyl group; an aminophenylethynyl group; a haloethenyl group; a halophenylalkynyl group; or an alkylester-substituted pentenyl group; and pharmaceutically acceptable salts thereof.
The term "7-substituted sancycline compounds" includes sancycline compounds witii a substituent at the 7 position, as described in formula L In a further embodiment, both R74 and R7 are each methyl,
■ . . . , i-
In a further embodiment, R is a fiised ring moiety of the formula I Where Q is C or a heteroatom. Examples of sancycline compounds with this R7 substituent include 7-(2-benzofuran) sancycline.
In yet another embodiment, R is an acylfuranyl group. Examples of sancycline compounds with this R substituent include 7-(3-fonnylfuranyl) sancycline.
In yet another embodiment, R7 is a tri-, tetra- or penta- halo substituted phenyl group. Examples of sancycline compounds with this R substituent include 7-(2,3,4,5,6-pentafluorophenyl) sancycline.
In yet another embodiment, R is an aminomethylphenyl group. Examples of sancycline compoimds with this R7 substituent include 7-(4-aminometiiylphenyl) sancycline.
In yet another embodiment, R' is an acylaminomethyl group. Examples of sancycline compounds with this R7 substituent include 7-(4-formylaminomethylphenyl) sancycline.
In yet another embodiment, R is an alkylesterphenyl group. Examples of sancycline compoimds with this R7 substituent include 7-(4-carboxyphenyl methylester) sancycline iand 7-(2-carboxyphenylethyiester) sancycline.
In yet ianother embodiment, R7 is an alkyiphenyl group. Examples of sancycline compoimds with this R7 substituent include 7-(4-tolyl) sancycline.
In yet another embodiment, R is an acylphenyl group. Examples of sancycline compounds with this R siibstituent include 7-(3-formylphenyl) sancycline, 7-(4-formylphenyl) sancycline, 7-(3-acetylphenyl) sancycline, 7-(2-acetylphenyl) sancycline, 7-(3-acetylpbenyl) sancycline, and744"acetylphenyl) sancycline.
In yet ahotiier embodiment, R is an iacylalkoxyphenyl group. Examples of sancycline compounds with this R7 substituent include 7-(3-fbrmyl-6-methojsyphenyl) sancycline.
In yet another embodiment, R is a mefhylphenyl group. Examples of sancycline compounds with this R7 substituent include 7-(4-melhylphenyl) sancycline.

In yet anotheR7 embodiment, R7 is a dimethylphenyl gR7oup. Examples of sancycline compounds with this R7'4 substituent include 7-(3,5-dimethylphenyl)
sancycline.
In yet anotheR7 embodiment, R7 is a caR7boxj4henyl gR7oup. Examples of sancyclme compounds with this R7 substituent include 7-(3-caR7boxyphenyl) sancycline.
In yet anotheR7 embodiment, R7 is a caR7boxyalkynyl gR7oup. Examples of sancycline compounds with this R7 substituent include 7-(caR7boxyethynyl) sancycline.
In yet anotheR7 embodiment, R7 is a thiophene gR7oup. Examples of sancycline compounds with this R7 substituent include 7-(3"thiophene) sancycline, 7-(3-methyl-l-thiophene) sancycline, and 7-(3-methyl-5-thiophene) sancyclme.
In yet anotheR7 embodiment, R7 is a halothiophene gR7oup. Examples of
» ■■■'■■
sancycline compoimds with this R7 substituent include 7-(3-chloR7o-2-thiophene) sancycline and 7-(4-chloR7o-2-thiophene) sancycline.
In yet anotheR7 embodiment, R7 is an alkoxycaR7bonylphenyl gR7oup. Examples of sancycline compounds vAih this R7 substituent include 7-(2-ethoxyt4iR7bonylphenyl) sancycline.
In yet anotheR7 embodiment, R74 is an alkoxyphenyl gR7oup. Examples of sancycline compounds wifli this R7 substituent include 7-(2-ethoxyphenyl) sancycline, 7-(3-ethox5T)henyl) sancycline, 7-(4-methoxyphenyl) sancycline, and 7-(2,5-dimethoxyphenyl) sancycline.
In yet anotheR7 embodiment, R7 is an alkoxyphenylalkynyl gR7oup. Examples of sancycline compounds with tMs R7 substituent include 7-(4-methoxyphenylethynyl) sancycline.
In yet anotheR7 embodiment, R7 is an alkoxypyR7idyl gR7oup. Examples of
sancycline compounds with this R7 substituent include 7-(4-methoxy-5-pyR7idyl)
sancycline. ,
In yet anotheR7 embodiment, R7 is a cyclopentyl oR7 cyclppentenyl gR7oup.
Examples of sancycline compounds with this R7 substituent include 7-(cyclopentenyl)-
sancycline.
In yet anotiieR7 embodunent, R7 is a cyclohexylalkynyl gR7oup. Examples
of sancycline compounds with this R7 substituent include 7-(cyclohexylethynyl)
sancycline.
In yet anoflieR7 embodiment, R7 is a cyciohexenylaUcynyl gR7oup. Examples of sancycline compounds with this R7J sub4tuent include 7-(l-etiiynyH-cyclohexyl) sancycline.
In yet anotheR7 embodiment, R7 is a cyclohexenylhaloalkenyl gR7oup. Examples of sancycline compounds with this R7 substituent include 7-(l-chloR7ovinyl-l-cyclohexyl) sancycUne.

In yet another embodiment, r' is a hydroxycyclohexylalkynyl group. Examples of sancycline compounds with this r substituent include 7"(l-ethynyl-l-hydroxycyclohexyl) sancycline.
In yet another embodiment, r is a phenylalkynyl group. Examples of sancycline compounds with this r substituent include 7-(phenylethynyl) sancycline, 7-(tolylethynyl) sancycline, and 7-(4-methoxyphenyletiiynyl) sancycline.
In yet anotiier embodiment, r isaphenylalkenylgroup. Examples of sancycline compounds with this r substituent include 7-(2-vinylpyridyl) sancycline and 7-(vinylphenyl) sancycline.
In yet anoflier embodiment, r is an aminoalkynyl group. Examples of sancycline compoimds with this r substituent include 7-(dimethylaminoethynyl) sancycline.
In yet another embodiment4 r is a cyclobutylalk4nyl group. Examples of sancycline compounds with this r substituent include 7-(cyclobutylmethenyl) sancycline.
In yet another embodiment, R is a pyridylalkynyl group. Examples of sancycline compounds with this r substituent inciude 7-(2-pyridylethynyl) sancycline and 7-(3-pyridylethynyI) sancycline.
In yet another embodiment, r is a pyridylalkenyl group. Examples of sancycline compounds with this r substituent include 7-(4-pyridylethenyl) sancycline.
In yet another embodiment, r is a nitrophenylalkynyl group. Examples of sancycline compounds with this r substituent include 7"(4-nitrophenylethynyl) sancycline.
In yet another embodiment, r is a nitrophenylalkenyl group. Examples of sancycline compoimds with this r substituent include 7-(4-nitrostyryl) sancycline.
In yet ano&er embodiment, r is an alkynyl group. Examples of sancycline compounds with this r substituent include 7"(ethynyl) sancycline.
In yet another embodiment4 r is a cyanoalfcynyl grotip. Examples of 4-sancycline compounds wth this r substituent include 7"(cyano-l-pentynyl) sancycline.
In yet another embodiment, r is a cyanoalkenyl group. Examples of sancycline compounds with this r substituent include and 7-(cyanohexenyl) sancycline.
In yet another embodiment, r is a cyanophenyl group. Examples of sancycline compounds vath this r substituent include 7-(3-cyanophenyl) sancycline and 7-(4-cyanophenyl) sancycline.
In yet another embodiment, r is a hydroxylphenylethynyl group. Examples of sancycline compounds with this r substituent include 7-(3-hydroxylphenylethynyl) sancycline.

