ZA200505179B

ZA200505179B - 9-substituted minocycline compounds

Info

Publication number: ZA200505179B
Application number: ZA200505179A
Authority: ZA
Inventors: Mark L Nelson; Roger Frechette; Peter Viski; Mohamed Ismail; Todd Bowser; Jimmy Dumornay; Glen Rennie; Gui Liu; Darrell J Koza; Paul Sheahan; Karen Stapleton; Paul Hawkins; Beena Bhatia; Atul Verma; Laura Mcintyre; Tad Warchol
Original assignee: Tufts College; Paratek Pharm Innc
Priority date: 2000-07-07
Filing date: 2005-06-27
Publication date: 2006-04-26
Also published as: CN101525303A

Description

£i

Related Applications

This application claims priority to U.S. Provisional Patent Application Serial No. 60/275,621, entitled “9-Substituted Minocycline Compounds,” filed on March 13, 2001, and

U.S. Provisional Patent Application Serial No. 60/216,580, entitled “9-Substituted Minocycline

Compounds,” filed on July 7, 2000; both of these applications are hereby incorporated herein by reference. This application is related to U.S. Provisional Application Nos. 60/154,701, filed on September 14, 1999; 60/193,972, filed on March 31, 2000, 60/193,879, filed on March 31, 2000; 60/204,158, filed on May 15, 2000; 60/212.030, filed June 16, 2000; and 60/212 471. filed June 16, 2000, the entire contents of each of which are 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 from many parts of the world for evidence of microorganisms capable of producing bacteriocidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. The elucidation of the chemical structure of these compounds confirmed their similarity and furnished the analytical basis for the production of a third member of this group in 1952, tetracycline. A new family of tetracycline compounds, without the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967; and minocycline was in use by 1972.

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; 4,018,889; 4,024,272; and 4,126,680. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions. 50 Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum. inclusion conjunctivitis, and psittacosis. Hence, tetracyclines became known as "broad spectrum” antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to

20° v - the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., pneumococci and Salmonella). The rise of tetracycline- resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice.

Summary of the Invention

The invention pertains, at least in part, to minocycline compounds of formula I:

NR7R” R® R* .

RS Xx OR’

JLT Te

OR‘? :

ORY © OR" © 0 4) wherein:

X is CHC(R'*Y’Y), CR®RS, S, NR®, or O;

R%L RY, RY R” and R” are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;

R*isNR*RY, alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;

R%, R3, RY R'! and R'? are each hydrogen or a pro-drug moiety;

R3 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alky! carbonyloxy, or aryl carbonyloxy;

Rand R® are 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, thionitroso, or —~(CHy)osNR*C(=2")ZR%,

Z is CR*R*, S, NR” or 0; 7’ isNR”, O or S;

R% R*® R*, R% R* and R’f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, : heterocyclic, heteroaromatic or a prodrug moiety; : 30 R® 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, alkylsulfonyi, alkylamino, or an arylalkyi;

v .

Y’ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl. amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts, esters and prodrugs thereof.

The invention also pertains, at least in part, to 9-substituted minocycline compounds of the formula (II):

A wv R’ Ry a

OH

ATT

OH lo} OH fo] to) an wherein:

RY, RY R” and R” are each alkyl; and

R’isa pyridylethynyl group; an alkenylcarbamate group; a halo group; an alkylacrylate group; a naphthyl group; a haloacetyl group; an alkyl carbamate group; a cyclopentyl or cyclopentenyl group; a benzofurany! group; a phenylpropiononeamino group; a tosylamino group; a methoxypyridyl group; an alkeneamino group; an N-t-butyl group; a t-butylamide group; a hydroxybutylamino group; a hydroxypropylamino group; a phenyl group; a nitrophenyl group; a nitrophenyl alkyny! group; an aminopheny! group; an alkoxyphenyl group; a halophenyl urea group; a cyanophenyl! group; a carboxyphenyl group; an acylphenyl group; an alkylphenyl group; a halophenyl group; an alkoxyphenyl group; a carboxyalkylphenyl group; a phenylalikynyl group; an alkynyl group; an alkylglycineethylester group; a styrene group; a thiophene group; and an alkylaminophospho group; and pharmaceutically acceptable salts, esters and prodrugs thereof.

The invention also pertains to methods of using the minocycline compounds of the _ invention to treat subjects suffering from states which can treated using the minocycline compounds of the invention.

The invention also pertains to pharmaceutical compositions comprising the minocycline compounds of the invention and a pharmaceutically acceptable carrier. The invention also pertains to the use of a minocycline compound of the invention for the manufacture of a medicament, e.g., a medicament for the treatment of a tetracycline responsive state.

Detailed Description of the Invention

The present invention pertains, at least in part, to novel 9- substituted minocycline compounds. These minocycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other v of - known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.

NR'R” R’ rR

RS X OR’?

JTL I

R H

OR"?

OR® © OR" © 0 (D wherein:

X is CHC(R'®Y’Y), CR®RS, S, NR®, or O;

RZ, RY, RY, R” and R” are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;

R'is NR*R*, alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;

R*, R? RY R!" and R'? are each hydrogen or a pro-drug moiety;

Riis hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;

Rand R® are 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, thionitroso, or <(CHy)e.sNR**C(=2")ZR*,

Zis CR™R™, S, NR® or 0; 2 isNR*, Oor S; rR? R%® R* R% R% and R*' are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;

R? is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; rR"? is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; : Y’ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsuifonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts, esters and prodrugs thereof.

