9-substituted minocycline derivatives, pharmaceutical compositions containing them and their use

Description

9-INTRODUCED SUBSTITUTED MIHOCYCL1H DERIVATIVES The development of the tetracycline antibiotics was a direct result of the systematic screening of soil samples collected in various parts of the world for the presence of microorganisms that could be used to produce bactericidal and / or bacteriostatic preparations. The first novel compound thus obtained was introduced under the name chlortetracycline in 1948. Oxytetracycline became available two years later. The elucidation of the chemical structures of these compounds confirmed the similarity of the compounds and provided an analytical basis for the preparation of the third member of the group, tetracycline, in 1952. In 1957, a new group of tetracycline derivatives was prepared, which, unlike the earlier tetracyclines, did not contain a methyl group attached to the ring; this group of compounds became available to the public in 1967; by 1972, minocycline was also used. Recent research has focused on the development of novel tetracycline antibiotic formulations that are effective under a variety of therapeutic conditions and dosage regimens. Novel tetracycline analogs have also been investigated that may be as effective or more effective than the originally introduced tetracycline derivatives. Examples include U.S. Patent Nos. 2,980,584; 2,990,331; 3,082,717; 3,165,531; 3,454,897; 3,557,280; 3,874,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,880. These patents cover typical pharmaceutical formulations of tetracycline and tetracycline analogs. you S's you you Is you R s you 4 you M CVMU AÖ ALA WAll L * ♦♦ Historically, tetracyclines, after their initial development and introduction, soon proved to be very effective against rickettsiae (human cell parasites); certain gram-positive and gram-negative bacteria; and the causative agents of phloemophograns&ma venereum, inclusion conjunctivitis, and parrot disease. Thus, tetracyclines became known as “broad-spectrum” antibiotics. After their activity against / nv / fro microorganisms, their efficacy against experimentally induced infections, and their pharmacological properties were determined, the tetracycline group was used very widely for therapeutic purposes within a short time. However, the widespread use of tetracyclines for both serious and mild diseases has led directly to the development of antibiotic resistance, even among highly sensitive commensal (living in symbiosis with higher organisms) and pathogenic (such as pneumococci and Salmonella) bacteria.The increase in the number of organisms resistant to tetracycline has led to a decrease in the general use of tetracyclines and tetracycline analogues as antibiotics. The present invention relates, at least in part, to substituted minocycline derivatives of general formula (I), wherein: X represents a group of the general formula CHC(R13Y'Y), CRSR6, C1CRSR6, a sulfur atom, a group of the general formula NR8 or an oxygen atom; R4, R4, R4', R?, and R7' are each independently a hydrogen atom, alkyl, alkenyl, alkoxy, alkylthio, alkylsulfyl, alkylsulfonyl, alkylamino, arylalkyl, anisoport, heterocyclic group, heteroaromatic group, or prodrug (derivative that is converted into the active ingredient in the body) group; R4 represents a group of the formula NR4R4, alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen atom; R2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 are each hydrogen or a prodrug group; It represents a hydroxyl group, a hydrogen atom, a hydroxy group, alkanoyl, aryl, alkyl substituted with aryl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkH-amino, alkyl substituted with aryl, alkylcarbonyl or arylcarbonyloxy group; R and R6' (if they can be interpreted) are each independently a hydrogen atom, a methylene group, a halogen atom, a hydroxy group, a halogen atom, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkyl group, an alkyl sulfinyl group, an alkyl sulfonyl group, an alkyl amino group, or a hydroxy group substituted with a hydroxy group; R represents a group of the general formula -NRScC(~Z'}ZR33; Z is a group of the general formula GR9dR8e, NRsb, sulfur or oxygen atom; Z! represents an oxygen, sulfur atom or a group of the general formula NR: Röö, RSb, RSc, R9c, R98, and RSÍ each represent, independently of each other, a hydrogen atom, an alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, 3ΐΜί~$ζυΙίΙηίΙ, alkylsulfonyl, alkylamino, aryl substituted by aryl, aryl group, heterocyclic, heteroaromatic group or prodrug-like group: R8 represents a hydrogen atom, a hydroxyl group, a halogen atom, a thiol, an alkyl, an alkenyl, an alkynyl, an aryl, an alkoxy, an alkylthio, an alkylsulfonyl, an alkylsulfonyl, an alkylamino, or an alkyl group substituted with an aryl salt; R'3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a thiol, an alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an alkyl group substituted with an aryl group; and Y5 and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, oxy-, or alkyl substituted with arh group; and pharmaceutically acceptable salts, esters and prodrugs thereof. The present invention also relates, at least in part, to 9-substituted minocycline derivatives of the general formula (II), wherein; R4, R4', R7' and Rr represent alkyl groups; and R9 means pyrrhelethynyl group; alkenyl carbamate group; halogen atom; alkyl acrylate group; naphth group; halogenated acetyl group; alkyl carbamate group; cyclopentyl or cyclopentenyl group; benzofuranyl group; phenyl propionone amino group; tozi Ia m 1 η o - group; met ο x 1 - p I ridi 1 - group; a I k e n »ami η o»c group; N - ter rc ie r- bot i I - group; ter o I e r- bo 111-amide group; όΐόΓθχί-όο1ϋ-3ηιΙηο»οδοροΓΐ; hydroxy-propyl» -amino group; phenyl group; nltro-phenyl group; nitrophenyl· -alkynyl group; aminophenyl group; alkoxyphenyl group; halophenyl urea ester; cyanophenyl group; carboxyphenyl· group; acylphenyl group; alkylphenyl group; halogenated phenyl group; alkoxy-substituted phenyl group; carboxyalkyl-substituted phenyl group; phenylalkynyl· group; alkynyl group; alkylglycine ethyl ester group; sphyryl group; thiophenyl group;and alkylaminophospho; and pharmaceutically acceptable salts, esters and prodrugs thereof; The present invention also provides the use of the 9-substituted minocycline derivative of the present invention in the manufacture of pharmaceutical compositions for the treatment of conditions responsive to tefracycline (patients suffering from a pathological condition responsive to the minocycline derivatives of the present invention). The present invention also provides pharmaceutical compositions comprising a 9-substituted minocycline derivative and a pharmaceutically acceptable carrier. The present invention is, at least in part, novel, 9-substituted minocycline derivatives. These minocycline derivatives are useful in the treatment of a variety of conditions that can be treated with tetracyclines, such as bacterial infections and tissue proliferations, as well as other known, general uses of minocycline and tetracycline derivatives, such as tetracycline efflux inhibitors and gene expression modifiers. The present invention relates, at least in part, to substituted minocycline derivatives of the general formula (!), wherein; X is CHC(R13Y'Y), CR6R6, C=CR6R6, sulfur, NR'S or oxygen; R2, R4, R4, R7, and IV 'are each independently hydrogen, alkyl, alkenyl, alkoxy, alkylthio, alkyl -sulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl group, heterocyclic group, heteroaromatic group or prodrug (derivative that is converted into the active substance in the body) type group; R4 represents a group of the formula NR4R4', alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen; R2, R1, R11 and R12 are each hydrogen or a prodrug group; R is a hydroxy group, a hydrogen atom, a thiol, alkaloyl, aroyl, alkyl-substituted aroyl, aryl:heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulphonyl, alkylsulphonyl, alkylamino, alkyl-substituted alkyl, alkylcarbonyloxy, or a 1-carbon group; R6 and R7 (if applicable) are each independently hydrogen, methyl, halogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, alkylamino, or alkyl substituted with aryl; R9 is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl substituted with aryl group, amino, aryl substituted with alkenyl, alkynyl substituted with aryl group, thionitroso, or a group of the general formula -NR9cC(~Z1)ZR9a; represents a group of general formula CR9gR9s, NRS5, sulfur or oxygen atom; 2' represents an oxygen atom, a sulfur atom or a group of the general formula NR9f; R93, RSo, RSc, R9d, R98, and R9i each independently represent a hydrogen atom, an acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, alkyl substituted with aryl group, a heterocyclic, heteroaromatic group or a prodrug-like group; R 5 represents a hydrogen atom, a hydroxyl group, a halogen atom, a thiol, an alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or alkyl substituted with an aryl group; R13 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or alkyl substituted with arO; and Y' and Y are each independently hydrogen, halogen, hydroxyl, phenyl, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or alkyl substituted with arh; and their pharmaceutically acceptable salts, esters and prodrugs, The term minocycline derivatives refers to compounds of formula (1) above. In one embodiment, X is a group of the general formula CR&R6'; R2, R2', R&, Re, R6', R8, R9, Rw, Rn, and R12 are each hydrogen; R4 is a group of the general formula MR4R4, in which R4, R4'', Rz, and R7' are lower alkyl groups, such as methyl. R9 may be, among others, a substituted or unsubstituted heteroaryl group. The group may be, among others, a substituted or unsubstituted heteroaryl