In yet another embodiment, K' is a dialkylamidoalkenyl group. Examples of sancycline compoimds with this r substituent include 7-(N,N-dimethylacrylamide) sancycline and 7-(dimethylamidoetfienyl) sancycline; In yet another embodiment, r is a dialkylamidophenyl group. Examples of sancycline compounds with this r substituent include 7-(3-dimethylamidophenyl) sancycline.
In yet another embodiment, r is an aminophoaylethyl group. Examples of sancycline compounds with this r substituent include 7-(4-aminophenylethyl) sancycline.
In yet another embodiment, r is an aminophenylethynyl group. Examples of sancycline compounds with this r substituent include 7"(4-aminophenylethynyl) sancycline.
In yet another embodiment, r is a haloethenyl group. Examples of sancycline compounds with this r substituent include 7-(2-chloroethenyl) sancycline.
In yet another embodiment, r is a halophenylalkyiiyl group. Examples of sancycline compounds with this r substituent include 7-(2-fluorophenylethenyl) sancycline.
In yet another embodiment, r is an alkylester-substituted pentenyl group. Examples of sancycline compounds with this r substituent include 7-(l-iodo-l,3-dicarboethoxy-l,3-butadiene) sancycline, .
In yet another embodiment, r is an aminophenylalkynyl group. Examples of sancycline compounds with this r"4 substituent include 7-(4-ammophenylvinyl) sancycline.









In a further embodiment, tiie invention pertains to 7-substituted tetracycline compounds of the formulae:
The invention also pertains to each of the 7-substituted tetracycline compounds shown in Table 2, as well as their pharmaceutically acceptable salts, esters, and prodrugs.
The tetracycline compounds of this invention can be synfliesized using the methods described in Schemes 1-8.
Certain 7-substituted tetracycline compounds can be synthesized by the method shown in Scheme 1. Although in each scheme saiicycline is used as the tetracycline compound, one of skill in the art will appreciate that the methodology can.4 also be applied to other tetracycline compounds such as tetracycline and doxycycline.


Generally, 7-substituted tetracycline compounds can be synthesized as
shown in Scheme 1 for sancycline. Sancycline (1 A) is treated with sulfuric acid and
sodium nitrate. The resulting product is 7-nitro (IB) sancycline (in a mixture with the 9-
position isomers). The nitro sancycline compound is then treated with hydrogen gas and
a platinum catalyst to yield the 7-amino sancycline compound, IC. To sjoithesize 7
derivatives, the 7-amino sancycline compound is treated with HONO, to yield the
diazonium salt (ID). The salt can subsequently be treated with numerous compoxmds
possessing an alkene or n bond functional group such as alkenes, aryls, and alkynyls
(e.g., rBr) yielding the 7-substituted sancycline compound (IE).


As shown in Scheme 2, tetracyclme compounds of the iriventidn Wherem r is a carbamate or a urea derivative can be synthesized using the following protocol. Sancyclihe (2A) is treats with NaNOa under acidic conditions forming 7-4 sancycline (2B) in a mixture of positional isomers. 7-nitrosancycUne (2B) is then treated with H2 gas and a platinxmi catalyst to form the 7-amino sancycUne derivative (2C). To form the urea derivative (2E), isocyanate (2D) is reacted with the 7-amino sancycline derivative (2C). To form the carbamate (20), the appropriate acid chloride ester (2F) is reacted with 2C.
■ '4


As shown in Scheme 3, tetracycline compounds of the invention, wherein r is a heterocyclic (i.e, iMazole) substituted amino group can be synthesized using thie above protocol. 7-amino sancycline (3 A) is reacted wth 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 a-haloketone (3E) to produce a thiazole substituted 7-amino sancycline (3F).

7- alkenyl tetracycline compounds, such as 7-alkynyl sancycline (4A) and 7-alkenyl sancycline (4B), can be hydrogenated to form alkyl 7- substituted tetracycline compoimds (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 palladiimi/carbon catalyst imder pressure, to jdeld the product.


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 compoxmd (5B) can be Synthesized from sancycline by treatmg sancycline (5A) with at least one equivalent N-iodosuccinimide (NIS) Under acidic conditions- The reaction is quenched, and tiie restilting 7-iodo sancycline (5B) can then be purified using standard techniques known in tiie art. To form the aryl derivative, 7-iodo sancycline (5B) is treated with an aqueous base (e.g., NaaCOa) and an appropriate boronic acid (5C) and under an inert atmosphere. The reaction is catalyzed witii a palladium catalyst (e.g., Pd(OAc)2). The product (5D) can be purified by metiiods known in the art (such as HPLC), Other 7-aryl and alkynyl tetracycline compounds can be synthesized using similar protocols.
The 7-substituted tetracycline compounds of the invention can also be syntiiesized using Stille cross couplings. Stille cross couplings can be performedusing an appropriate tin reagent (e,g., r-SnBua) and a halogenated tetracycline compound, (e.g., 7-iodosancycline). The tin reagent and tiie iodosancycline compound can be treated with a palladium catalyst (e.g., Pd(PPh3)2Cl2 or Pd(AsPh3)2Cl2) and, optionally, with an additional copper salt, e.g., Cul. The resulting compound can then be purified using techniques known in tiie art.


The aiyl derivatives formed by Suzuki or Stille couplings, can be further derivitized. For example in Schenie 6, a fonnyl aryl sancycline (6A), an aniine, and a solvent (e.g., 1,2 dichloroethane) are combined in a reaction flask. A reducing agent is tiien added (e.g., NaBH(0Ac)3. and the reaction is allowed to proceed proceed to completion to yield the product (6B). The product is purified and characterized using standard methods.