The term minocycline compounds refers to compounds of formula (I) above. In an embodiment, the term minocycline compounds include compounds wherein X is CR®R®’; RZ,

R* R° RS, RY, RE, R® R'% R' and R!? are each hydrogen; R*is NR*R*"; and RY, RY, rR’, and R7 are each lower alkyl, e.g., methyl.

Examples of R? include substituted and unsubstituted aryl groups. The aryl groups include substituted and unsubstituted heteroaryls (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl. benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, or deazapurinyl), substituted or unsubstituted phenyl, and groups with more than one aromatic ring, such as naphthyl.

Examples of substituents of R? include, but are not limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, 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.

In a further embodiment, the aryl R® group is substituted with one or more substituents such as, for example, carboxylate, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, halogen, alkoxy, alkoxycarbonyl, amido, alkylcarbonyl, or nitro.

In another embodiment, R® is substituted or unsubstituted alkynyl. The alkynyl R’ group may be substituted with a substituted or unsubstituted aryl group, such as, for example, phenyl. The possible substituents for the substituted phenyl group include, for example, those listed supra, for the aryl R® group. Furthermore, the substituted alkynyl R? group may be 75 substituted with a heteroaryl (e.g, pyridinyl), alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl, } hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, erc.), alkenyl (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, efc.), carboxylate, silyl (e.g., trialkylsilyl, e.g, trimethylsilyl), aralkyl, or a alkyloxycarbonyl group.

Each of these groups may also be further substituted, with such substituents as alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, 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, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.

In a further embodiment, the alkynyl R? group is substituted with an aminoalkyl group.

The aminoalkyl group may then also be substituted with, for example, an alkyl. alkenyl, alkynyl, acyl, carbonyl, or alkylsulfone group.

In another further embodiment, the alkynyl R” group is substituted with a cycloalkenyl group, such as, for example, cyclopentene.

In another embodiment, R® is alkyl. The alkyl group may be substituted or unsubstituted. Examples of alkyl groups include, for example, both straight chain, branched and cyclic alkyl groups. For example, alkyl groups include methyl, ethyl, i-propyl, n-propyl, i- butyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Cyclic alkyl groups include groups with one or more rings, such as, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, erc. In an embodiment, the alkyl R® group is 2- cyclopentylethyl.

Examples of substituents of alkyl groups include, for example, halogens (e.g., fluorine, chlorine, bromine, iodine, erc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, perfluoromethoxy, perchloromethoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, carboxy, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, alkenyl, sulfonato, sulfamoyl, sulfonamido, nitro, alkenyl, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.

In another embodiment, the minocycline compound of the invention is a compound wherein R® is -NR¥*C(=2")ZR%*, -CH,NR*C(=Z")ZR*, ~(CH,),NR*C(=Z")ZR%, or (CHa)

NR¥*C(=2")ZR*. In certain embodiments, R® is _NR*C(=2")ZR* or -CH;NR*C(=Z")ZR*.

Examples of R* include hydrogen. Z’ may be, for example, S, NH, or O. Examples of Z include NR® (e.g, when R®® is hydrogen, alkyl, erc.), O or S. ) Examples of R*? groups include aryi groups such as substituted and unsubstituted phenyl. Examples of possible substituents of aryl R® groups include, but are not limited to, alkyl (e.g, methyl, ethyl, propyl, butyl, pentyl, hexyl, perfluormethyl, perchloroethyl, etc.), alkenyl, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, propoxy, perfluoromethoxy, perchloromethoxy, etc.), alkylcarbonyloxy, : arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl! aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato,

sulfamoyl, sulfonamido, nitro, acetyl, alkyl, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl groups.

In certain embodiments, at least one of the substituents of the substituted phenyl is nitro, alkoxy (e.g., methoxy, methylenedioxy, perfluoromethoxy) alkyl (e.g., methyl, ethyl, propyl, butyl, or pentyl), acetyl, halogen (e.g, fluorine, chlorine, bromine, or iodine), or amino (e.g., dialkylamino). In certain embodiments, the alkoxy group is perhalogenated, e.g., perfluoromethoxy.

Examples of aryl R* groups include, but are not limited to, unsubstituted phenyl, para- nitrophenyl, para-methoxy phenyl, para-perfluoromethoxy phenyl, para-acetyl phenyl, 3, 5- methylenedioxyphenyl, 3,5-diperfluoromethyl phenyl, para-bromo phenyl, para-chloro phenyl, and para-fluoro phenyl.

Other examples of aryl R*? groups include substituted and unsubstituted heterocycles (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, pyrolidinyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, or deazapurinyl) and substituted and unsubstituted biaryl groups, such as naphthyl and fluorene.

R®® also may be substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, butyl, pentyl, erc. Examples of substituents include but are not limited to halogens (e.g., fluorine, bromine, chlorine, iodine, ezc.), hydroxyl, alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, ~ sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, alkenyl, heterocyclyl, alkylaryl, aryl and heteroaryl.

R® also can be substituted or unsubstituted alkenyl. Examples of substituents for alkenyl R* groups include those listed above for alkyl R% groups. Examples of alkenyl R* groups include pent-1-enyl.