group (for example, a furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, mephendioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isoxazolyl, naphthridinyl, thiazolyl, isothiazolyl, or deaza-porinyl group), a substituted or unsubstituted phenyl group, and a group having more than one aromatic ring, such as a naphthyl group. The substituent group R may include, but is not limited to: alkyl, alkenyl, halogen, hydroxyl, alkoxy, δΙΚίΙ-^δΓόοηΙΙ-χί-, alkyloxycarbonyl, arH-carbonyloxy, alkoxycarbonyl-oxyl, θπΙοχΙ-ΚοΓόοηΙ-χί-, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aryl-substituted alkylaminocarbonyl, alkenylaminocarbonyl, arylcarbonyl, alkylcarbonyl substituted with aryl group, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylcarbonyl, phosphate, alkyl substituted with aryl group, phosphonato, phosphinato, cyano-, amino-, acyl-amino·, amido-, imino-, sulfhydryl·, alkyl-, sulfate-, anlthio-, thio-carboxylate-, alkylsulfinyl·, sulfonato-, sulfamoyl·, sulfonamido-, nitr-ο-, cyano-, azido-, heterocyclyl-, alkyl-substituted aryl·, aryl- or heteroaryl-group, In one embodiment, the group R9 of the commodity group is substituted with one or more groups, for example, carboxylate, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, carbonyl, alkoxy, alkoxycarbonyl, amido, alkylcarbonyl, or nitro. In a further embodiment, R9 is a substituted or unsubstituted alkynyl group. The R9 group, which is an alkynyl group, may be replaced by a substituted or unsubstituted aryl group, such as phenyl. The substituent group of the substituted phenyl group may include, but is not limited to, those listed above for the R9 group, which is an alkynyl group. Furthermore, the K9 group, which is an alkynyl group, may be replaced by heteroaryl (e.g., pyridinyl), alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.), alkenyl (e.g., ethenyl, propenyl, lexenyl, etc.), carboxylate, silyl (e.g., trialkylsilyl, -syl·), alkyl·, or alkoxycarbonyl substituted with a group All these groups can be further substituted with substituents such as alkyl, alkene, halogen, hydroxyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, carboxylate, alkylcarbonyl, alkH-aminocarbonyl, arylalkylcarbonyl, »** l, alkylcarbonyl, arylcarbonyl, aminoalkyl, etc. substituted alkylcarbonyl, alkenylcarbonyl, alkoxy, thio, aminocarbonyl, alkylthiocarbonyl, phosphato, phosphino, phosphino, chloro, amino, alkylamino, amide, imino, sulfhydryl, alkyl, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, chloro, azido, heterocyclic, alkylaryl, aryl and heteroaryl groups. In a further embodiment, the alkynyl group means The R* group is substituted with an amino-alkyl group. The amino-alkyl group may be further substituted, for example, with an alkyl, alkenyl, alkyl, acyl, carbonyl, or alkylsulfonyl group. In a further embodiment, the alkyne group R8 is substituted with a cycloalkene group, such as a cyclopentene group. In another embodiment, R9 is an alkyl group. The substituted or substituted alkyl group. The alkyl group is a straight chain, branched chain, and cyclic alkyl group. Examples of alkyl groups include, but are not limited to: methyl, ethyl, isopropyl, η-propyl, isobutyl, n-butyl, tert-butyl, pentyl, nonyl, decyl, etc. The cyclic alkyl group includes a single or multi-ring group, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc. In one embodiment, the R9 alkyl group is a 2-cyclopentane, Alkyl includes halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, perfluoromethoxy, perfluoro-dichloro alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkeneaminocarbonyl, carboxyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxynyl, silylaminocarbonyl, alkylthiocarbonyl, phosphonato, phosphinatato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, alkenyl, sulfonato, sulfamoyl, sulfonamido, nitro, alkenyl, cyano, azido, heterocyclyl, alkyl-substituted aryl, aryl and heteroaryl groups. In another embodiment, the minocycline derivative of the present invention is a compound in which R is a group of the formula -NR C(=Z')ZR. For example, RS is a hydrogen atom, Z is a sulfur atom, NH, or oxygen atom, and Z is a NRS group (for example, when R is hydrogen, alkyl), oxygen, or sulfur atom. The R98 group may include, but is not limited to, an aryl group, such as a substituted or unsubstituted phenyl group. The R93 substituent group of the product group may include, but is not limited to: an alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, perfluoromethyl, perchloroethyl, etc.), an alkenyl group, a halogen atom (e.g. fluoro, chloro, bromo, iodine, etc.).}, hydroxyl, alkoxy group (e.g. methoxyl, ethoxyl, propoxy, perfluoro-methyl, perchloromethoxyl, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkynylaminocarbonyl, arylalkyl, aminocarbonyl, a I ke η II - ami η o - carb ο nh -, a I ki I - carb ο ni I -, ar I - carb ο η i I -, ar 11 a I ki 1 -carbonyl-, alkenylcarbonyl, alkoxycarbonyl, silyl-, aminocarbonyl-, alkylthiocarbonyl-, phosphate-, phosphonato-, phosphinato-, cyano-, amino-, acylamino-, amide-, imino, sulfhydryl, alkylthio, arithio, ♦ •fr* thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfoyl, sulfonamide, nitro, acetyl, alkyl, clano, azido, heterocyclic, alkyl substituted with aryl, anyl and heterocyclic groups. In certain embodiments, at least one substituent of the substituted phenyl group is nitro, alkoxy (e.g., methoxy, methylenedioxy, perfluoromethoxy), alkyl (e.g., methyl, ethyl, propyl, butyl, or pentyl), acetyl, halogen (e.g., fluoro, chloro, bromo, or iodo), or amino (e.g., dialkylamino). In certain embodiments, the alkoxy group is perhalogenated, e.g., perfluoromethoxy. An RSa group meaning an aryl group may include, but is not limited to, substituted phenyl, p-nitrophenyl, p-methoxyphenyl, p-perfluoromethylphenyl, p-acetylphenyl, 3,5-methylenedioxyphenyl, 3,5-diperfluoromethylphenyl, p-bromophenyl, p-chlorophenyl, and p-fluorophenyl. The group RSa representing an aryl group may also be a substituted or unsubstituted heterocyclic group (for example, furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinoline, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, methylenedioxyphenyl, indolyl, thlenyl, pyrimidyl, pyrazinyl, punyl, pyrazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, naphthridyl, thiazolyl, isothiazolyl, or deazapurinyl group) and a substituted and unsubstituted biaryl group, such as naphthyl and fluorenyl group. R8a may be a substituted or unsubstituted alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl, etc.). The substituent group may include, but is not limited to, a halogen atom (e.g. fluoro, chloro, bromo, iodine, etc.), hydroxyl, alkoxy group (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy12 -carbonyloxy-, carboxylate-, alkyl-carboml·, alkH-amino-carboml·, aria I k Π ~ am í no ~ karbo ni í ~fa 1 keni 1-am ί η o - carbon í l·, a ik II - ο ο η ί I -, aryl-carbonyl-, arylalkyl-carbonyl-, alkenyl-carbonyl·, alkoxy-carbonyl·, sllíl-. aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, alkylamino, amylino, imino, sulfhydryl, alkylthio, aniline, thiocarboxylate, sulfate, alkylsulfonyl, sulfonato, sulfamoyl, sulfonamido, nitro, fluoromethyl, cyano, azido, alkenyl, heterocyclyl, alkyl-substituted aryl, aryl and heteroaryl groups. RSa may be a substituted or unsubstituted alkenyl group. The R9a group, which means an alkenyl group, may be substituted with, among others, the groups listed above for the R9a group, which means an alkyl group. The R9a group, which means an alkene group, may be, among others, the l-pentene group. In one embodiment, Z' is an NH group, Z is an NH group, and Rys is an alkyl group. The present invention also provides compounds in which R is aminoalkyl (e.g., aminomethyl). The aminoalkyl group R may be further substituted. The substituent may include, but is not limited to, an aryl group such as a substituted or unsubstituted phenyl group (e.g., methylenedioxyphenyl or p-(perfluoromethoxy)phenyl) or a heteroaromatic group which enables the compound of the present invention to exert its intended effect. Examples of minocycline derivatives of the present invention include the compounds listed in Table 1, as well as (MG), (MG), (MM), (MW), (ΜΙ), (NB), (MK), (NG), (ML), (NF), (NG), (MO), (MP), V^* / > Vxv. / '$ V*sv / '$ vv&~ / s \>x í / ? / 5(OO), (OD), (OE), (ΟΓ), (GM), <ON), (OQ), (OV), (OR), (OS), (GT), (QV) képletű vegyületek. * % * *· * * *** *>·> Pharmaceutically acceptable salts of these compounds are also within the scope of the present invention. Additional compounds of the present invention are listed in Table 1. A further object of the present invention is, at least in part, 9-substituted minocycline derivatives of general formula (II), wherein the formula R4, R4', R7' and R8 are alkyl; and R8 means a pyridine group; an alkyl carbamate group; a halogen atom; an alkyl acrylate group; a naphthyl group; a halogenated acetyl group; an alkyl carbamate group; a cyclopentyl or cyclopentenyl group; a benzofuranyl group; a phenyl propionone amino group; a phosphonyl amino group; a methoxypyridyl group; an alkene amino group; an N-tert-butyl group; a tert-butyl amido group; a hydroxybutyl amino group; a hydroxypropyl amino group; a phenyl group; a nitrophenyl group; a nitrophenyl alkynyl group; a 3Γηίηο-Ιβηϋ-θ5θροΓΐ; an alkyl phenyl group; a halophenyl carbamate group; a cyanophenyl group; carboxyphenyl group; acylphenyl group; alkyl substituted phenyl group; halogenated phenyl group; alkoxy substituted phenyl group; carboxyl substituted phenyl group; phenyl substituted alkynyl group; alkynyl group; alkylglycine ethyl ester group; styrene group; thiophenyl group; and alkylaminophosphonic group;and pharmaceutically acceptable salts thereof; "A"9-substituted minocycline derivative" means minocycline derivatives bearing a substituent group at