The compounds of the invention can dso be synthesized using cross coupling reactions. As shoAvn in Scheme 7, Heck-tj4e cross-coupl4 performed by suspending a halogenated tetracycline compound (e.g., 7-iodosancycline, 7A) and an appropriate palladium or other transition metal cataLyst (e.g., Pd(0Ac)2 and Cvl) in an appropriate solvent (e.g., degassed acetonitrile). The substrate, a reactive alkene (7B) or alkyne (7D), and triethylamine are then added and titie mixture is heated for several hours, before being cooled to room temperature. The resulting 7-substituted alkenyl (7C) or 7-substituted all4nyl (7E) tetracycline compound can then be pmified using techniques known in the art


To prepare 7-(2'-Chloro-alkenyl)-tetracycline compounds, the following procedure can be used, 7-(alkynyl)-sancycline (8A) is dissolved in saturated methanol and hydrochloric acid and stirred. The solvent is then removed to yield the product
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, cyclopetityl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can fiirttier 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 aUcyl has 6 or fewer carbon atoms in its backbone (e.g., C1-C6 for straight chain, C3-C6 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 C1-C6 includes alkyl groups contdning 1 to 6 carbon atoms.
Moreover, the term alkyl includes both "unsubstituted alkyls" and
44kubstituted 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,
alkylcarbonylo5ig4, arylcarbonyloxy, aikoxycaA aryloxycarbonyloxy,
cafboxylate, alkylcgrbonyl, arylcarbonyl, alkbxycarbonyl, aminocatbonyl, , alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, di arylamino, diarylamino, and alkylarylamino), acylamirio (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthib, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulforiainido, nitro, trifluoronlethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be fiirther 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 imnatural amino acids.
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 pyrunidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylesnedioxyphenyl, 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, alkylcarbonylo>Q4, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, pho4hate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidirio, 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 ajicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
Tlie terni "alkenyl" includes imsatLu-ated aliphatic groups
length and possible substitution to the alkyls described above, but that contain at least
one double bond., -
For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g.j, ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyelopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups j 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., C24C6 for straight chain, G3-C6 for blanched 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 C2-C6 includes alkenyl groups containing 2 to 6 carbon atoms.
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, aiyloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoearbonyl, 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, aiylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic of heteroaromatic moiety.
The term "alkynyl" includes unsatumted aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl4 heptynyl, octynyl, nonynyl, decynyl, etc.), braiiched-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 mdre 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,, C2-C5 for strai4t cham, C3-C6 for branched chain). The term includes alkynyl groups containing 2 to 6 carbon atoms.
Moreover, the term alkynyl includes both "unsubstituted aliynyls" and-4 "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 mclude, for example, alkyl groups, alky groups, halogens;, hydro4l, allg4lcarbonyloxy, arylcaAonyloxy, alkoxycarbonyloxy, aiyloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, dkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoearbonyl, 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, allylsulfinyl, sulfonato4 sulfamoyl, sulfonamido.

nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having firom one to five carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms.
The term "acyl" includes compounds and moieties which contain the acyl radicd (CH3CO-) 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, all4lcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyt alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, 4Icarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkyltihdo, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato4 sulfamoyl, sulfonamido, nitro, -trifluoromethyl, cyano, azido, heterocyclyl, 4Ikylaryl4 or an aromatic or heteroaromatic moiety.
The term "acylamino" includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes aUg4lcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
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.
The terms "alkoxyalkyl", "alkylaminpalkyl" and/44 include alkyl groups, as described above, which fiirther include oxygen, nitrogen or sulfiir atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen4
«
nitrogen or sulfiur atoms.
The term "alkoxy" includes substituted and unsubstituted alkyl, alkeJnyl,
4 ■
and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include rnethpjg4 ethoxy, isopropyloxy, propoxy, butoxy, and pent05cy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, h4 alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy4 carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, diaUg4laminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino.

aiylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido4 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.
The term "anune" or "amino" includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term includes "alkyl amino" >\iiich comprises groups and compounds wherein the nitrogen is bound to at least one additional alkyl group. TTie term "dialkyl mnino" 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, respectively4 The term "alkylarylamino," "alkylaminoaryl" or "aiylaminoalkyl" 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 attynyl group bound to a nitrogen atom which is also bound to an alkyl group.
The term "amide," "amido" or "aminocarbonyl" includes compoxmds 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 boimd to an amino group
bound to a carbonyl group. It includes aaylaminocarbonyl and arylcarbonylamino
groups which include aryl or heteroaryl moieties bound to an amino group which is
boimd to the carbon of a carbonyl or thiocarbonyl group. The terms
"alkylaminocarbonyl," "alkenylaminocarbonyl," "alkynylaminocarbonyl,"
"arylammocaibonyl," "allQ4lcarbonylanunOi" "alkenylcarbonylamino,"
"alkynylcarbonylamino," and "aiylcarbonylaimno" are included in term "amide."
Amides also include urea groups (aminocarbonylamino) and earbaniates
(oxycarbonylamino). x
The term "carbonyl" or "carboxy" includes compounds and moieties \44ch contain a carbon connected with a double bond to an oxygen atom. Tlie carbonyl caa be further substituted with any moiety which allows the compounds of the invention to perform its intended fimction. 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.

The term 'thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
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 alfcyl group.
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, ethoxycarbonylj propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alk>iiyl groups are as defined above.
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 alkthioalkyiiyls. The term "alkthioalkyls" include compoimds with an alkyl, alkenyl, or alkynyl group bonded to a sulfiir atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or all The term "hydroxy" or "hydroxyl" includes groups with an-OH or-O". 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.
The terms "polycyclyl" or "polycyclic radical" refer to two or more cyclic
rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aiyls 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 ?itoms 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, aiyloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, .
allg4laminoacarbonyl, arylalkylaminocarbonyU alkenylaminocarbonyl, alkylcarbonyl,
: arylcaJrbonyl, arylalkyl carbonyl, aUcenylcarbonyl, aminocarbonyl, alkylfliiocarbonyl,
alkoxylj phosphate, phosphonato, phosphinato, cyano, ajmido, amino (including alkyl
amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), anaidind,
imino, suLfhydryl, allylthio, arylthio4 thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,
alkylaryl, or an aromatic or heteroaromatic moiety. v