In an embodiment, Z’ is NH, Z is NH, and R%is alkyl.

The invention also pertains to compounds wherein R’ is aminoalkyl (e.g., aminomethyl). Aminoalkyl R® groups may be further substituted. Examples of substituents include aryl groups, such as, for example substituted or unsubstituted phenyl (e.g, methylenedioxyphenyl or para-perfluoromethoxyphenyl), or heteraromatic groups which allows the compound cf the invention to perform its intended function.

Examples of minocycline compounds of the invention include those listed in Table 1, as well as the ones listed below: ~~ ~Nn~ ~N" ~~ ~n" Sy

H HT H H= H HET = = OH = AC OH = =~ OH oBNeoee: sess lieS Uses

NH L Ha yor Nar Yh kz NEY PY Yar Yr

OH O OH 0 © sg oH 0 OHO © oH © oHCo © oO 0 o ~~ Sa 0 ~n Sn SN Vid { LE No 8 2% om H HT . “YL £ IN og TL ° NNN == OH

H

S A A A NH, A A ge NH, 0, N | NH-

H H FH H " oH S y= < on OH O oH O © I Io) moe ome 0 OH O OH O © ~~ Sn SN ~NT SN SN

KH HT H HT FE H HY

—0 z =A OH = =A OH Fy RS OR [eS ¥ see j 0,

A = Ne H XE NH; § vy NF Ne

Hoon oH oN _# OH Hh wo of o oi 0 OH 0 © Ss; OH O OH O O he 5

Sn ~NT ~n~ ~n~ he ~n

H HT H HF H HF

= AA OH Br. IAG OH AGA OM r CCDC. "OU {J

Ay 2 NH; iN rE NH: Hn £) NH;

BO H OH H H OH

H on 0 oto 0 OH O oH 0 © oH 6 ono ©

F ~,y ~~ Ny ~~ . ~~ ~~" N Ww OHS N HoH

H HT cl ZAGEA OH ct Fa Te OX

R A NH Ay = Nr °” > Sn Na

NN B H -1 on

OH © OH © o

Fo HoH Lo oe 8 OH O OH 0 © : ~ ~" ~ ~ ~~ Ny

H HF TF A oH H HF

Pa OH ° > 3 3 3 A OH ; x - ;

NTN £3 td

PN f NH; <n = ~A, f Hy

IH 3H . } on 0 oH Oo © 5 Zu

OH [o] OM [oe] Qo oH o OH o [=] ~~ “nv” ~~ ~~ ~~ ~~

H H3 HOHE H HT 0 ENN EAGAN SAGA oH i Ay Ey NH, 7 NH, 5 NH

OH O OH O © OH rd OH oH [+] «1.1 [=] o OH [eo] OH o [so] ~ ~y ~~" ~~ Sy Sn”

LD H HT 8 Eo 0) o aN on EA om : P3

J } NH, N f) NH; (} N £ 3

H or N a) NH; ry oH © NCH }

OH [+] OH [o] [<] Iva SH . oH © OH © ts) ~~ ~y” Ww ~~ ~~ "BD EEA OH dE:

Hi Fa OH " : Pa OH oN pe NH, H

Nt NH, Y o Jk gs NH, o £, 0 oH O OH OC © = c

OH C OH 0 0 OH O OH © 0 [e)

) ~n" ate “nT he ae Su " PRP ~ EASA AEA

J ) | NH, . er ILL OL n S 7 POS

MEE DASC AIS EV IRI PORN

~n" x oY o SN py by o ~n PM ey » " ! H i Wool 7 I i a _N A NH, Oo. N Ny 2 NH. PLN A NE NH.

AT r OK © TET [o] BOI T OH O I) [eo] T oH © ors o

ST y oN ~N7T u ng ~n” 3 Ju ¥Scece NTE co ee NTPs eee o ~ N NE NH» N__N Sr NH» 2 N,N J Nt NH;

CIT T oH 0 ad T JJ r OH O oxo lo] JT r Lr od o lo) t

ST T oH © To 0

Pharmaceutically acceptable salts of these compounds are also included. Other compound of the invention are listed in Table 1.

The invention also relates, at least in part, to 9-substituted minocycline compounds of the formula: 7 rR” 4 RY

UN RO

OH

Cr xrx.

Rg IAN

OH 0 OH 0 0 dn wherein:

RY, R*,R”, and R” are each alkyl; and

R’ is a pyridylethynyl group; an alkenylcarbamate group; a halo group; an alkylacrylate group; a naphthyl urea group; a haloacetyl group; an alkyl carbamate group; a cyclopentyl or cyclopenteny! group; a benzofuranyl group; a phenylpropiononeamino group; a tosylamino group; a methoxypyridyl group; an alkeneamino group; an N-t-butyl group; a t-butylamide group; a hydroxybutylamino group; a hydroxypropylamino group; a phenyl group; a nitrophenyl group; a nitrophenyl alkynyl group; an aminopheny! group; a halophenyl urea group; an alkoxyphenyl group; a cyanophenyl group; a carboxyphenyl group; an acylphenyl group; an alkylphenyl group; a halophenyl group; an alkoxyphenyl group; a carboxyalkylphenyl group; a phenylalkyny! group; an alkynyl group; an alkylglycineethylester group; a styrene group; a thiophene group; an a'kyiaminophespho group; and pharmaceutically ‘acceptable salts thereof.