the 9-position. In a further embodiment, the compound is minocycline. In one embodiment, R 9 is an alkenyl carbamate. An example of a tetracycline derivative bearing this R 9 substituent is 9-isopropenyl carbamate minocycline. ♦♦ * κ * Λ •ί * *»<* In one embodiment, R9 is a ρίπόΙΙ-βϋηΙΙ-group. A tetracycline derivative bearing this R9 substituent is, for example, 9~(2-ρίπεΙίΕβ1ίπΙ!5«πιΙηοοίΚΗη, In one embodiment, R3 is halogen. Examples of tetracycline derivatives bearing this R3 substituent include 9-iodo-minocycline, In one embodiment, R9 is an alkyl acrylate group. An example of a tetracycline derivative bearing this R9 substituent is G-butyracluate-aminocyclohexane. In one embodiment, R3 represents a naphthylcarbamate group. Examples of tetracycline derivatives bearing this R3 substituent group include G-naphthyl-minocycline urea, In one embodiment, R 9 is a halogenated acetyl group. An example of a tetracycline derivative having this R 9 substituent is 9-chloroacetyl-aminocyclourea. In one embodiment, Rs is an alkylcarbamate group. Examples of tetracycline derivatives bearing this Rs substituent group include O-neopentyl minocycline carbamate, In one embodiment, R9 is cyclopentyl or cyclopentenyl. An example of a tetracycline derivative bearing this R8 substituent is 9-cyclopentenyl minocycline. In one embodiment, R9 is a benzofuranyl group. Examples of tetracycline derivatives bearing this R9 substituent include 9-benzofuranylaminocycline, In one embodiment, R9 is phenylpropioneamino. An example of a tetracycline derivative having this R9 substituent is 9-(phenylpropiononeamino)aminocycline. In one embodiment, Rb is tosylamino. An example of a tetracycline derivative bearing this R8 substituent is 9-tosylaminoaminocycline. « Λ ?· « * ·*·♦·>'· ·*·» In one embodiment, R9 is a methoxypyridyl group. An example of a tetracycline derivative bearing this R9 substituent is 9-(2-methoxy-3-pyridine)-aminocycline. In one embodiment, R 9 represents an alkene-amino group. An example of a tetracycline derivative bearing this R 9 substituent is 9-(N 2'-hydroxydecyl-9'-ene-amino)minocycline. In one embodiment, R8 is N-tertiary-butyl. An example of a tetracycline derivative bearing this R9 substituent is N-tertiary-butylminocycline hydrochloride. In one embodiment, R9 is tert-butylamide. Examples of tetracycline derivatives bearing this R9 substituent include 9-BOC-NH-minocycline, In one embodiment, R9 is a hydroxybutylamino group. A tetracycline derivative bearing this R9 substituent is, for example, 9-{R-2,-hydroxybutylamino)-mincycline. In one embodiment, R 9 represents a hydroxy-prophamino group. An example of a tetracycline derivative bearing this R 9 substituent is 9-(1M-[3-chloro-2-hydroxypropyl]-amino)-methylenecyclotetracycline. In one embodiment, R8 is phenyl. Examples of tetracycline derivatives bearing this R9 substituent include G-fenif-minocycline hydrochloride and 3-p-follyl-minocycline. In one embodiment, R9 is nitrophenyl. Examples of tetracycline derivatives bearing this R9 substituent include 9-(3:-nitrophenyl)aminocyclohexyl. In one embodiment, R9 is a nitro-phenyl-alkynyl group. An example of a tetracycline derivative bearing this R9 substituent is O-C6'-nitro-phenyl-epynyl-minocycline. In one embodiment, Rs is amino-phenyl. -group. An example of a tetracycline derivative bearing this R9 substituent group is 9-(3-aminophenyl)-minocycline. In one embodiment, R9 is a halophenylcarbamate group. An example of a tetracycline derivative bearing this R9 substituent group is 9-(4-chloro-2-trifluoromethylphenyl)-aminocyclocarbamide. In one embodiment, R 9 is an alkoxyphenyl group. Examples of tetracycline derivatives bearing this R 9 substituent include 9-(p-methoxyphenyl)-minocycline, 9-(4'-methoxyphenyl)-minocycline, and 9-(3,4-methylenedioxylphenyl)-minocycline. In one embodiment, R 9 represents a clanophenyl group. An example of a tetracyclic derivative bearing this R 9 substituent is 9-(4'-cyanophenyl)-minocycline. In one embodiment, R9 is a phenyl group substituted with a carboxyalkyl group. An example of a tetracycline derivative bearing this R9 substituent is 9-(4'-carboxyphenyl)-minocycline. In one embodiment, R9 is phenyl substituted with an acyl group. An example of a tetracycline derivative having this R9 substituent is 9-(3-formylphenyl)-minocycline. In one embodiment, R9 is phenyl substituted with an alkyl group. An example of a tetracycline derivative bearing this R9 substituent is 9-(4'-tert-butylphenyl)-misocycline. In one embodiment, R9 is a phenyl group substituted with a halogen atom. Examples of tetracycline derivatives bearing this R9 substituent group include 9-(3-chlorophenyl)-minocycline, 9-(2',4'-difluorophenyl)-minocycline, 9-(3',4'-difluorophenyl)-minocycline, 9-(4'-chlorophenyl)-minocycline, 9-(3,4-dichlorophenyl)-minocycline, and 9-(4'-trifluoromethylphenyl)-minocycline. In one embodiment, R8 is a phenyl group substituted with an alkoxy group. An example of a tetracycline derivative bearing this R9 substituent is 9-(3-ethoxy-phenyl)-minocycline. In one embodiment, R9 is phenyl substituted with a carboxyalkyl group. In this R1 <helyettesítő csoportot viselő tetraciklín származék például a 9-(4~karboxí-metíl· -feníl)~mínoclklln. In one embodiment, R9 is a phenyl-alkynyl group. Examples of tetracycline derivatives bearing this R9 substituent include ε-(phenylethyl)-minocycline, 9-(3-hydroxyphenylethynyl)-minocycline, 5-[beta]-tolyl-minocycline, and 9-(p-phenylethoxyphenylethynyl)-minocycline. In one embodiment, R9 is an alkyl group. Examples of tetracycline derivatives having this R9 substituent include 9-ethynyl minocycline, 9-(p-fluoroethynyl)-minocycline, 9-(trimethyl-silicyclohexyl)-minocycline, B-Cpropionyl-minocycline, 9-(cyclohexyl-ethynyl)-minocycline, and 9-(cyclohexyl-hydroxy-ethynyl)-minocycline. In one embodiment, R 9 represents an alkylglycine ethyl ester group. Examples of tetracycline derivatives bearing this R 9 substituent group include 9-propylglycine ethyl ester minocycline hydrochloride and 9-methylglycine ethyl ester minocycline. In one embodiment, R9 is a styryl group. Examples of tetracycline derivatives bearing this R9 substituent include 0-Cstyryl-minocycline and 9-(45-fluoro-styryl)-minocycline. In one embodiment, R9 is a thiophenyl group. Examples of tetracycline derivatives bearing this R9 substituent group include O-[S-thiophenyl]-aminocycline, and O-[S-chloro-S'-thiophenyl]-aminocycline, In one embodiment, R9 is an alkylaminophospho group. Examples of tetracycline derivatives bearing this R9 substituent include G-Cp-methoxyphenH-aminophospho-minocycline, and 9-(phenytoin-1-yl)-phosphonyl)-cyclotetracycline. w * * · · * * * BC *«* *** *♦** ** * * The minocycline derivatives of the present invention can be prepared using the methods shown in Schemes 1-6. The 9-substituted minocycline derivatives can be prepared by the general procedure depicted in Scheme 1. In general, 9-substituted minocycline derivatives can be prepared as shown in Scheme 1 by reacting minocycline of Formula 1A with sulfuric acid and sodium nitrate. The resulting compound is 9-nitro-minocycline of Formula 1B. The nitrominocycline is then reacted with hydrogen gas and a platinum catalyst to give 9-amino-minocycline of Formula 1C. The 9-substituted derivatives are prepared by reacting 9-amino-minocycline with H2NG to give the diazonium salt of Formula 1D. The salt can then be reacted with a variety of compounds bearing alkene or π-bonded functional groups, such as planar, aryl and alkyne derivatives (e.g. RsBr), to provide the 9-substituted minocycline derivative of formula 1E. As shown in Scheme 2, the minocycline derivatives of the present invention, in which R9 is a carbamate or urea derivative, can be prepared by the following procedure. Minocycline of formula 2A is reacted with sodium nitrite in acidic medium to give 9-nitro-minocycline of formula 2B. The ε-nitro-minocycline of formula 2B is then reacted with hydrogen gas and a platinum catalyst to give 9-amino-minocycline of formula 2C. The urea derivative of formula 2E is prepared by reacting the isocyanate of formula 2D with the 9-amino-minocycline of formula 20. The carbamate of formula 2G is prepared by reacting the corresponding acid chloride ester of formula 2F with the compound of formula 2C. Scheme 3 shows a method for preparing aminoalkanes of the present invention in which R is an amino group substituted with a heterocyclic group (e.g., thiazole). The 9-aminoalkane of Scheme 3A is reacted with the Fmoc isothiocyanate of Formula 38 to give the protected thiocarbamate of Formula 3C. The protected thiocarbamate of Formula 3C is deprotected to give the tetracyclocarbamate or tetracyclocarbamate of Formula 3D. The tetracyclocarbamate of Formula 3D is reacted with the α-haloketone of Formula 3E to give the thiazole substituted 9-aminoalkane of Formula 3F. As shown in Scheme 4, the 9-alkenyl minocycline derivatives of formula 4A can be hydrogenated to give the 9-alkyl-substituted minocycline derivatives of formula 4B. Scheme 4 shows the selective hydrogenation of the 9-position double bond using hydrogen gas and a palladium / carbon catalyst. 