The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
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 metaboUzed 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) "Pharnmceutical Salts", J. Pharm, Sci. 66:1-19). The prodmgs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its firee acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of :j>rodrug moieties include substituted and imsubstituted, branch or unbmnched lower -alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amiiio lower-alkyl esters (e.g., dimethylauMnoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower aUg4l 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.
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 enantioniers 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 stmctures and other icompoimds and moieties discussed in this application also include all tautomers thereof
The invention also pertains to methods for treating a tetracycline responsive states in subjects, by administering to a subject an effective amount of a 7- -substituted tetracycUne compound of the invention (e.g., a compoimd of Formula (I) or shown in Table 1), such that the tetracycline responsive state is treated.
The language "tetracycline compound req>bnsive 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 infections (including those which are resistant to other tetracycline compounds), cancer, diabetes, and other states for which tetracyclme compounds have been found to be active (see, for example, U.S. Patent Nos. 5,789,395; 5,834,450; and 5 j532,227). Compounds of the invention can be used to prevent or control important mammalian and veterinary diseases such as diarrhea, mrinary 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)).
Bacterial infections may be caused by a wide variety of gram positive and gram negative bacteria. The compounds of the invention are usefiil 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 brotii dilution method described in Wmtz, J. A,, National Commission/or Clinical Laboratory Standards, Document M7'A2, vol. 10, no. 8, pp. 13-20,2""4 edition, Villanova, PA (1990).
The tetracycline compounds may also be used to treat infections traditionally treated with tetracycline compoimds suchas, 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 toeat infections of, eg., K pneumoniae. Salmonella4 E. hirae, A. baumanii, B. catarrhalis, H. influenzae, P. aei4ginosa, E.faecium, E, coli, S. aureus or E.faecalis, In one embodiment, the tetmcycline 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 pharmaceulically acceptable carrier.
The language "effective amount" of the compound is that amoxmt necessary or sufficient to treat or prevent a tetracycline ci3mpound responsive state. The effective amount can vary depending on such factors as the size and wei4t of the subject, the type of illness, or the particular tetracycline compound For example, the choice of the tetracycline cpmpoxmd can affect what constitutes an 44effective amoxmt". 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 compoxmd -4 without undu4 experimentation.
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, advantageouslyj an animal, e.g., a manmial, e.g., a human.
In the therapeutic methods of the invention, one or more tetracycline compounds of die invention may be administered alone to a subject, or more typically a compoxmd of the invention will be administered as part of a pharmaceutical composition in mixture vsdth 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.
The invention also pertains to pharmaceutical compositions comprising a therapeutically effective amount of a tetmcycline compound (e.g., a compound of Formula 1, Table 2, or other compound described herein) and, optionally; a pharmaceutically acceptable carrier.
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 pharaiaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, Tinagnesium stearate, talc, silicic acid, viscous paraffin4 perfume oil, fatty acid imonoglycerides 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 tiie invention.
The tetracycline compounds of the inventioh that are basic in nature are capable of fonning 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 nontoxic acid addition salts, i.e., salts containing pharmaceiitically acceptable anions, such as the hydrochloride, hydrobrornide4 hydroiodide, nitrate, sulfate, bisulfatCi phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citmte, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fiimarate, gluconate, glucaronate, saccharate4 fonnate, benzoate, glutamate4 methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pahnoate [Le., 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 tibe free base compound by treatment witibt an alkaline recent and subsequently convert the latter free base to a pharmaceutically acceptable acid adiiition 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 meditim or in a suitable organic solvoit, such as methanol or elhanol. 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.
The preparation of other tetracycline compounds of the invention not specifically described in Ihe foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
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 phannaceutically acceptable base salts of those tetracycline
compounds of the invention that are acidic in nature are tho4 that formnon-toxic base
salts with such compounds.. Such non-to5dc base salts include, but are not limited to
those derived from such phannaceutically acceptable cations such as alkali metal cations
(e.g., potassium and sodiimi) and alkaline earth metal cations (e.g., calcium and
magnesivun), anunoniwn or water-soluble amine addition salts such as N-
methylglucanune-(megluiiune), and the lower alkanolammonium and other base salts of
pharmaceutically acceptable organic amines. The pharaiaceutically acceptable base
addition sdts of tetracycline compounds of the invention that are acidic in nature may be
formed with pharmaceutically acceptable cations by conventional metiiods. 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 alfcyl alcohol solution of the tetracycline compound of the
invention may be mixed with an alkoxide of the desired metal and the solution
subsequentiy evaporated to dryness. (■
The preparation of otheir tetracyclinecompbunds of theinvention hot specifically described in the foregoing e3q)eriinental section can be accompU4ed using4 combinatioi\s of the r4ctions described above that will be apparent to those skilled in theart
. The tetracycline compounds ofthe 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 ofthe subject being treated and the particular route of administration chosen. Variations may occur depending upon the species of tiie 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.

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 tiie invention.
The tetracycline compounds of the invention may be administered alone 4r in combination with pharmaceuticaliy 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 admimsitered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceuticaliy acceptable inert carriers in the form of tablets, capsules, lozengesy troches, hard candies, powders, sprays, creams, salves, siq)positories, jellies, gels, pastes, lotions, ointments, aqueotxs suspensions, injectable solutions, elisors, 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 firom about 5.0% to about 70% by weight
For oral administrntioUj tablets containing various excipients such as jmicrocrystalline cellulose, sodium citrate, calcitmi carbonate, dicalciimi phosphate and .4glycine may be employed along with various disintegrants such as starch (and preferably com, potato or tapioca starch), alginic acid and certain complex isilicates, 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 usefiil for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this icormection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral admitdstration, 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 therof

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 shotild 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 prepeu4ations 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.
Additionally, it is also possible to administer the compounds of the present invention topic4ly when treating inflammatory conditions of the skin. Examples of methods of topical administration include transdermal, buccal or sublingual application. Fortopical appUcations, therapeutic compoimds 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, isopropylpahnitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodium lauryl sulfate 5% in water, and the like. In addition, materials such4 as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired;
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 com starch and/or potato starch. A syrup, elixir or the like can he used wherein a sweetened vehicle is employed. Sustained release compositions can be formulated including those wherem the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
In addition to treatmejit of human subjects, the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of livestock such as catde, sheep4 goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys and Ihe 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.

It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compoimd 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 ascertmned by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines.
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 pet 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 miUigrams per kilogram body weight of recipient per day. The desired dose is suitably administered once daily, or several sub4doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day4or other appropriate schedule. It will also be understood that normal, conventionally known precautions will be taken regarding the administration of tetracyclines generally to ensure their efficacy imder normal use circumstances. Esqpecially when employed for then treatment of humans and animals in vivo4 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.
Furthermore, the invention also pertains to the use of a tetricycline compound of formula I, for tiie preparation of a medicament The medicament may include apharmaceuticdly acceptable carrier and the tetracycline compound is an effective amount, e.g., an effective amount to treat a tetracycline responsive state.
EXEMPLIFICATION OF THE EWENnON
Compounds of the invention may be made as described below, with-modifications to the procedure below within the skill of those of ordinary skill in the art
EXAMPLE 1: Synthesis of 7-SubstiitutedSancycIines
■7Iodo Sancycline
One gram of sancycline was dissolved in 25 mL of TFA (trifluoroacetic acid) that was cooled to 0 C (on ice). 1.2 equivalents of N-iodosuccinimide (NTS) was added to the reaction mixture and reacted for forty minutes. The reaction was removed

irom uie jiuc DULU aiiu was iuiuwcu lu react at room lemperaiure lor an aaaiuonai live hours. The mixture was then analyzed by HPLC and TLC, was driven to completion by the stepwise addition of NIS. After completion of the reaction, the TFA was removed in vacuo and 3 mL of MeOH was added to dissolve the residue. The methanolic solution was the added slowly to a rapidly stirring solution of diethyl ether to form a greenish brown precipitate. The 7-iodo isomer of sancycline weis purified by treating the 7-iodo product with activated charcoal., filtering through Celite, and subsequent removal of the solvent in vacuo to produce the 7-isomer compound as a pure yellow solid in 75% yield. MS(M+H) (foraiic acid solvent) 541.3. Art: Hypersil C18 BDS Colunm, 11,73
4HNMr (Methanol d4-300 MHz) 8 7.87-7.90 ( d, IH), 6.66-6.69 (d, IH), 4,06 (s, IH), 2.98 (s, 6H), 2.42 (m, IH), 2.19 (m, IH), 1.62 (m, 4H), 0,99 (m, 2H)
Compound B (7-Phenyl Sancycline)
74odosancycline, 150 mg (0,28 mM), Pd(0Ac)2 and 1 0 mL of MeOH are added to a flask with a stir bar and the system degassed 3x using argon, NaaCOa (87 mg, 0.8 mM) dissolved in water and argon degassed is added via syringe is added along wth phenylboronic acid (68 mg, 0.55 mJM4 in MeOH tiiat was also degassed. The reaction was followed by HPLC for 2 hours and cooled to room temperature. The solution was filtered, and dried to produce a crude mixtmre. The solid was dissolved in dimethylforaiamide and injected onto a preparative Iff LC system using CI 8 reverse-phase silica The firaction at 36-38 minutes was isolated,.and the solvent removed in vacuo to yield the product plus salts. The ssits were removed by extraction into 50:25:25 water, butanol, ethyl acetate and dried m vacwo. This solid was dissolved in MeOH and the HCl salt made by bubbling in HCl gas. The solvent was removed to produce the product in 42% yield as a yellow soUd4
rt21.6min: MS (M+H, formic acid solvent): 49L3 -
4HlSravlr (Methanol d4-300 MHz)5 7.87 ( d, J=r8.86Hz, IH), 7.38 (m, 5H), 6464 (d, 8.87 Hz, IH), 4.G0 (s, IH), 3.84 (s, 2H), 3.01 (s, 6H), 2;46 (m, 2IQ, L63 (m, 4H), 0.95 (m,2H)
Compoxmd E (7-(4'"Chlorophenyl) Sancycline)
7-iodosancycline4 500 mg (0.91 mM), Pd(QAc)2 21 mg, and 20 mL of MeOH are added to a flask with a stir bar and the system degassed 3x using argon. NaaCOa (293 mg, 2,8 mM) dissolved in water and argon degassed is added via syringe is added along with 4-Cl-phenylboronic acid (289 mg, 1.85 mM) in MeOH that was also degassed. The reaction was followed by HPLC for 45 minutes and cooled to room