The term "9-substituted minocycline compound” includes minocycline compounds with a substituent at the 9 position. In another embodiment, the compound is a derivative of minocycline.

In an embodiment, R’ is an alkenylcarbamate group. Examples of tetracycline compounds with this RY substituent include 9-isopropeny! carbamate minocycline.

In an embodiment, R’ is a pyridylethyny! group. Examples of tetracycline compounds with this R® substituent include 9-(2-pyridylethynyl) minocycline.

In an embodiment, R’ is a halo group. Examples of tetracycline compounds with this

R® substituent include 9-iodo minocycline.

In an embodiment, R is an alkylacrylate group. Examples of tetracycline compounds with this RY substituent include 9-butylacrylate minocycline.

In an embodiment, R’isa naphthyl urea group. Examples of tetracycline compounds with this R°substituent include 9-naphthy] minocycline urea.

In an embodiment, R® is a haloacetyl group. Examples of tetracycline compounds with this R’® substituent include 9-chloroacetyl minocycline urea.

In an embodiment, R® is an alkyl carbamate group. Examples of tetracycline compounds with this R? substituent include 9-neopenty! minocycline carbamate.

In an embodiment, R’ is a cyclopentyl or cyclopentenyl group. Examples of tetracycline compounds with this R? substituent include 9-cyclopentene minocycline.

In an embodiment, R® is a benzofurany! group. Examples of tetracycline compounds with this R® substituent include 9-benzofurany! minocycline.

In an embodiment, R’ is a phenylpropiononeamino group. Examples of tetracycline compounds with this R?® substituent include 9-(phenylpropiononeamino) minocycline.

In an embodiment, R’ is a tosylamino group. Examples of tetracycline compounds with this R® substituent include 9-tosylamino minocycline.

In an embodiment, R® is a methoxypyridy! group. Examples of tetracycline compounds with this R® substituent include 9-(2-methoxy-3-pyridyl) minocycline.

In an embodiment, R® is an alkeneamino group. Examples of tetracycline. compounds with this R? substituent include 9-(N-2'-hydroxydecyl-9'-ene-amino) minocycline.

In an embodiment, R? is an N-t-butyl group. Examples of tetracycline compounds with this R® substituent include N-t-butyl-minocycline HCL.

In an embodiment, R® is a t-butylamide group. Examples of tetracycline compounds with this R® substituent include 9-BCC-NH minocycline.

In an embodiment, R’ is a hydroxybutylamino group. Examples of tetracycline compounds with this R? substituent include 9-(N-2'-hydroxybutylamino) minocycline.

In an embodiment, R® is a hydroxypropylamino group. Examples of tetracycline compounds with this R® substituent include 9-(N-3-chloro, 2-hydroxylpropylamino) ninocycline.

In an embodiment, R? is a phenyl group. Examples of tetracycline compounds with this R substituent include 9-phenyl minocycline HCI and 9-p-tolyl minocycline.

In an embodiment, R? is a nitrophenyl group. Examples of tetracycline compounds with this R® substituent include 9-(3'-nitrophenyl) minocycline.

In an embodiment, R® is a nitrophenyl alkynylgroup. Examples of tetracycline compounds with this R? substituent include 9-(4'-nitrophenylethynyl) minocycline.

In an embodiment, R’ is an aminopheny! group. Examples of tetracycline compounds with this R® substituent include 9-(3-aminophenyl) minocycline.

In an embodiment, R’ is a halophenyl urea group;. Examples of tetracycline compounds with this R?® substituent include 9-(4-chloro,2-trifluoromethylphenyl) minocycline urea.

In an embodiment, R’ is an alkoxyphenyl group. Examples of tetracycline compounds with this R? substituent include 9-(p-methoxyphenyl) minocycline, 9-(4'-methoxyphenyl) minocycline, and 9-(3,4-methylenedioxyphenyl) minocycline.

In an embodiment, R® is a cyanophenyl group. Examples of tetracycline compounds with this R® substituent include 9-(4'-cyanophenyl) minocycline. :

In an embodiment, R? is a carboxyalkylphenyl group. Examples of tetracycline compounds with this R’ substituent include 9-(4'-carboxyphenyl) minocycline.

In an embodiment, R’ is an acylphenyl group. Examples of tetracycline compounds with this R? substituent include 9-(3-formylphenyl) minocycline.

In an embodiment, R® is an alkylphenyl group. Examples of tetracycline compounds with this R? substituent include 9-(4'-t-butylphenyl) minocycline.

In an embodiment, R is a halopheny! group. Examples of tetracycline compounds with this R® substituent include 9-(3-chlorophenyl) minocycline, 9-(2',4'-difluoropheny!) minocycline, 9-(3,4-difluorophenyl) minocycline, 9-(4'-chlorophenyl) minocycline, 9-(3,4- dichlorophenyl) minocycline, and 9-(4'-trifluoromethylphenyl) minocycline.

In an embodiment, R? is an alkoxyphenyl group. Examples of tetracycline compounds with this R® substituent include 9-(3-ethoxyphenyl) minocycline.

In an embodiment, R’ is a carboxyalkylphenyl group. Examples of tetracycline . compounds with this R® substituent include 9-(4-carboxymethylphenyl) minocycline.