9-alkyl minocycline derivatives can be prepared similarly by hydrogenation of 9-alkynyl minocyclines. Scheme 5 shows a general procedure for the preparation of minocycline derivatives substituted with an aryl group at the 9-position. Scheme 5 shows the Suzuki coupling of iodo-minocycline and an arylboronic acid. The iodo-minocycline of formula 58 can be prepared by reacting minocycline of formula 5A with at least one equivalent of M-iodosuccinimide (MIS) under acidic conditions. The reaction is frozen, and the resulting 9-methyl-minocyline of formula SS can be purified by conventional methods known per se. To prepare the aryl derivative, the 9-methyl-minocyline of formula 58 is reacted with an aqueous base (e.g., sodium carbonate) and the appropriate boronic acid of formula 5C in a neutral atmosphere. The reaction is catalyzed by a palladium catalyst (such as Pd(OAc)2). The product of formula 5D can be purified by methods known per se (such as HPLC). Other 9-methyl- and 9-alkyne minocycline derivatives can be prepared by similar reaction sequences. The 9-substituted minocycline derivatives of the present invention can also be prepared by a Stille-type cross-coupling reaction. The Stille-type cross-coupling reaction can be carried out using a suitable tin reagent (e.g., R-SnBu3) and a halogenated tetracycline derivative (e.g., 9-iod-minocycline). A palladium catalyst (e.g., Pd(PPh3)2Cl2 or Pd(AsPh3)2Cl2 catalyst) and optionally a copper salt, e.g., CuI, are added to the tin reagent and the iodo-minocycline. The resulting compound is then purified by methods known per se. The compounds of the present invention can also be prepared by a Heck-type cross-coupling reaction. As shown in Scheme 6, the Heck-type cross-coupling reaction can be carried out by using a halogenated tetracycline derivative (e.g., 9-iodo-minocycline), a reactive planar 8B or alkyne 6D, and a suitable palladium or other transition metal catalyst. The resulting minocycline derivative substituted at the 9-position with an alkenyl group (compound 6C) or at the 9-position with an alkynyl group (compound 6E) can be purified by methods known per se. * * Λ «· The term alkyl group means 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, tertiary-butyl, isobutyl, etc.), cyclic (alicyclic) alkyl groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. The term alkyl group also includes alkyl groups that may contain atoms such as oxygen, nitrogen, sulfur, or phosphorus atoms replacing one or more carbon atoms of the hydrocarbon skeleton.In certain embodiments, a straight or branched chain alkyl group has 8 or fewer carbon atoms in its backbone (e.g., 1 to 8 carbon atoms in a straight chain, 3 to 6 carbon atoms in a branched chain), more preferably 4 or fewer carbon atoms. Similarly, in preferred embodiments, cycloalkyl groups have 3 to 8 carbon atoms in the ring structure, more preferably 5 to 6 carbon atoms. The term C1-6 alkyl group includes alkyl groups having 1 to 8 carbon atoms. In addition, the term "alkyl" includes both substituted alkyl groups and substituted alkyl groups, the latter term meaning alkyl groups containing groups replacing a hydrogen atom attached to one or more carbon atoms of the hydrocarbon skeleton, such substituents including, but not limited to, alkenyl and alkynyl groups, halogen, hydroxyl, alkyl carbonyl, aryl carbonyl, aryl carbonyl, aryloxycarbonyl, carboxylate, alkyl carbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl22 (iocarbonyl, alkyloxy, phosphate, phosphonaph, phosphinate, cyano-, amino-group (including alkylamino-, dialkylamino-, arylamino-, diarylamino-, and alkylarylamino-group), alkylamino-group (including alkylcarbonylamino-, anlcarbonylamino-, carbamoyl-, and ureldo-group), amidino-, imino-, sulfhydryl-, alkylthio-,arylthio, thiocarboxylate, sulfato, sulfonal, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkyl substituted aryl, or heteroaromatic. Cycloalkyl groups may also be substituted, for example, with the substituents described above. The term "alkyl-aryl" or "aryl-alkyl" refers to a substituted alkyl group (e.g., phenylmethyl (benzyl) group). The term "alkyl" also includes the side chain groups of natural and unnatural amino acids. The term "aryl group" includes groups of 5 to 8 membered simple ring aromatic groups containing between 0 and 4 heteroatoms, such as benzene, phenyl, pyrrole, furan, thiophene, phthalazole, isothioazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine and the like. The groups also include, inter alia, multi-ring, fused aromatic groups, such as three-ring, bicyclic groups, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiazole, benzothiazole, methyldioxyphenyl, quinoline, isoquinoline, naphthylridine, indophenylfuran, pun, deazapurine, or indolizine groups. Groups of 5 to 8 membered simple ring aromatic groups containing between 0 and 4 heteroatoms in the ring include heterocyclic groups, heteroaryl groups or heteroaromatic groups”. The aromatic ring may be substituted at one or more positions with groups such as those mentioned above, such as halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, alkylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphine, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkyl-aryl-amino-, ach-amino- (including alkylcarbonyl-amino-, arylcarbonyl-amino-, carbamoyl-, and ureido-), amidino-, imino-, sulfhydryl-, alkylthio-, arylthio-, ethoxycarboxylic-, sulfate-, sulfonato-, sulfamoyl-, sulfonamido-, nitro-, influoromethyl-, cyano-, azido-, heterocyclic group, alkyl-anl-,or an aromatic or heteroaromatic group. The groups may be combined with or linked to non-aromatic alicyclic or heterocyclic groups to form a polycyclic group (e.g., a fetraUn group)., The term "alkyl group" means a saturated aliphatic group analogous in chain length and substitution possibilities to the alkyl groups described above, and containing at least one double bond. For example, the term "alkenyl group" includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, phenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, deoxyenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctphenyl), cycloalkenyl groups substituted with alkyl or alkenyl groups, and alkenyl groups substituted with cycloalkyl or alkyl alkenyl groups. The term "alkenyl group" also includes alkenyl groups in which one or more carbon atoms in the hydrocarbon backbone are replaced by oxygen, nitrogen, sulfur, or phosphorus atoms. In certain embodiments, the straight or branched chain alkenyl group contains 6 or fewer carbon atoms in the backbone (e.g., 2 to 6 carbon atoms for a straight chain, 3 to 8 carbon atoms for a branched chain).Similarly, cycloalkenyl groups may contain from 3 to 3, more preferably 5 or 6, carbon atoms in the ring structure. A C2-C8 alkenyl group contains from 2 to 8 carbon atoms. In this regard, the term alkenyl group includes both substituted alkenyl groups and substituted alkenyl groups, the latter term meaning alkenyl groups which contain groups replacing a hydrogen atom attached to one or more carbon atoms of the hydrocarbon skeleton.Examples of such substituents include: alkyl and alkynyl groups, halogen atom, hydroxyl, alkylcarbonyl, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkyloxyl, phosphate, phosphonate, phosphine, phosphonate, chloro, amino group (including alkylamino, dialkylamino, anlamino, diarylamino, and alkylarylamino groups), acyl-amino group (mainly alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups), amidine©-, imino-, sulfhydryl-, alkylthio-, arylthio-, thiocarboxyl-, sulfato-, sulfonato-, sulfamoU-, sulfonamido-, nitro-, trifluoromethyl-, clano-, azido-group, heterocyclic group, alkyl-substituted aryl-, or aromatic or heteroaromatic group. The term "alkyl group" means an unsaturated aliphatic group analogous in chain length and substitution possibilities to the alkyl groups described above, and containing at least one triple bond. XX ·♦*·♦' * * * * *. * χ Ví* ♦ ** * ♦ 3» «».* 3«. '«'K~' For example, the term “alkynyl group” includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and alkynyl groups substituted with cycloalkyl or cycloalkenyl groups. The term “alkynyl-branched” also includes alkyl groups in which one or more carbon atoms in the hydrocarbon backbone are replaced by oxygen, nitrogen, sulfur, or phosphorus. In certain embodiments, the straight-chain or branched-chain alkynyl group contains 8 or fewer carbon atoms in the backbone (e.g., 2 to 8 carbon atoms for a straight-chain, 3 to 6 carbon atoms for a branched-chain). A C2-8 alkynyl group contains between 2 and 8 carbon atoms. In addition, the term "alkynyl" includes both unsubstituted alkynyl groups and "substituted alkynyl groups", the latter term meaning alkynyl groups containing groups replacing a hydrogen atom attached to one or more carbon atoms of the hydrocarbon skeleton.Examples of such substituent groups include; alkyl and alkynyl groups, halogen atom, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxycarbonyl, diaminocarbonyl, alkylthiocarbonyl, alkoxycarbonyl, phosphato, phosphono, phosphinate, phenyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbosmoyl and ureldo groups), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, fluoro, trifluoro26. χ* is a cyano, azibc group, heterocyclic group, alkyl-substituted aryl, or aromatic or heteroaromatic group. Unless otherwise specified by the carbon number, the term "lower alkyl" refers to an alkyl group as described above containing from 1 to 5 carbon atoms in the hydrocarbon skeleton. Similarly, the terms "lower alkene" and "lower alkynyl" refer to groups containing, for example, from 2 to 5 carbon atoms. The term "acyl group" refers to compounds and groups containing an acyl radical (of the formula CH3CO-) or a carbonyl group. The term includes substituted acyl groups. The term "substituted acyl group" includes acyl groups in which one or more hydrogen atoms are replaced, for example, by one of the following groups: alkyl, and ωΙΚΙηΙΙ-οδοροΗ, halogen atom, hydroxyl, ωΙΚΠ-ΚοτΡοηΗ-ωχί-, aryl-carbonyl-oxy-, alkoxy-carbonyl-oxyl·, οπ1οχΙ~ΚθΓ0οη11»ω1-, carboxylate-, alkyl-carbonyl·, aryl· carbonyl·, ωΙΚοχί-Κο^οηΙΙ-, amino-carbonyl·, alkyl-amino-carbonyl·, di-Ik I l· am In o - carb ο η I l·, al ki l· fio car rb ο η i I ~, a I kil·ο x H -, phosphate-, phosphonato-, phosphinato-, cyano-, amino-group {including alkyl amino, dialkyl amino, aryl amino, diaryl amino, and alky aryl -amino group), acylamino group (including alkylcarbonyl, -amino, anicarbonylamino, carbamoyl