temperature. The solution was filtered, and dried to produce a crude mixture. The solid was dissolved in dimetiiylformamide and injected onto a preparative HPLC system using C18 reverse-phase silica. The fraction at 39 minutes was isolated, and the solvent removed in vacuo to yield the product plus salts. The salts were removed by extraction into 50:25:25 water, butanol, ethyl acetate and dried in vacuo. This solid was dissolved in MeOH and tiie HCl salt made by bubbling in HCl gas. The solvent was removed to produce the product in 57% yield as a yellow solid.
rt 20.3 min: MS (M+H, formic acid solvent): 525.7
4HNMr (Methanol d4-300 MHz)5 7.49-7.52 ( d, J=8.54 Hz, IH), 6.99-7.01 (d, 8.61
Hz, IH), 4.12 (s, IH), 3.67 (m, IH), 3.06 (s, 6H), 2.58 (m, 2H), l;62(m, 4H), 1.01 (m,
;2H)
Compound A (7-(4'-Fluorophenyl) Sancycline)
7-iodosancycline, 200 mg (03 mM), Pd(OAc)2 8.3 mg, and 10 mL of MeOH are added to a flask wiih a stir bar and the system degassed 3x using argon. NaiCOs (104 mg, LI mM) dissolved in water and argon degass4 is added via syringe is added along witiL4-F-phenylboronic acid (104 mg, 0.7 mM) in MeOH that was also degassed. The reaction was followed by HPLC for 20 minutes and cooled to room temperature. Tlie solution was filtered, and dried to produce a crude mixture. The solid was dissolved in dimethylformamide and injected onto a preparative HPLC system using CI8 reverse-phase silica. The fraction at 19-20 minutes was isolated, and the solvent removed in vacuo to yield the product plus salts. The salts were rnoved by extraction into 50:25:25 water, butanol, ethyl acetate and dried m vacwo. This solid was dissolved in MeOH and the HCl salt made by bubbling in HCl gas. The solvent was removed to produce the product in 47% yield as a yellow solid. rt 19.5 mm: MS (M+H, fomiic acid solvent): 509.4
'HNMR (Methanol dj-SOO MHZ)5 6.92-6.95 (d, IH), 7.45-7.48 Compound AT (7-(4'-Iodo-r,3'-carboefcoxy-rv,3'-butadiene) Sancycline) .
7-I-Sancycline (1 gm, 1.86 mmol), was dissolved in 25 mL of acetonitrile and was degassed and purged wifli nitrogen (three times). To this susjpension Pd(0Ac)2 (20 mg, .089 mmol), Cul (10 mg, .053 mmol), (o-tolyl)3p (56 mg, .183 mmOl) were added and purged with nitrogen. Ethyl propiolate (linL) and trieliiylamine (1 mL) were added to the suspension. It turned to a brown solution upon addition of EtaN. The

reaction mixture was then heated to 70 degrees C for two hours. Progress of the reaction was monitored by HPLC. It was then cooled down to room temperature and was filtered through celite. Evaporation of the solvent gave a brown solid, which was then purified on preparative HPLC to give a yellow solid.
Compound AI (7-(2'-Chloroethenyl>Sancycline)
To a solution/suspension of 0.65 g (1 mmol) of 7-iodo sancycline, 0.05 g tetrakis triphenyl phosphinato palladate, 0.012 g palladium acetate, 0.05 g copper (I) iodide in 10 mL acetonitrile, 2 mL triethylamine and 0.5 g trimethylsilyl acetylene was added at room temperature. The reaction proceeded for two hours before being filtered through a celite bed and concentrated. The crade product was purified by preparative HPLC. The collected firactions were concentrated and the residue was taken up in about 1 mL of methanol and 2 mL of HCl saturated methanol. The product was precipitated with ether. The solids were filtered offand dried imder reduced pressure. NMr spectroscopy and LC-MS showed that the compound was 7-(2"Chloroethenyl) sancycline.
Compound D (7-(44"aminophenyl) Sancycline)
To a solution of 200 mg of 7-(4-nitrophenyl) sancycline in 50 mL methanol, 10 mg of 10% palladium on charcoal catalyst was added. Tlie reaction mixture was shaken xmder 40 psi hydrogen pressure for 2 hours and was then filtered followed by concentration. The residue was further purified by preparative HPLC. 35 mg was isolated as the HCl salt and tiie structure was proved by MNr and LC-MS to be 7-(4-aminophenyl) sancycline.


SCHEME 9
A flask was charged with 74odosancycline (3,0 g, 4.57 mmol, 9A), Pd(OAc)2 (0.102 & 0.46 mmol), Cul (0.044 g, 0.23 mmol), and P(0"ToI)3 (0.278 g, 0.91 mmol) and the contents were suspended in anhydrous acetonitrile. After purging this mixture with dinitrogen at 60 4'C (bath temperature), 1,7-octadiyne (0.305 mL, 2.29 mmol, 9B) was added to it, followed by the addition of triethylamine. The dark colored solution was stirred at 60 ""C for 3h, filtered through a bed of celite, dried. A methanol: DMF: TFA (90:8:2) solution of the product (9C) was purified on preparative HPLC column. The final product (9C) was characterized by HPLC, MS, and 4H NMr spectroscopy.

7-I-Sancycline (1 gm, 1,86 mmol), taken in 25 mL of acetonitrile was degassed and purged with nitrogen (three times). To this suspension Pd(0Ac)2 (20 mg, .089 mmol), Cul (10 mg, .053 mmol), (o-tolyl)3p (56 mg, 0.183 mmol) were added and pxirged with nitrogen for few minutes. NN-Dunethylpropyne (308 mg, 3,72 mmol) and triethylamine (1 mL) were added to the suspension. It was turned into a brown solution upon addition of EtaN. The reaction mixture was then heated to 70 °C for 3 hours. Progress of the reaction was momtored by HPLC. It was then cooled down to rt and was filtered through celite. Evaporation of the solvent gave a brown solid, which was then purified on preparative HPLC to give a yellow soUd. The structure of this compound has been characterized using IH NMr, HPLC, and MS.