In an embodiment, R’ is a phenylalkynyl group. Examples of tetracycline compounds with this R? substituent include 9-(phenylethyny!) minocycline, 9-(3-hydroxyphenylethynyl) minocycline, 9-(p-tolylethynyl) minocycline, and 9-(p-methoxyphenylethynyl) minocycline.

In an embodiment, R’ is.an alkynyl group. Examples of tetracycline compounds with this R® substituent include 9-ethynyl minocycline, 9-(p-fluoroethynyl) minocycline, 9- (trimethylsilylethynyl) minocycline, 9-(propionyl) minocycline, 9-(cyclohexenylethynyl) minocycline, and 9-(1-cyclohexyl-1-hydroxyethynyl) minocycline.

In an embodiment, R’ is an alkylglycineethylester group. Examples of tetracycline compounds with this R® substituent include 9-propylglycineethylester minocycline HCl, and 9- methylglycineethylester minocycline.

In an embodiment, R’ is a styrene group. Examples of tetracycline compounds with this R® substituent include 9-(styrene) minocycline, 9-(4'-fluorostyrene) minocycline.

In an embodiment, R® is a thiophene group. Examples of tetracycline compounds with this R® substituent include 9-(2-thiophene) minocycline, and 9-(5'-chloro-2'-thiophene) minocycline.

In an embodiment, R? is an alkylaminophospho group. Examples of tetracycline compounds with this R? substituent include 9-(p-methoxyphenylaminophospho) minocycline, and 9-(phenylaminophospho) minocycline.

The minocycline compounds of this invention can be synthesized using the methods described in Schemes 1-6. 9-substituted minocyclines can be synthesized by the following general method, shown in Scheme 1. oo FY" wt ET on © 2 0 ” ~ on R © wy HY pn FE pe $Y y ,

OH © ToT a] on HO STAT o : ) H 41 T iE

SCHEME 1

Generally, 9-substituted minocycline compounds can be synthesized as shown in : 25 Scheme 2 by treating minocycline (1A), with sulfuric acid and sodium nitrate. The resulting product is 9-nitro (1B) minocycline. The nitro minocycline compound is then treated with hydrogen gas and a platinum catalyst to yield the 9-amino minocycline compound, 1C. To synthesize 9 derivatives, the $-amino minocycline compound is treated with HONO, to yield the diazonium salt (13). The salt can subsequently be treated with numerous compounds possessing an alkene or nm bond functional group such as alkenes, aryls, and alkynyls (e.g.,

R7Br) yielding the 9-substituted minocycline compound (1E).

N(Me)y oH Nive) N(Me) oH Nime),

H HB OH 9,50, H H oH

NaNO,

NN NH, ow N NH

OH [e] OH o o bn Q OH [o] eo] 2B 2A

Hy PL

N(Me), OH N(Me); « NiMe) oH N(Me), eo ; : oH N— i i om

N EN NH, » HN SN NK; oH <Q OH o [o} oH [o] OH [o] [o] 2E 1

Nie) e

Pr fw h i - OH ; J

BN | R¥0 cl

RO N x NE

OH fe] OH [e] [o] 2G

SCHEME 2

As shown in Scheme 3, minocycline compounds of the invention wherein Risa : carbamate or a urea derivative can be synthesized using the following protocol. Minocycline (2A) is treated with NaNO, under acidic conditions forming 9-nitro minocycline (2B). 9- nitrominocycline (2B) is then treated with H, gas and a platinum catalyst to form the 9-amino minocycline derivative (2C). To form the urea derivative (2E), isocyanate (2D) is reacted with the 9-amino minocycline derivative (2C). To form the carbamate (2G), the appropriate acid chloride ester (2F) is reacted with 2C.

HaC MIC. CH

AN CH ~ 13 (MeN UI ) (MexN Po ! OH IB S OH 1) = Fmoc

Fmoc-NCS NH

HaN Nl NH TOOT oon hd ?

OH H OH

OH O OH O © H H 3A . ac

HC R HC

_CH \., CH {(Me}N or Sy : AY (MeRN on ¥ :

S LOH o ® al OH

PY 92008 NH; PON Ni Ni;

HN” TN I» aan én

OH O oH © Q OH OH © [0]

IF

3D

SCHEME 3

Claims

1. A minocycline compound of formula I: NR'R" rR’ R* R" X OR’ CLT ¥ 2s OR" © OR" © 0 0) wherein: X is CHC(R"}Y’Y), CR®R®, S, NR®, or O; R? is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aikylsulfinyl,

. alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R* and R*" are each alkyl , alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R” and R” are each alkyl , alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R* is NR*RY", alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R%, R3, RR! R! and R'? are each hydrogen or a pro-drug moiety; R’ 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 independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, } alkylamino, or an arylalkyl; R’ is, methyl, ethyl, propyl, substituted alkyl, ethenyl, propenyl, substituted alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso, or —(CH,),sNR**C(=2")ZR%; Z is CR™R*, S, NR* or O; Z’ is NR”, OorS; R% R%® R* R* R* and R* are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R? is hydrogen, hydroxyl, thiol, aikyi, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfony!, alkylaminoe, or an arylaikyi; -46 - Amended sheet: 17 April 2007

R'? is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; Y’ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts, esters and prodrugs thereof.