and ureido groups), aminido, imino, sulfhydryl, alkylthio, aryl, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido group, heterocyclic group, alkyl substituted aryl, or aromatic or heteroaromatic group. The term "acylamino group" refers to groups in which the acyl group is attached to an amino group, such groups as alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido. The term "aroyl group" refers to compounds and groups in which an aryl or heteroaromatic group is attached to a carbonyl group. Examples of aroyl groups are phenylcarboxy, phenylaromatic, etc. The terms "alkyl-amino-alkyl-alkyl" and "alkyl-amino-alkyl-alkyl" mean an alkyl group as described above which further contains heteroatoms, such as oxygen, nitrogen or sulfur atoms, replacing one or more carbon atoms of the hydrocarbon skeleton. The term "alkoxy" refers to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentyloxy. Examples of substituted alkoxy groups include, but are not limited to, halogenated alkoxy groups.Alkoxy groups may be substituted with groups such as: alkyl, alkynyl, halogen, hydroxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkyloxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, anamino, dianamino, and alkylarylamino), acylamino salt (including several among them alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups), amidino, iramino, sulfhydryl, alkylthio, arylthio, bocarboxylate, sulfato, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkyl-substituted aryl, or aromatic or heteroaromatic * * « ** »* ψ ♦ * *. Φ ♦·»♦ »♦. group. An alkoxy group substituted with a halogen atom includes, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "amine" or "amino group" refers to compounds in which a nitrogen atom is covalently bonded to at least one carbon atom or heteroatom. The term also includes "alkylamino groups," i.e., groups and compounds in which the nitrogen atom is bonded to at least one additional alkyl group. The term "dialkylamino" refers to groups in which the nitrogen atom is bonded to at least two additional alkyl groups. The terms "arH-amino" and "diarylamino" refer to groups in which the nitrogen atom is bonded to at least one and two additional alkyl groups, respectively. The term "alkyl-aryl-amino" or "alkyl-amino" refers to an amino group that is attached to at least one alkyl group and at least one aryl group. The term "alkamino-alkyl" refers to an alkyl, alkenyl, or alkynyl group and an alkyl group attached to the nitrogen atom. The term “amide” “amido-H” or “aminocarbonyl” refers to compounds or groups in which a nitrogen atom is attached to a carbon atom of a carbonyl or thiocarbonyl group. The term also includes “alkaliminocarbonyl” or “alkylaminocarbonyl” groups in which an alkyl, alkenyl, aryl or alkyl group is attached to an amino group attached to a carbonyl group. It also includes arylaminocarbonyl and arylcarbonylamino groups in which an aryl or heteroaryl group is attached to an amino group attached to a carbon atom of a carbonyl or thiocarbonyl group. The term “amide” refers to both “alkylamino- carbonyl group", "aribamino-carbonyl group", alkyl-carbonyl- am I π o ~ os ο portot ”t„ alkene ni I - carb ο n 11 - ami η o - cs ο portot, "at ki η N ~ -carbonyl-amino-groupot· and "aryl-carbonyl-amino-groupor, Amides are also carbamido- (ureido-) and carbamafo- (oxycarbonyl-amino-groups. The term "carbonyl group" or "carboxy group" refers to compounds and groups in which a carbon atom is divalently bonded to an oxygen atom. The carbonyl group may be further bonded to a substituent group that enables the compound of the present invention to exert its intended effect. Carbonyl groups may be substituted, for example, with the following groups: alkyl, alkenyl, alkynyl, aryl, alkoxy, aromatic groups, etc. Compounds containing a carbonyl group include, for example, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "thiocarbonyl group" or "thiocarboxyl group" refers to compounds and groups containing a carbon atom double-bonded to a sulfur atom. The term "ether" refers to compounds or groups that contain an oxygen atom bonded to two different carbon atoms or heteroatoms. The term includes, for example, an "alkyloxyalkyl group" in which an alkyl, alkenyl, or alkyl group is covalently bonded to an oxygen atom that is covalently bonded to another alkyl group. The term "ester" refers to compounds and groups in which a carbon atom or a heteroatom is attached to the oxygen atom attached to the carbon atom of a carbonyl group. The term "ester" includes 3ΐΚοχ1~&0ίόοχΙ~08οροΓ^3ΐ, such as methoxycarbonyl·, ethoxycarbonyl-, ρΓοροχΙ-ΚοΓόοηΙΙ-Η butoxycarbonyl-k pentyloxycarbonylH“CGroup, etc. The meaning of the alkyl·, alkenyl-, or alkynyl-group is as defined above. The term “thioether” refers to compounds and groups containing a sulfur atom bonded to two different carbon or heteroatoms. Examples of thioethers include, but are not limited to, alkyl-thioalkyl, alkyl-thioalkenyl, and alkyl-thioalkynyl groups. The term “BiO- The term "hydroxyl group" or "hydroxyH group" means a group with the structure -OH or -O'. The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogen" generally refers to a group in which all hydrogen atoms are replaced by halogen atoms. The terms "polycyclic group" or "multicyclic group" mean two or more ring groups (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclic groups) in which the rings connected to each other have two or more common carbon atoms, e.g., the rings are fused. Ring groups connected to each other by non-adjacent carbon atoms are called "bridged" rings. Each ring of the multicyclic group is substituted with the groups described above, for example halogen atom, hldroxyl·, akyl-carbonyl-oxl·, anl-carbonyl-oxl·, akcxi-carbonyl-oxl·, ar Η ο xi - ka rb ο n íl· ο xi -, carb οχ i 1 á t -, a I k Π ~karb ο η i 1 -, a I kox í ~ karb ο η II-, alkn-amino-carbonyl·, aryl-group alkyl-amino-carbonyl-, alkenii-amino-carbonyl·, alkyl-carbonyl·, aryl-carbonyl·, rf 4S ** ¥ * « * * X * í **% J * *% ,| «·»* »**' *ίθ *** **-* árúkroptá! substituted alkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylcarbonyl, alkoxy,phosphate, phosphonato, phosphinato, clano, amide, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylamino substituted with alkyl groups), acylamino (including alkylcarbonylamino, anylcarbonylamino, carbamol, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamol, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkyl, alkyl substituted with alkyl groups, or aromatic or heteroaromatic groups, The term "heteroatom" as used herein refers to any atom of an element other than carbon or hydrogen. Preferred heteroatoms include nitrogen, oxygen, sulfur, and phosphorus. The term "prodrug group" includes groups which are converted to hydroxyl groups during metabolism, as well as groups which preferably remain esterified. Preferably, prodrug groups are converted to hydroxyl or other preferred groups during metabolism by esterase enzymes or otherwise. Prodrugs and their uses are known per se (see, for example, Berge et al. (1977), "Pharmaceutical Salts", J. Pharmacol. 66:1-19). Some prodrugs may be prepared during the final separation and purification of the compounds, or separately by reaction of the free acid form or hydroxyl derivative of the purified compound with a suitable esterifying agent. Hydroxyl groups may be converted to esters, for example, by treatment with a carboxylic acid.Examples of prodrug groups include substituted and optionally branched or unbranched lower alkyl esters (e.g. propionic acid esters), lower alkyl esters, etc. -ί Γ Iό esters, lower alkyl esters substituted by two lower alkyl groups with an amino group (e.g. dimethylaminoethyl ester), lower alkyl esters substituted by an amino group with an acyl group (e.g. dimethylaminoethyl ester), lower alkyl esters substituted by an acyl group (e.g. dimethylaminoethyl ester), lower alkyl esters substituted by an acyl group (e.g. pivatoyloxymethyl ester), aryl esters (phenyl ester), lower alkyl esters substituted by aryl groups (e.g. benzyl ester), aryl and lower alkyl esters substituted by aryl groups (e.g. methyl, halogen or methoxy ester), amides, lower alkyl amides, di(low C10-12 alkyl amides and hydroxyl amides. Preferred prodrug groups are propionic acid esters and acyl esters. It is noted that several compounds of the present invention contain asymmetric carbon atoms. It is therefore understood that isomers resulting from asymmetry (e.g., all enantiomers and diastereomers) are within the scope of the present invention, unless otherwise indicated. Such isomers may be prepared in substantially pure form by conventional separation techniques and stereochemically controlled reactions. Furthermore, the structures and compounds discussed in this application are intended to include all of their tautomeric forms, The present invention also provides the use of an effective amount of a 9-substituted minocycline derivative of the present invention (e.g., a compound of general formula (!), or a compound listed in Table i<) in the manufacture of a pharmaceutical composition administered to a patient for the treatment of a pathological condition that can be controlled by a tetracycline derivative. «·* ··> GOOD The term "condition treatable by a tetracycline derivative" means a disorder that can be treated, prevented, or otherwise alleviated by administration of a substituted minocycline derivative of the present invention. Conditions treatable by a tetracycline derivative include bacterial infections (including those resistant to other tetracycline derivatives), cancer, diabetes, and other conditions for which tetracycline derivatives have been found to be effective (see, for example, U.S. Patent Nos. 5,789,395; 5,834,450; and 5,532,227). The compounds of the present invention are useful