7"(alkynyl)-sancycline (100 mg) was taken in 20 ml of saturated MeOH/HCl and stirred for 20 min. The solvent was then evaporated to give a yellow powder. The structure of this compound has been characterized using IH NMr, HPLC, and MS.

7-(3 '-Methoxyphenylethynyl)-sancycline (Immol)/ was taken in saturated solution of MeOH/HCl. To this solution 10% Pd/C was added and was subjected to hydrogenation at 50 psi for 12 hrs. It was then filtered through celite. The solvent was evaporated to give a yellow powder. Finally, it was precipitated jfrom MeOH/diethylether. The structure of this compound has been cha4cterized using IH NMr, HPLC, and MS.

NN-Dimethylglycine (1.2 mmol) was dissolved in DMF (5 mL) and O-Benzotriazol-l-yl-A4, N, N\ iST'-tetramethyluronium hexafluorophoq)hate (HBTU,L2 mmol) was added- The solution was then stirr6d for 5 minutes at room temperature. To this solution, 7-aminosancycline (1 mmol, lOA) was added, followed by the addition of diisopropylethyl amine (DIEA, 1.2 mmol). The reaction was then stirred at room temperature for 2 hours. The solvent, DMF, was removed on vaccum. The crade material was dissolved in 5 mL of MeOH and filtered using autovials and purified using preparative HPLC. The structure of the product (lOB) has been characterized using IH NMr,HPLC,andMS.



7-iodo-sancycline (12A, Ig, 1.5 3mmol), Pd(0Ac)2 (34 mg, 0.153 irnnol), and MeOH (50 mL) were combined in a 250 mL 2 neck round bottom flask equipped with a condenser and argon line. The solution was then purged with argon (15min) while heated in an oil bath to approximately 70°C. Sodium carbonate (482mg, 4.58mmol) was dissolved in water (3-5mL) and added to reaction flask. The flask was ttien purged with argon for another 5 minutes, 2-Methoxy-5-fonnylphenyl boronic acid (12B, 333mg, l,83nimol) was dissolved in MeOH (5mL) and added to reaction flask. The flask was then purged again with argon for 10 minutes. The reaction was monitored to completion within 3 hours. The contents of the flask were filtered through filter paper and the remaining solvent was evacuated. To make the hydrochloric acid salt, the residue was dissolved in MeOH (sat. HCl) to make the HCl salt. The solution was then filtered and the solvent was evacuated. The product (12C) was then characterized by 4H NMr, LC-MS.

The aldehyde (12A, Ig, 1.82mmolVdimethylaniine HC1(13B, 297 mg, 3.64 mmol), triethylamine (506 jxL, 3.64 mmol), and 14-DCE (7 mL) were combined in a 40 mL vial. The contents were dissolved wiihin several minutes of shaldng or stirring. Sodiim triacetoxyborohydride (772 mg, 3.64 mmol) was flieri added as a solid. The reaction was monitored by HPLC and LC-MS and was complete within 3 hours. The reaction was quenched with MeOH (2 OmL) and the isolvent was subsequently evacuated. The residue was redissoWed in 3mLDMF arid separated on a C-18 coliimn. Fractions jfrom the prep column dried down in-vacuo and tiie HCl salt was made by dissolving contents in methanol (sat HCl). The solvent was reduced and a yellow powder formed (13C). Characterized by 4H NMr, LC-MS, HPLC,

Example 2: In vitro Minimum Inhibitory Concentration (MIC) Assay
The following assay is used to determine the efficacy of the tetracycline compounds gainst common bacteria. 2 mg of each compound is dissolved in 100 41 of DMSO. The solution is then added to cation-adjusted Mueller Hinton broth (CAMHB), which results in a final compound concentration of 200 (ig per mL The tetracycline compound solutions are diluted to 50 \xL volvimes, with a test compound concentration of .098 4ig/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 1x104 CFU/ml. At 0D=1, cell densities for different genera should be approximately:

50 |al of the cell suspensions are added to each well of microtiter plates. The final cell density should be approximately 5x104 CFU/ml- These plates are incubated at 35°C in an ambient air incubator for approximately 18 far. 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. Compounds of the invention indicate good inhibition of growth.
In Table 2, compounds which were good inhibitors of growth of a particular bacteria are indicated with 4, compounds which were very good inhibitors of a partictdar bacteria are indicated with 44, and compounds with were particularly good inhibitors of a particular bacteria ai4e indicated with 4 44.
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain using no more than routing experimentation, numerous equivalents to the specific procedures -4 described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the following clmms. The contents of dl references, patents, and patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and mediods of those patents, applications and other documents may be selected for the present invention and embodiments thereof.










































































wherein:
X is CHC(R13Y' Y), CR6R6, C=CR6R6, S, NR6, or O;
R2, R2', R4', and R4" are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R4 is NR4 R4 , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;
R2',R3,R10,RuandR12 are each hydrogen or a pro*drug moiety;
R5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R°and R° are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,or an arylalkyl;
R is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, oR9 is hydrogen, nitro, alkyl, alkenyl, alkynyl,aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso(e.g.^— N-S), or -(CH2)o-3NR9cC(-Z')ZR9a;
ZisCR^R^S.NR^ofO;
Z'isO,S,orNR9f;
W is CR7dR7c, S, NR7b or O;
W'isO,NR7fS;
R7a, R7b, R7c, R7d, R7e, R9a, R9b, R9c, R9d, and R*3 are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an aiylalkyl; and
Y5 and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an aiylalkyl, and pharmaceutically acceptable salts thereof.
2. The tetracycline compound of claim 1, wherein R4 is NR4 R4", X is CRV; R2, Ry, R6, R6', R8, R9, R10, Rn, and R12 are eachhydrogen; R4' and R4" are lower alkyl; and R5 is hydroxy or hydrogen.
3. The tetracycline compound of claim 2, wherein R4 and R4" are each methyl and Rs is hydrogen.
4. The tetracycline compound of any one of claims 1-3, wherein R7 is aryl.
5. The tetracycline compound of claim 4, wherein R is substituted or unsubstituted phenyl.
#
6. The tetracycline compound of claim 5, wherein said phenyl is substituted
with a substituent selected from the group consisting of alkyl, alkenyl, halogen,
hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,
alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,
alkylcarbonyl, alkylaminoacarbonyl, aiylalkyl aminocarbonyl, alkenylaminbcarbonyl,
alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, ■ i
alkoxycarbonyl, silyi, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl,
phpsphonato, phosphinato, cyano, amino, acylamino, amido/imino, sulfhydryl,
alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl,
sulfonamide, aitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryL
7. The tetracycline compound of claim 6, wherein said substituent is substituted or unsubstituted alkyl.
8. The tetracycline compound of claini 5, wherein said alkyl is substituted with a heterocycle.
9. The tetracycline compound of claim 8, wherein said heterocycle is nxorpholine, piperdine, or pyrrolidine.