2. The minocycline compound of claim 1, wherein R* is NR*R"’; X is CR°R?; RZ, R?, R> RS, R®, RS, R% R! rR", and R'? are each hydrogen; and, R* RY R”, and R”" are each lower alkyl.

3. The minocycline compound of claim 2, wherein RY, RY, R’, and R” are each methyl. 4, The minocycline compound of any one of claims 1-3, wherein R’ is substituted or unsubstituted aryl.

5. The minocycline compound of claim 4, wherein R’ is substituted phenyl.

6. The minocycline compound of claim 5, wherein said substituted phenyl is substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, formyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

7. The minocycline compound of claim 6, wherein said substituted phenyl is substituted with one or more substituents selected from the group consisting of carboxylate, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, halogen, alkoxy, alkoxycarbonyl, amido, alkylcarbonyl, and nitro.

8. The minocycline compound of claim 4, wherein R? is substituted or unsubstituted heteroary!. -47 - Amended sheet: 17 April 2007

9. The minocycline compound of claim 8, wherein said heteroaryl is selected from the group consisting of furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, or deazapurinyl.

10. The minocycline compound of claim 9, wherein said heteroaryl is thienyl or benzofuranyl.

11. The minocycline compound of anyone of claims 1-3, wherein R’ is substituted or unsubstituted alkynyl.

12. The minocycline compound of claim 11, wherein said substituted alkynyl group is substituted with a substituted or unsubstituted aryl group.

13. The minocycline compound of claim 12, wherein said aryl group is substituted or unsubstituted phenyl.

14. The minocycline compound of claim 13, wherein said phenyl group is substituted with a group selected from alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, 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.

15. The minocycline compound of claim 12, wherein said aryl group is heteroaryl.

16. The minocycline compound of claim 11, wherein said alkynyl group is substituted with alkyl, alkenyl, carboxylate, silyi, aralkyl, or a alkyloxycarbonyi group.

17. The minocycline compound of claim 14, wherein said alkyl substituent is aminoalkyl. -48 - Amended sheet: 17 April 2007

18. The minocycline compound of claim 17, wherein said aminoalkyl is substituted with an alkylsulfonamide group.

19. The minocycline compound of claim 16, wherein said alkynyl group is substituted with a cycloalkenyl! group.

20. The minocycline compound of claim 19, wherein said cycloalkenyl group is cyclopentenyl.

21. The minocycline compound of any one of claims 1-3, wherein R’ is methyl, ethyl or substituted alkyl.

22. The minocycline compound of claim 21, wherein said substituted alkyl group is substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, alkenyl, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.

23. The minocycline compound of claim 21, wherein said substituted alkyl group is 2-cyclopentylethyl.

24. The minocycline compound of anyone of claims 1-3, wherein R’ is (CH): NR*C(=Z’)ZR**.

25. The minocycline compound of claim 24, wherein R® is -CH,NR**C(=Z")ZR**

26. The minocycline compound of claim 25, wherein R% is hydrogen.

27. The minocycline compound of claim 25 or 26, wherein Z’ is S.

28. The minocycline compound of claim 25 or 26, wherein Z’ is O. -49- Amended sheet: 17 April 2007

29. The minocycline compound of any one of claims 25-28, wherein Z 1s NR.

30. The minocycline compound of any one of claims 25-28, wherein Z is O.

31. The minocycline compound of any one of claims 25-28, wherein Z is S.

32. The minocycline compound of claim 29, wherein R°® is hydrogen.

33. The minocycline compound of any one of claims 24-32, wherein R* is aryl.

34. The minocycline compound of claim 33, wherein R* is substituted or unsubstituted phenyl.

35. The minocycline compound of claim 33, wherein said phenyl group is substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, acetyl, alkyl, cyano, azido, heterocyclyl, alkylaryl, aryl and heteroaryl.

36. The minocycline compound of claim 35, wherein said substituents are selected from nitro, alkoxy, alkyl, acyl, halogen, or amino.

37. The minocycline compound of claim 36, wherein said amino group is dialkylamino.

38. The minocycline compound of claim 36, wherein said alkoxy group is methoxy.

39. The minocycline compound of claim 36, wherein said alkoxy group is methylenedioxy.

40. The minocycline compound of claim 38, wherein said alkoxy group is perhalogenated. -50- Amended sheet: 17 April 2007

41. The minocycline compound of claim 40, wherein said alkoxy group is perfluoromethoxy.

42. The minocycline compound of claim 36, wherein said alkyl group is methyl, ethyl, propyl, butyl, or pentyl. 43, The minocycline compound of claim 36, wherein said halogen is fluorine, chlorine, bromine, or iodine.

44. The minocycline compound of claim 33, wherein said aryl group is unsubstituted phenyl, para-nitrophenyl, para-methoxy phenyl, para- perfluoromethoxy phenyl, para-acetyl phenyl, 3, S-methylenedioxyphenyl, 3,5- diperfluoromethyl phenyl, para-bromo phenyl, para-chloro phenyl, or para-fluoro phenyl.