for the curative or prophylactic treatment of important mammalian diseases and veterinary diseases such as diarrhea, urinary tract infections, skin infections, ear, nose, and throat infections, wound infections, mastitis, etc.Furthermore, the present invention includes the use of the compounds of the present invention in which the pathological condition is pathological tissue proliferation (see van der Bozert et al., Cancer Res., 48:6886-8890 (1988)). Bacterial infections can be caused by a variety of gram-positive and gram-negative bacteria. The compounds of the present invention are useful as antibiotics against organisms that are resistant to other tetracycline derivatives. The antibiotic activity of the minocycline derivatives of the present invention can be determined by the Zn v / fro standard medium dilution method described in Example 2 or in Waifz, JA, A / ahona / Comnvssion for C / / nfca / L&boratory Sfandsrds, Oocumenf A47-A2, vol. 18, no. 8, pp 13-20, 2nd edition, Vilíanova, PA (1990). The minocycline derivatives of the present invention can also be used to treat diseases conventionally treated with tetracycline derivatives, such as rickettsiae, certain gram-positive and gram-negative bacteria. -negative bacteria, or diseases caused by pathogens responsible for the diseases of / lymphogranuloma venereum, inclusion conjunctivitis, parrot disease. The tetracycline derivatives can be used to treat diseases caused by K. pneumomae, Salmonella: E. coli, A. spp. cafarrha / s, H. influenzae. F. aeruginosa, E. coli; E. coli, S. aureus, or E. faecalis. In one embodiment, the minocycline derivative is used to treat bacterial infections that are resistant to treatment with other tetracycline antibiotics. The substituted minocycline derivatives of the present invention can be administered together with a pharmaceutically acceptable carrier. The term "effective amount" refers to an amount of the compound that is necessary or sufficient for the curative or prophylactic treatment of a pathological condition that can be treated with a tetracycline derivative. The effective amount may vary depending on certain factors, such as the size and weight of the patient, the type of disease, or the particular substituted tetracycline derivative. For example, the choice of minocycline derivative may affect what is considered an effective amount. One skilled in the art will be able to determine the above factors and, without undue experimentation, determine an effective amount of minocycline derivative. The present invention also provides the use of the compounds of the present invention in the manufacture of a pharmaceutical composition for the treatment of infections caused by microorganisms and associated pathological conditions. The pharmaceutical composition comprises one or more minocycline derivatives. The patient may be a plant or, preferably, an animal, such as a mammal, such as a human. amount administered to a patient In the therapeutic applications of the present invention, one or more minocycline derivatives of the present invention are administered to the patient in their own form, or typically, the compound of the present invention is administered in a pharmaceutical composition in admixture with a conventional excipient, i.e., a pharmaceutically acceptable organic or inorganic carrier suitable for parenteral (bypassing the gastrointestinal tract), oral or other desired administration, which carrier does not adversely react with the active compounds and is not harmful to the patient. The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a minocycline derivative and, optionally, a pharmaceutically acceptable carrier. The term pharmaceutically acceptable carrier is intended to include materials which can be co-administered with the minocycline derivatives and which enable the minocycline derivative(s) to exert the intended effect, such as the curative or prophylactic treatment of a pathological condition amenable to the tetracycline derivative. Suitable pharmaceutically acceptable carriers include water, saline solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silica, viscous paraffin, fragrance, fatty acid monoglycerides and diglycerides, petroleum ether fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.The pharmaceutical compositions may be sterilized and, if necessary, mixed with auxiliary substances such as anti-adherents, preservatives, stabilizers, wetting agents, emulsifiers, salts for regulating osmotic pressure, buffers, coloring, flavoring and / or aromatizing agents and the like which do not adversely react with the active compounds of the present invention. The basic substituted minocycline derivatives of the present invention can form a variety of salts with various inorganic and organic acids. In the preparation of the basic monocycline derivatives of the present invention with pharmaceutically acceptable acid addition salts, acids which form non-toxic acid addition salts, i.e. salts containing pharmaceutically acceptable anions, may be used, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, acetate, lactal, salicylate, citrate, acid citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, styrofoam, mylate, gentisinate, metal arate, gluconate, glucuronate, saccharate, formate, benzoate, glufamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2Κ1ότοχίΙ~3~η3ίΙοόί)| salts.Although the salts in question must be pharmaceutically acceptable for administration to a patient, e.g., a mammal, it is often desirable in practice to first isolate the tetracycline derivative of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt, then simply convert the former salt back to the free base form of the compound with a basic reagent, and then convert the latter free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the basic compounds of the present invention can be readily prepared by reacting the basic compound with a solution of a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent or a suitable organic solvent, e.g., methanol or ethanol. The desired solid salt can be readily obtained by careful evaporation of the solvent. Additional mycocycline derivatives of the present invention, not detailed in the following experimental section, can be prepared by methods obvious to those skilled in the art, by combining the reactions described above. The acidic minocycline derivatives of the present invention can form a variety of bases. In the preparation of pharmaceutically acceptable base salts of the acidic minocycline derivatives of the present invention, bases which form non-toxic base salts with the compounds in question can be used as reagents. Examples of such non-toxic base salts include pharmaceutically acceptable cations such as alkali metals (e.g., potassium and sodium) and alkaline earth metals (e.g., calcium and magnesium), salts of ammonium ions, or water-soluble amine addition salts such as N-methylglucamine (megtumim), and lower alkanol-substituted ammonium salts or salts of pharmaceutically acceptable organic amines with other bases. The pharmaceutically acceptable base addition salts of the acidic minocycline derivatives of the present invention can be prepared from pharmaceutically acceptable cations by methods known per se.Thus, the salts in question can be prepared simply by reacting the minocycline derivative of the present invention with an aqueous solution of the desired pharmaceutically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a solution of the minocycline derivative of the present invention in a lower alcohol is mixed with the desired metal alkyl oxide derivative, and then the resulting solution is evaporated to dryness. Additional minocycline derivatives of the present invention, not detailed in the following experimental section, can be prepared by methods obvious to those skilled in the art, by combining the reactions described above. The milnoeikiin derivatives and their pharmaceutically acceptable salts of the present invention can be administered orally, parenterally or topically. In general, the compounds in question are administered in the most advantageously effective dosage, the amount of which depends on the body weight and condition of the patient being treated, and on the chosen method of administration. Depending on the race of the patient being treated and the individual response to the drug in question, and on the selected pharmaceutical form and the frequency and duration of administration, variations are possible. The pharmaceutical compositions of the present invention may be administered alone or in combination with other known compositions for the treatment of tetracycline-responsive conditions in animals, such as mammals. Preferred mammals include companion animals (e.g., cats, dogs, ferrets, etc.), farm animals (cattle, sheep, pigs, horses, goats, etc.), experimental animals (rats, mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas). The term co-administration includes the simultaneous administration of the composition of the present invention and the known composition, the administration of the composition of the present invention first, followed by the known composition, or the administration of the known composition first, followed by the composition of the present invention. Any known therapeutic composition for the treatment of tetracycline-responsive conditions may be used in the methods of the present invention. The milnoeikiin derivatives of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents, in single or multiple doses, by any of the above-mentioned routes. For example, the novel therapeutic agents of the present invention may be advantageously administered in a variety of dosage forms, i.e., tablets, capsules, lozenges, lozenges, hard lozenges, powders, aerosols, creams, patches, suppositories, gels, ointments, milky creams, balms, aqueous suspensions, injectable solutions, elixirs, syrups, etc., combined with various pharmaceutically acceptable inert carriers. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents, etc. Furthermore, orally administered pharmaceutical compositions may be suitably sweetened and / or flavored.The therapeutically active compounds of the present invention are typically present in the dosage forms in question in an amount of from about 5.0 to about 70% by weight. For oral administration, tablets containing various binders such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may contain various disintegrating agents such as starch (preferably corn, potato or tapioca starch), alginic acid or certain complex silicates, and granulating agents such as polyvinylpyrrolidone, sucrose, gelatin or acacia. In addition, anti-caking agents such as magnesium stearate, sodium lauryl sulphate and tafum are often very useful in the preparation of tablets.Solid preparations of this kind can also be used as fillers for gelatin capsules; in this respect, lactose or milk sugar and high molecular weight polyethylene glycols are also preferred. If an aqueous suspension and / or elixir is required for oral administration, the preparation will contain, in addition to the active ingredient, various sweetening or flavoring agents, coloring agents or dyes, and, if necessary, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof. For parenteral administration (including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection), solutions of the therapeutic compound of the present invention in sesame or peanut oil or aqueous propylene glycol can be used. The aqueous solutions are suitably buffered as necessary (preferably greater than pH ~ 8), and the liquid solvent is first adjusted to an isotonic (ensuring the same osmotic pressure as body fluids) concentration. Such aqueous solutions are suitable for intravenous administration. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection. All of these solutions can be easily prepared under sterile conditions by conventional pharmaceutical procedures well known to those skilled in the art. For parenteral administration, suitable formulations include solutions, preferably oily or aqueous solutions, and suspensions., emulsions or implanted dosage forms, including suppositories. The therapeutic compounds may be prepared in multiple or single sterile dosage forms, for example, by dispersion in a liquid vehicle, such as sterile physiological saline solution commonly used for injection or 5% saline-dextrose solution. In addition, the compounds of the present invention may be administered topically for the treatment of inflammatory skin diseases. Topical administration forms include transdermal, buccal, or sublingual administration. For topical administration, the therapeutic agents may be suitably mixed with a pharmaceutically inert topical vehicle, such as a gel, balm, cream, or lotion. Such topical vehicles include, but are not limited to, water, glycerin, alcohol, propylene glycol, and the like. -glycol, fatty alcohols, triglycerides, fatty acid esters or mineral oils, Other possible topical carriers; liquid petroleum ether, isopropyl palmitate, polyethylene glycol, 95% ethanol, 5% aqueous solution of polyoxyethylene monolaurate, 5% aqueous solution of sodium lauryl sulfate, etc. Furthermore, antioxidants, wetting agents, viscosity stabilizers and similar substances may be added to the composition if necessary. Tablets, dragees or capsules containing talc and / or a carbohydrate carrier (preferably lactose and / or corn starch and / or potato starch), a binder and the like are particularly suitable for internal use. If a sweetened carrier is required, a syrup, elixir or the like can be used. Sustained-release preparations can also be used, for example in which the active ingredient is protected by differently degradable coatings, such as microcapsules, multilayer coatings, etc. In addition to the treatment of human patients, the therapeutic methods of the present invention also have significant veterinary applications, the treated patient may be a legume, such as cattle, sheep, goats, cows, pigs, etc.; poultry, such as chickens, ducks, geese, turkeys, etc.; horses; and pets, such as dogs and cats. Furthermore, the compounds of the present invention may also be used to treat non-animal organisms, such as plants. It is obvious that the actual, preferred amount of active compounds may vary depending on the compound used in a given therapeutic treatment, the dosage form, the route of administration, the specific site of application, etc. The most appropriate dosage amounts for specific administration methods can be readily determined by the skilled artisan using standard dosage determination techniques, taking into account the above guidelines. In general, the dosages of the compounds of the present invention for treatment are the same as those of the prior art tetracycline therapies. See, for example, Rhys / c / ans' öesk Reference. A sufficiently effective dosage of one or more compounds of the present invention is, for example, between 0.01 and 100 mg / kg of body weight / day, preferably between 1 and 20 mg / kg of body weight / day. The desired dosage amount is preferably administered once daily, or in several divided doses, for example 2 to 5 divided doses, at appropriate intervals throughout the day, or according to another suitable dosing regimen. It is clear that the administration of minocyclines should be subject to the general, commonly known precautions which ensure the efficacy of the compounds in normal use. Particularly in the case of therapeutic treatment of humans and animals, the physician should take considerable precautions to avoid the commonly known contraindications and toxic effects. Thus, the usual procedure should take due account of the commonly known adverse side effects, such as gastrointestinal discomfort and inflammation, renal toxicity, hypersensitivity reactions, changes in the blood count, and reduction of absorption caused by aluminum, calcium or magnesium ions. The present invention also provides the use of a minocycline derivative of formula (I) or (II) in the manufacture of a pharmaceutical composition. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier and an effective (i.e. effective in treating a condition responsive to tetracycline) amount of the tetracycline derivative. -»· The serine compounds of the present invention can be prepared by the methods described below, with modifications customary in the art. Example 1: Preparation of the Minocycline Derivatives of the Present Invention Preparation of 9-lode-minooikiine To 200 ml of 97% melansulfonic acid, 30 g (58.58 mmol) of minocycline bishydrochloride were added portionwise at room temperature. The dark yellow solution was stirred at room temperature while 38 g (169.7 mmol) of N-iodo-sulfurimide was added in 8 equal portions over 3.0 hours. The reaction was monitored by analytical LG until the disappearance of the starting material. The reaction was quenched slowly with 2 L of ice water containing 17.83 g (1134.1 mmol) of sodium sulfate with rapid stirring. This mixture was stirred at room temperature for about 30 minutes. The aqueous layer was extracted six times with 200 mL of ethyl acetate, and the aqueous layer was poured onto 259.8 g (3.08 mol) of n-butanol in 300 mL of sodium hydrogen carbonate. The fractions were separated and the aqueous layer was extracted four times with 250 mL of n-butanol. The organic fractions were combined and washed three times with 250 mL of water and once with 250 mL of saturated aqueous sodium chloride solution. The resulting organic fraction was evaporated to dryness under reduced pressure. The residue was suspended in about 800 ml of methanol, and anhydrous hydrochloric acid gas was bubbled into the mixture until complete dissolution. The resulting solution was evaporated under reduced pressure.The filtrate was evaporated under reduced pressure. This material was redissolved in 300 ml of methanol, treated with 0.5 g of charcoal, filtered and the filtrate was evaporated under reduced pressure. The material thus obtained was triturated under reduced pressure with methyl tert-butyl ether. ΦX The solid was separated by filtration, washed with ether, and finally with hexane. The material was dried under reduced pressure to give 22.8 g of a light yellowish-brown powder. General procedure for the preparation of 9-alkynyl methylcyclohexane derivatives 1 mmol of 9-iodomethylcyclohexane, 50 g of tetrakistriphenylphosphinatopalladate, 12 mg of palladium acetate, 32 mg of copper(I) iodide are dissolved / suspended in 10 ml of acetone. 2-5 ml of triethylamine and 3-5 mmol of the alkylcyclohexane derivative are added. The reaction mixture is stirred vigorously at room temperature to 70°C. The reaction time is between 2 and 24 hours. When the reaction is complete, the dark suspension is filtered through a pad of celite and evaporated. The crude product is purified by preparative WPLC. The combined fractions are evaporated and dissolved in about 1 ml of methanol. Approximately 3 ml of methanol saturated with hydrochloric acid was added and the product was precipitated with ether. General procedure for the preparation of 9-arh-aminoethyl derivatives 0.15 mmol 9-iodo-mmocycline, 3.2 mg PdOAc, 229 μΙ 2 M sodium carbonate and 2 equivalents of phenylboronic acid are dissolved / suspended in 10 ml methanol. The reaction flask is flushed with argon gas and the reaction is allowed to proceed for at least four hours or until the consumption of starting material and / or the appearance of products can be detected by HPLC. The suspension is filtered through a pad of celite and purified by preparative HPLC on a divinN-benzene column. Compound of formula (QU) (9-{4-trifluoromethoxy-phenylureido>methyl· -minocycline (Scheme 7)) To 150 mg (0.25 mmol) of 9-methyl-amino-minocycline trihydrochloride is added at 25°C and 67 * Λ* ♦* $ ♦ * * X * χ +« * * Ο, Λ * Λ- ♦ · «.