10. The tetracycline compound of claim 5, wherein said phenyl is substituted
with an amino group.
1L The tetracycline compound of claim 10, wherein said amino group is
substituted with one or more substituent selected from the group consisting of alkyl, alkenyl, alkynyl, carbonyl, alkoxy and axyl group.
12. The tetracycline compound of claim 11, wherein said amino group is substituted with an alkoxy group.
13. The tetracycline compound of claim 11, wherein said amino group is substituted with a substituted or unsubstituted phenyl group.
14. The tetracycline compound of claim 13, wherein said substituted phenyl is substituted with a halogen.
15. The tetracycline compound of claim 13, wherein said substituted phenyl amino group is substituted with a second substituted amino group.
16. The tetracycline compound of claim IS, wherein said second substituted amino group is substituted or unsubstituted aryl.
17. The tetracycline compound of claim 16, wherein said second substituted amino group is a second substituted phenyl.
18. The tetracycline compound of claim 5, wherein said phenyl group is substituted with alkoxy.
19- The tetracycline compound of claim 5, wherein said phenyl group is
substituted with an alkoxycarbonylamino group. :
20. The tetracycline compound of claim 4, wherein said aryl group is
substituted or unsubstituted napthyl.
.21 • The tetracycline compound of claim 20, wherein said naphthyl grouj) is
substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy,

carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aiylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, aiylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, dkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl,
22. The tetracycline compound of claim 21, wherein said substituent is amino orformyL
23. The tetracycline compound of claim 4, wherein R is heteroaryl.
.24. The tetracycline compound of claim 23, wherein said heteroaryl is
selected from the group consisting of furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyL, naphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl.
25. The tetracycline compound of claim 24, wherein saidiieteroaryl is thiazolyl, thiophenyl, or furanyl.
26. The tetracycline compound of any one of claims 1-3, wherein R7 is substituted or unsubstituted alkyl.
27. The tetracycline compound of claim 26, wherein said alkyl is a straight or branched chain.
28. The tetracycline compound of claim 27, wherein said alkyl is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyi, t-butyl, pentyl, or hexyl.
29. The tetracycline compound of claim 26, wherein said alkyl comprises a cycloalkyl.
30. The tetracycline compound of claim 29* wherein said cycloalkyl is
cyclopentyl, cyclohexyl, cyclopropyl, or cyclobutyl.

31. The tetracycline compound of claim 26, wherein said alkyl is substituted with one or more substituents selected from the group consisting of alkenyl, halogen, hydroxy!, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyioxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aiylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylearbony^ alkoxycarbonyl, silyl, aminocarbonylj alkylthiocarbonyl, phosphate, araikyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.
32. The tetracycline compound of claim 31, wherein said alkyl is substituted with an amino, hydroxy, carboxy, carbonyl or aryl group.
33. The tetracycline compound of claim 32, wherein said aryl group is heteroaromatic.
34. The tetracycline compound of claim 33, wherein said heteroaromatic
group is furanyl,imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl,
benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl,
methylenedioxyphenyl, indolyl, thien^l, pyridinyi, pyrazolyl, pyrimidyl, pyrazinyl,
purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphtbridinyl, thiazolyl, isothiazolyl, and
deazapurinyl.
35. . The tetracycline compound of claim 34, wherein said heteroaromatic,
group is pyridinyl.
36. . The tetracycline compound of claim 32, wherein said aryl group is
substituted or unsubstituted phenyl.
37. The tetracycline compound of claim 36, wherein said phenyl group is substituted with sulfoiiamido or alkyl. :
38. The tetracycline compound of claim 32, wherein said carbonyl group is ; motpholinylcarbonyl.
39. The tetracycline compound of any one of claims 1-3, wherein R is
substituted or unsubstituted alkenyl.

40. The tetracycline compound of claim 39, wherein said alkenyl group is substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, aiylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.
41. The tetracycline compound of claim 40, wherein said alkenyl group is substituted with an aminocarbonyl or alkoxycarbonyL
42. The tetracycline compound of claim 41, wherein said aminocarbonyl is dialkylaminocarbonyl.
43. The tetracycline compound of claim 40, wherein said alkenyl group is substituted with one or more halogens.
44. The tetracycline compound of claim 40, wherein said alkenyl group is substituted with one or more hydroxy groups.

45. The tetracycline compound of claim 40, wherein said alkenyl group is substituted with a heteroaryl. •
46. The tetracycline compound of claim 45, wherein said heteroaryl is selected from the group consisting of foranyl, imidazolyl, benzothiophenyl, benzofuranyl, quinoiinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl* ben2»thiai:olyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyridinyl, pyrazolyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl isooxazolyl, iiaphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl.
47. The tetracycline compound of claim 46, wherein said heteroaryl is thiazolyl.

48. The tetracycline compound of claim 40, wherein said aryl substituent is substituted or unsubstituted phenyl.
49. The tetracycline compound of claim 48, wherein said substituted phenyl is substituted with one or more halogens, alkoxy, hydroxy, or alkyl groups.
50. The tetracycline compound of claim 49, wherein said substituted phenyl is substituted with one or more fluorines.
51. The tetracycline compound of any one claims 1-3, wherein R7 is substituted or unsubstituted alkynyl.
52. The tetracycline compound of claim 51, wherein said substituted alkynyl is substituted with an aryl.
53. The tetracycline compound of claim 52, wherein said substituted alkynyl is substituted with substituted or unsubstituted phenyl.

54. The tetracycline compound of claim 53, wherein said substituted phenyl is substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, alkylcarbonylamino, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate* aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.
55. Thq tetracycline compound of claim 54, wherein said phenyl is substituted with alkylcarbonylamino or sulphonamido
56. The tetracycline compound of claim 51, wherein said substituted alkynyl is substituted with a tetracycline moiety.
57. The tetracycline compound of any one of claims 1-3, wherein R is
alkylcarbonylamino.

58.
carbonyl.
The tetracycline compound of any one of claims 1-3, wherein R is
59. The tetracycline compound of claim 58, wherein R is substituted or unsubstituted alkyl carbonyl.
60. The tetracycline compound of claim 59, wherein said alkyl carbonyl is substituted with an aryl.
61. The tetracycline compound of claim 60, wherein said aiyl substituent is heteroaryl.
62. The tetracycline compound of claim 61, wherein, said heteroaryl substituent is pyridinyl.
63. The tetracycline compound of any one claims 1-3, wherein R7 is substituted or unsubstituted imino.
64. The tetracycline compound of any one of claims 1-3, wherein said substituted imino is substituted with an hydroxy or alkoxy group.
65. The tetracycline compound of any one of claims 1-3, wherein R7 is NR7c(C=W')WR7a.
66. The tetracycline compound of claim 55; wherein R7c is hydrogen, W* is oxygen and W is oxygen.