45. The minocycline compound of claim 35, wherein R** is arylcarbonyl.

46. The minocycline compound of claim 33, wherein R* is biaryl.

47. The minocycline compound of claim 46, wherein Ris naphthyl.

48. The minocycline compound of any one of claims 24-32, wherein Ris substituted or unsubstituted alkyl.

49. The minocycline compound of claim 48, wherein R* is unsubstituted alkyl.

50. The minocycline compound of claim 49, wherein R* is methyl, ethyl, propyl, butyl, or pentyl.

51. The minocycline compound of claim 48, wherein said alkyl is substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyi, arylcarbonyi, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, -51- Amended sheet: 17 April 2007 sulfonamido, nitro, trifluoromethyl, cyano, azido, alkenyl, heterocyclyl, alkylaryl, aryl and heteroaryl.

52. The minocycline compound of any one of claims 24-32, wherein R* is substituted or unsubstituted alkenyl.

53. The minocycline compound of claim 52, wherein R* is pent-1-enyl. 54 The minocycline compound of claim 24, wherein Z’ is NH, Z is NH, and R* is alkyl. . . . . 9.

55. The minocycline compound of any one of claims 1-3, wherein R” is —-N=S.

56. A minocycline compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: NT SN NT nT ~~ Sn H HT H HT H HT = Fa OH = = OH = = A OH J i agate. | otic. auch. ( HH wo oo o Sst Z mo oh © Pro a™ oo [Xe] i POO i JP Wow gy A fA Nr Ay Nr 2 Ne Q N NH, HoH On EL hk - I 3 bo] Hoe ome 0 0 OH 0 OHO © have ~n SN SN ST ~NT —0 o g 4 3 OH 4 B= OH You o 8.83 OH TA, NZ He o H _z x2 NH; F ny NE Ne TY wo ao 0 YN 7 io od o OH 0 oi'o © hi % — SN “NT ~n” hg Nn hd H H = H HZ H HT = = x OH Br = z OH = TA OH 0 o [o] [e] a orth, ouch. aortic. Hoon 0 ono © " ono oo 0 TR oo awe 0 ; F ] ~ ~ ~n \ Ng ~n . Ng H HT [v] = A OH [o!] z =A OH Locke, TOL OAC NH, £3 NH; ) Ao NE Na oH 5a oR al Ton FN wow Lolo Lond d OH 0 OH O © 0 ~n ~~ ~~ ~n ~~ Ny H HF 223 on H HF EASA 0 + AGA OH x NH PUNE ) NH Je “No N ER ) VER ons ° Ss b] EN hs OH O OH 0 © oH © OH © ° -52- Amended sheet: 17 April 2007

~~ ~a” ~~ ~~ ~n ~~ H HF H HT 4 HE o 3 z OH 3 z H oH £ d z oH JCC Sesced sooo H oH £ A Xr: OH O OH 0 © OH Zz OH OH O0O OH O © 4g OH 0 OH 0 © ~~ ~~ ~~ Np Sy Sy PSH oH a} HF EE ion QU CCC CCIIx ad Yoeees NH, 0. N A NHz (o} N on : ToT : oN ~ Ey NH, Cr T oH © Ms ° OH [0] OH [e} le} ~ ~v SN SN : H oN Nr NH Ion oS NH, “ or T on 0 oS oO OH [o] OH 0 [0] [eo] 0 a ~n ~a” “a7 4g 8% 8 23 ou NH MA NE NH, F N 2 Nz hi: N Bn Ng OH © os 0 OH O OH O © °

57. A minocycline compound of claim 1 or 56, for use in a method for treating a tetracycline responsive state in a mammal, comprising administering to said subject the minocycline compound, such that said subject is treated.

58. The minocycline compound of claim 57, wherein said tetracycline responsive state is a bacterial infection.

59. The minocycline compound of claim 58, wherein said bacterial infection is associated with E. coli.

60. The minocycline compound of claim 58, wherein said bacterial infection is associated with S. aureus.

61. The minocycline compound of claim 58, wherein said bacterial infection is associated with E. faecalis.

62. The minocycline compound of claim 58, wherein said bacterial infection is resistant to other tetracycline antibiotics.

63. The minocyciine compound of claim 57, wherein said minocycline compound is administered with a pharmaceutically acceptable carrier. -53- Amended sheet: 17 April 2007

64. The minocycline compound of claim 57, wherein said subject is a human.

65. A pharmaceutical composition comprising a therapeutically effective amount of a minocycline compound of claim 1 or 56 or a minocycline compound listed in Table 1 and a pharmaceutically acceptable carrier.

66. A 9-substituted minocycline compound of the formula: ANP Ro OH JOC OH [0] OH [o} le} a1 wherein: RY, R*, R”, and R”” are each alkyl; and R’ is a pyridylethynyl group; an alkenylcarbamate group; an alkylacrylate group; a naphthyl group; a haloacetyl group; an alkyl carbamate group; a benzofuranyl group; a phenylpropiononeamino group; a tosylamino group; a methoxypyridyl group; an alkeneamino group; a hydroxybutylamino group; a hydroxypropylamino group; a nitrophenyl group; a nitrophenylalkynyl group; an aminophenyl group; an alkoxyphenyl group; a halophenyl urea group; a cyanophenyl group; a carboxypheny! group; an acylphenyl group; an alkylphenyl group; a halophenyl group; a carboxyalkylphenyl group; a phenylalkynyl group; an alkynyl group; an alkylglycineethylester group; a styrene group; a thiophene group; and an alkylaminophospho group; and pharmaceutically acceptable salts thereof.