*«« *ί* ** ml (0.50 mmol) of triethylamine. While stirring, 75 ml (0.50 mmol) of 4-trifluoromethoxyphenylacetic acid were added and the resulting reaction mixture was stirred at 25°C for two hours. The reaction was monitored by analytical HPLC (4.6 x 50 mm reversed phase Luna €18 column, 5 minute linear gradient 1-100% buffer B, buffer A is 0.1% aqueous trifluoroacetic acid, buffer B is 0.1% acetonitrile trifluoroacetic acid). After the reaction is complete, it is quenched with 1 ml of water and the pH is adjusted to approximately 2.0 with concentrated hydrochloric acid. The solution is filtered and the residue is purified by preparative HPLC. Thus, mg Qü is obtained in 37% yield. The purity of Oü by LCMS is 95% (M+1 = lu let (9 - (4!- car rb oxi - phen 11) - mi η ocik II n) In a clean, dry flask, add 500 mg (0.762 mmol) of 9-jc -minocycline bishydroclondof, 17.2 mg (0.076 mmol) palladium(II) acetateof and 10 ml reagent grade methanol are placed. The solution is heated with stirring under argon gas for about 5 minutes. 1.1 3.81 mmol of 2M potassium carbonate are added followed by 238.3 mg (1.53 mmol) of p-carboxyphenylboronic acid in 5 ml of DMF. Both solutions are previously deaerated with argon gas for about 5 min. The reaction mixture is heated for 1 min, and the reaction progress is monitored by reverse phase. The reaction mixture is filtered under reduced pressure through a filter pad containing diatomaceous earth, and the filter pad is washed with DMF. The filtrate is evaporated to an oil under reduced pressure and the residue is treated with tert-butyl methyl ether. The crude product was purified by reverse phase HPLC on a DVB column using a gradient of water and methanol / acetone containing 1.0% trifluoroacetic acid. The product was identified by spectrophotometry: M+1 found: 678.58: the structure of the compound is confirmed by the ^H-NMR spectrum, Example 2: Determination of the Minimum Inhibitory Concentration (MIC) in vitro The following procedure is used to determine the activity of minocycline derivatives against common bacteria. 2 mg of each compound is dissolved in 100 µl DMSO. The solution is then added to cation-adjusted Müller-Hinton medium (CAMHB), resulting in a final concentration of 200 µg / ml. Solutions of minocycline derivatives are diluted to a volume of 50 µl, giving a concentration of 0.008 µg / ml of the test compound. Optical density (OD) determinations are made from fresh, logarithmic growth medium cultures of the bacterial strains tested. Dilutions are prepared to give a final cell density of 1 x 100 CFU / ml. At 0D~1, the cell densities of the various bacterial species are approximately as follows: E.co / / 1x10sCFU / ml S. aureus 5x10sCFU / ml Enferococcus sp. 2.5x109CFU / ml Add 50 μί of the cell suspensions to each well of a microtiter plate. The final cell density should be approximately 5x10sCFU / ml. Incubate the plates in an aerated incubator at 35° C for approximately 18 hours. Read the plates using a microplate reader and check visually if necessary. The MIC value is the lowest concentration of the tetracycline derivative that inhibits the growth of the bacteria. φ «λΧ» *» * * > Φ ϊ * % * « *« # :«? * ♦ »♦·« «* The compounds of the present invention exhibit good growth inhibition. In Table 1, compounds that are good inhibitors of the growth of a given bacterium are marked with *, compounds that inhibit the given bacterium very well are marked with **, and compounds that have particularly good inhibitory effects are marked with ***. It will be apparent to those skilled in the art, or can be ascertained by routine experimentation, that many equivalent methods to the methods of the present disclosure can be implemented. Such equivalent methods are also within the scope of the present invention as defined by the following patent claims. The entire contents of all publications, patents, and patent applications cited in this invention are hereby incorporated by reference into this invention. The corresponding components and methods of the cited patents, applications, and other documents are consistent with the present invention and its embodiments. Table 1 | compound S. aureus E. hirae E. coli compound with formula (KA) ** & | compound with formula (KB) ★ é· ** compound with formula (KC) ** 4>K * compound with formula (KD) Λ· * ' * compound with formula (KE) *** compound with formula (KF) *** compound with formula (KH) ** A * compound with formula (KI) Compound with formula (KJ) X * ί V !$ '· « * χ «Η·· βχ,χ <9* chemical Compound of formula (KL) i ** | * 5 Compound of formula (KM) • A* £ Compound of formula (KIM) : A A'*' ** f Compound of formula (KG) í ** i·* :: ---- Compound with formula (LM) Compound with formula (LG) THE# ·· :·» * * - V *·..» © * • .4 ¢. » « V'· (LP) formula compound (LQ) formula compound (LR) formula compound chemical (LT) formula compound formula compound —i mixes (LW) ké| 3ietü veyüiet ί * * ! { ΐ *Λ· :! (LX) kér ?letü veyüiet ! * * 1 * : • * * 1 ____________________J * : Compound of formula (LZ) being 8) compound with formula compound with formula (MH) compound with formula} compound with formula} compound with formula compound compound Long-lasting compound 5 Λ ' ' v : - | (MM) compound with formula Ϊ * * 1 **«♦ ♦ ·» X (NZ) formula compound ** ** * (OA) formula compound ·** * (OB) formula compound ** *-λ' (OC) formula compound *· * * (OD) formula compound NV *** (OE) formula compound * * (OF) formula compound ík NV * * (OG) formula compound ** NV * * (OH) formula compound -Á' * * NV (Öl) formula compound * * NV * (ÖJ) formula compound ** NV * (OK) formula compound ** NV ** (OL) formula compound & NV * (ÖM) formula compound ** NV * (ON) formula compound ** NV ·* (OO) formula compound *·* NV *fc * (OP) formula compound NV * * (00) formula compound NV A (OR) formula compound | * ........NV ( * Compound of formula (OS) * j NV j * Compound of formula (OT) ) * NV | * NV Compound of formula (OU) **· * * j Compound of formula (ÖV) NV * * 1 Compound of formula (ÖW) NY 1 NV NV | Compound of formula (OX) NV NV NV | Compound of formula (OY) HV NV NV Γ~ Compound of formula (OZ) NV NV NV i Compound of formula (PA) HV NV NV : | Compound of formula (PB) NV NV NV Compound of formula (PC) NV NV NV NV The Λ·* 4> (PO) compound NY NY NY (PE) compound NY NV NV (FF) compound NY NY NV (PG) compound NV NY NY (PH) compound NY NY NY (Pl) compound NY NV NY (PJ) compound NY NV NV (PK) compound NY NY (PL) compound NY NY NY (PM) compound NY NY NY (PN) compound NY NV NY (PO) compound NY NV NY (PP) compound NY NY NY (PG) compound NY NY NV (PR) compound NY NY NY (PS) compound NY NV NY (PT) compound NY NY NY (PU) compound NY F'l ΛΖ NV (PV) compound NY NV NY (PW) compound NY NY NY Ί (PX) compound NY NY MV (PY) formula compound NY NV NY 1 (PZ) compound NY NV NY j PATENT CLAIMS

Claims

The following (I) is a minocycline derivative having the general formula, nY'Y ...on _ .tex Xtx. ... íV Xsy g. >|· on o oh o and its pharmaceutically acceptable salts and prodrugs; wherein: R3 4,. R4 , R'\ and R' are each C1-5 alkyl; and Ry is a methyl group which is (a) amino, (b) C1-8 alkylamino, (c) di(C1-8 alkyl)>- or <d) 1-6 szénatomos alkilamino-csoporttal helyettesített, amelyben az 1-6 szénatomos síkil-amlno-csopori alkilcsoportja férni-,, metHéndloxifeníi- vagy para-perfluormetoxífeηIi-csőpor11aj helyettes11s11, ahol a prodrug-láncot az alábbi csoportból választjuk; 1-5 szénatomos alkilészter íáncok., C2-5 alkenyl esters, di(C1-5 alkyl)amino-(C1-5 alkyl esters, acylamino-<C1-5 alkyl!) esters, adoxy-(C1-5 alkyl esters, aryl esters, aryl 1-(C1-5 alkyl esters (substituted with methyl, halogen or methoxy substituents) aryl and aryl C1-5 alkyl ester chains, amides, C1-5 alkylamides, di-(C1-5 alkyl amides and hydroxyamides.

2. The minocycline compounds of Claim 1, wherein R4', R4', R7, and R7 are all methyl.

3. A compound according to claim 2, having the following general formula: wherein R9 is methyl, C1-6 alkylamino or C1-8 alkyl substituted with C1-8 alkyl.

4. A minocycline compound or pharmaceutically acceptable salt thereof having the formula:

5. A minocycline compound having the following formula or a pharmaceutically acceptable salt thereof. o. A minocycline compound having the following formula or a pharmaceutically acceptable salt thereof. A minocycline compound having the following formula or a pharmaceutically acceptable salt thereof.

8. A minocycline compound of the formula or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof. TI. A minocycline compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof for use in the treatment of a tetracycline-responsive condition in a mammal.

12. A tetracycline compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims for use according to claim 11, wherein said tetracycline-responsive condition is a bacterial infection.

13. A methnocycline compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims for use according to claim 12, wherein said bacterial infection is associated with E. coli, S. aureus or E. feacalls.

14. A minocillin compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims for use according to claim 12, wherein said bacterial infection is accompanied by other symptoms.

15. A minocillin compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims for use according to claims 11-14, wherein said compound is administered together with a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1-10 for the preparation of a pharmaceutical composition for the treatment of a tetracycline-responsive condition in mammals.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 10 and a pharmaceutically acceptable carrier.