67. The tetracycline compound of claim 65 or 66, wherein R is substitutec or unsubstituted phenyl.
68. The tetracycline compound of claim 67, wherein said substituted pheny is substituted with one or more substituents selected from the group consisting of alkyl halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, alkylcarbonylamino, arylcarbonyloxy, alkoxycarbonylanaino, alkoxycaibonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aiylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,

alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaiyl, aryl and heteroaryl.
69. The tetracycline compound of claim 65 or 66 wherein R7a is alkyl.
70. The tetracycline compound of any one of claims 1-3, wherein R is
sulfonamido.










iieteroatom; an acyliuranyl group; a tri-, tetm- or penta- halo substituted phenyl group; an aminomethylphenyl group; an acylaminomethyl group; an alkylesterphenyi group; an acylphenyl group; an acylalkynyl group; an acylalkoxyphenyl group; a methylphenyl group; a dimethylphenyl group; a carboxyphenyl group; a carboxyalkynyl group; a thiophene group; a halothiophene group; an alkoxycarbonylphenyl group; an alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoxypyridyl group; an alkylenepyridine group; a cyclopentyl or cyclopentenyl group; a cyclohexylalkynyl group; a cyclohexenylalkynyi group; a cyclohexenylhaloalkenyl group; a hydroxycyclohexylalkynyl group; a phenylalkynyl group; a phenylalkenyl group; an aminoalkynyl group; a cyclobutylalkenyl group; a pyridylalkynyl group; a pyridylalkenyl group; a nitrophenylalkynyl group; a nitrophenylalkenyl group; a cyanoalkynyl group; an alkynyl group; a cyanoalkenyl group; a cyanophenyl group; a dialkylamidoalkenyl group; a dialkylamidophenyl group; an aminophenylethyl group; an aminophenylethynyl group; a haloethenyl group; a halophenylalkynyl group; or an alkylester-substituted pentenyl group; and pharmaceutically acceptable salts, esters and prodrugs thereof
73. The compound of claim 72, wherein said compound is 7-(2-benzofuran) sancycline, 7-(3-formylfuranyl) sancycline, 7-(2,3,4,5,6-pentafiuorophenyl) sancycline, 7-(4-aminomethylphenyl) sancycline, 7-(4-formylaminomethylphenyl) sancycliiie, 7-(4-carboxyphenyl methylester) sancycline, 7-(2-carboxyphenyl ethylester) sancycline, 7-(4-tolyl) sancycline, 7-(3-*formylphenyl) sancycline, 7-(4-formylphenyl) sancycline, 7-(3-acetylphenyl) sancycline, 7-(2-acetylphenyl) sancycline, 7^3-acetylphenyl) sancycline; 7~(4-acetylphenyl) sancycline, 7-(3-fonnyl-6-methoxyphenyl) sancycline, 7-(4-methylphenyl) sancycline, 7-(3,5«dimethylphenyl) sancycline, 7-(3-carboxyphenyl) sancycline, 7-(carboxyethynyl) sancycline, 7-(3-thiophene) sancycline, 7-(3-methyl-2-thiophene) sancycline, 7-(3-methyl-5-thiopheaie) sancycline, 7-(3-ichloro-2-thiophene) sancycline and 7-(4-chloro-2-thiophene) sancycline, 7-(2-ethoxycarbonylphenyl) sancycline, 7-(2-ethoxyphenyl) sancycline, 7-(3-ethoxyphenyl) sancycline, 7-(4-methoxyphenyl) sancycline, 7^2,5-dimethoxyphenyl) sancycline, 7-(4-methoxyphenylethynyl) sancycline, 7-(4-methoxy-5-pyridyl) sancycline, 7-(cyclopentenyl) sancycline, 7-(cyclohexylethynyl) sancycline, 7-(l-ethynyM-cyclohexyl) sancycline, 7-(l-chlorovinyl-l-cyclohexyl) sancycline, 7-(l-ethynyl-l-

hydroxycyclohexyl) sancycline, 7~(phenylethynyl) sancycline, 7-(tolylethynyl) sancycline, 7-(4-methoxyphenylethynyl) sancycline, 7-(2-vinylpyridyl) sancycline, 7-(vinylphenyl) sancycline, 7-(dimethylaminoethynyI) sancycline, 7-(cycIobutylmethenyI) sancycline, 7-(2-pyridylethynyl) sancycline, 7-(3-pyridylethynyl) sancycline, 7-(4-pyridylethenyl) sancycline, 7-(cyano-l-pentynyl) sancycline, 7-(cyanohexenyl) sancycline, 7-(3-cyanophenyl) sancycline, 7-(4-cyanophenyl) sancycline, 7-(3-hydroxylphenylethynyl) sancycline, 7-(N,N-dimethylacrylamide) sancycline, 7-(dimethylamidoethenyl) sancycline, 7-(4-nitrophenyletbynyl) sancycline, 7-(4-nitrostyryi) sancycline, 7-(ethynyl) sancycline, 7-(N,N«dimethylacrylamide) sancycline, 7-(3-dimethylamidophenyl) sancycline, 7-(4-methoxyphenyl) sancycline, 7-(4-aminophenylethyl) sancycline, 7^2-chloroethenyl) sancycline, 7-(2-fluorophenylethenyl) sancycline, 7-(Modo-l,3-dicarboethoxy-1,3 -butadiene) sancycline, or 7-(4-aminophenyIvinyl) sancycline.
74. The compound of claim 1 or 71, wherein said compound is at least 75% free of positional isomers.;
75. The compound of claim 74, wherein said compound is at least 80% free of positional isomers.
76. The compound of claim 75, wherein said compound is at least 85% free of positional isomers.
77. The compound of claim 76, wherein said compound is at least 90% free of positional isomers.
78. The compound of claim 77, wherein said compound is at least 95% free of positional isomers.

79. A method for treating a tetracycline responsive state in a subject, comprising administering to said subject a tetracycline compound of claims 1,71, or 72, such that said subject is treated.
80. The method of claim 79, wherein said tetracycline responsive state is a bacterial infection.
81. The method of claim 80, wherein said bacterial infection is associated with E. coll

82. The method of claim 80, wherein said bacterial infection is associated with S. aureus.
83. The method of claim 80, wherein said bacterial infection is associated vnAiRfaecdlis.
84. The method of claim 80, wherein said bacterial infection is resistant to other tetracycline antibiotics.
85. The method ofclaim 79, wherein said subject is a human.
86. The method of claim 79, wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.
87. A substituted tetracycline compound selected from the group listed in Table 2.
88. A pharmaceutical composition comprising a therapeutically effective
amount of a tetracycline compound of claim 1,71,72, or 87 and a pharmaceutically
acceptable carrier.

89. A substituted tetracycline compound substantially as herein described'
and exemplified.
90. A method of treating a tetracycline responsive state in a subject
substantially as herein described and exemplified.


Documents:

162-chenp-2003-abstract.pdf

162-chenp-2003-assignement.pdf

162-chenp-2003-claims original.pdf

162-chenp-2003-claims duplicate.pdf

162-chenp-2003-correspondnece-others.pdf

162-chenp-2003-correspondnece-po.pdf

162-chenp-2003-description(complete) duplicate.pdf

162-chenp-2003-description(complete)orginal.pdf

162-chenp-2003-form 1.pdf

162-chenp-2003-form 26.pdf

162-chenp-2003-form 3.pdf

162-chenp-2003-form 5.pdf

162-chenp-2003-other documents.pdf

162-chenp-2003-pct.pdf


Patent Number 206972
Indian Patent Application Number 162/CHENP/2003
PG Journal Number 26/2007
Publication Date 29-Jun-2007
Grant Date 16-May-2007
Date of Filing 27-Jan-2003
Name of Patentee M/S. TRUSTEES OF TURTS COLLEGE
Applicant Address Ballou Hall, 4th Floor Medford, MA 02155.
Inventors:
# Inventor's Name Inventor's Address
1 NELSON, Mark, L 735 Worcester Road Wellesley, MA 02481
PCT International Classification Number C 07 C 237/00
PCT International Application Number PCT/US2001/020766
PCT International Filing date 2001-06-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/275,576 2001-03-13 U.S.A.
2 60/216,760 2000-07-07 U.S.A.