67. The 9-substituted minocycline compound of claim 65, wherein said compound is 9-isopropenyl carbamate minocycline, 9-(2-pyridylethynyl) minocycline, 9- butylacrylate minocycline, 9-naphthyl minocycline urea, 9-chloroacetyl minocycline, 9-neopentyl minocycline carbamate, benzofuranyl minocycline, 9- (phenylpropiononeamino) minocycline, 9-tosylamino minocycline, 9-(2-methoxy-3- pyridyl) minocycline, 9-(N-2'-hydroxydecyl-9'-ene-amino) minocycline, 9-BOC-NH minocycline, 9-(N-2'-hydroxybutylamino) minocycline, 9-(N-3-chloro,2- hydroxylpropylamino) minocycline, 9-p-tolyl minocycline, 9-3"-nitrophenyl minocycline, 9-(4-nitrophenylethynyl) minocycline, 9-(3-aminophenyl) minocycline, 9-(4-chloro,2-trifluoromethylphenyl) minocycline urea, 9-(p-methoxyphenyi) minocycline, $-{4'-methexysheny!} minocyciine, 5-(3,4-methylenedicxysheny? minocycline, 9-(4'-cyanophenyl) minocycline, 9-(4'-carboxyphenyl) minocycline, 9- -54 - Amended sheet: 17 April 2007

(3-formylphenyl) minocycline, 9-(4'-t-butylphenyl) minocycline, 9-(3-chlorophenyl) minocycline, 9-(2',4'-difluorophenyl) minocycline, 9-(3,4-difluorophenyl) minocycline, 9-(4'-chlorophenyl) minocycline, 9-(3,4-dichlorophenyl) minocycline, 9- (4'-trifluoromethylphenyl) minocycline, 9-(3-ethoxyphenyl) minocycline, 9-(4- carboxymethylphenyl) minocycline, 9-(phenylethynyl) minocycline, 9-(3- hydroxyphenylethynyl) minocycline, 9-(p-tolylethynyl) minocycline, 9-(p- methoxyphenylethynyl) minocycline, 9-ethynyl minocycline, 9-(p-fluoroethynyl) minocycline, 9-(trimethylsilylethynyl) minocycline, 9-(propionyl) minocycline, 9- (cyclohexenylethynyl) minocycline, 9-(1-cyclohexyl-1-hydroxyethynyl) minocycline, 9-propylglycineethylester minocycline HCL, or 9-methylglycineethylester minocycline, 9-styrene minocycline, 9-4'-fluorostyrene minocycline, 9-2-thiophene minocycline, 9-(5'-chloro-2'-thiophene) minocycline, 9-(p- methoxyphenylaminophospho) minocycline, 9-(phenylaminophospho) minocycline, 9-(p-methoxyphenylaminophospho) minocycline, or 9-(phenylaminophospho) minocycline.

68. A 9-substituted minocycline compound of claim 66 or 67, for use in a method for treating a tetracycline responsive state in a subject, comprising administering to said subject the 9-substituted minocycline compound such that said tetracycline responsive state in said subject is treated.

69. The minocycline compound of claim 68, wherein said tetracycline responsive state is a bacterial infection.

70. The minocycline compound of claim 69, wherein said bacterial infection is associated with E. coli, S. aureus, or E. faecalis.

71. The minocycline compound of claim 69, wherein said bacterial infection is resistant to other tetracycline antibiotics.

72. The minocycline compound of claim 68, wherein said compound is administered with a pharmaceutically acceptable carrier.

73. A minocycline compound seiected from the group listed in Tabie 1.

74. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 66, 67, or 73 and a pharmaceutically acceptable carrier. -55- Amended sheet: 17 April 2007

75. Use of a minocycline compound of claim 1 or 56, in the manufacture of a medicament, for use in a method for treating a tetracycline responsive state in a mammal, wherein the method comprises administering to said subject the minocycline compound, such that said subject is treated.

76. The use of claim 75, wherein said tetracycline responsive state is a bacterial infection.

77. The use of claim 76, wherein said bacterial infection is associated with E. coli.

78. The use of claim 76, wherein said bacterial infection is associated with S. aureus.

79. The use of claim 76, wherein said bacterial infection is associated with E. faecalis.

80. The use of claim 76, wherein said bacterial infection is resistant to other tetracycline antibiotics.

81. The use of claim 75, wherein said minocycline compound is administered with a pharmaceutically acceptable carrier.

82. The use of claim 75, wherein said subject is a human.

83. Use of a 9-substituted minocycline compound of claim 66 or 67, in the manufacture of a medicament, for use in a method for treating a tetracycline responsive state in a subject, wherein the method comprises administering to said subject the 9-substituted minocycline compound, such that said tetracycline responsive state in said subject is treated.

84. The use of claim 83, wherein said tetracycline responsive state is a bacterial infection. - 56 - Amended sheet: 17 April 2007

83. The use of claim 84, wherein said bacterial infection is associated with £. coli,

S. aureus, or E. faecalis.

86. The use of claim 84, wherein said bacterial infection is resistant to other tetracycline antibiotics.

87. The use of claim 83, wherein said compound is administered with a pharmaceutically acceptable carrier. -57- Amended sheet: 17 April 2007