WO2002012170A1 - Composes de tetracycline substitues en 8 - Google Patents

Composes de tetracycline substitues en 8 Download PDF

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Publication number
WO2002012170A1
WO2002012170A1 PCT/US2000/021366 US0021366W WO0212170A1 WO 2002012170 A1 WO2002012170 A1 WO 2002012170A1 US 0021366 W US0021366 W US 0021366W WO 0212170 A1 WO0212170 A1 WO 0212170A1
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WIPO (PCT)
Prior art keywords
doxycycline
compound
tetracycline
compounds
amino
Prior art date
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PCT/US2000/021366
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English (en)
Inventor
Mark Nelson
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Trustees Of Tufts College
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Filing date
Publication date
Application filed by Trustees Of Tufts College filed Critical Trustees Of Tufts College
Priority to AU2000265203A priority Critical patent/AU2000265203A1/en
Priority to PCT/US2000/021366 priority patent/WO2002012170A1/fr
Priority to US09/894,805 priority patent/US6624168B2/en
Priority to CA002415086A priority patent/CA2415086A1/fr
Priority to EP01950582A priority patent/EP1303479B1/fr
Priority to AT01950582T priority patent/ATE504562T1/de
Priority to PCT/US2001/020558 priority patent/WO2002004404A2/fr
Priority to JP2002509072A priority patent/JP4963771B2/ja
Priority to EP09175818A priority patent/EP2166000A1/fr
Priority to DE60144375T priority patent/DE60144375D1/de
Priority to AU2001271556A priority patent/AU2001271556A1/en
Publication of WO2002012170A1 publication Critical patent/WO2002012170A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • 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. 3,957,980; 3,674,859; 2,980,584; 2,990,331; 3,062,717; 3,557,280; 4,018,889; 4,024,272; 4,126,680; 3,454,697; and 3,165,531, the text of all of which are incorporated herein by reference .
  • These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.
  • 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, including conjunctivitis, and psittacosis.
  • tetracyclines became known as "broad spectrum" antibiotics.
  • the tetracyclines as a class rapidly became widely used for therapeutic purposes.
  • the invention pertains, at least in part, to 8-substituted tetracycline compounds of the formula:
  • R 4 and R are each methyl;
  • R 5 is hydrogen or hydroxyl;
  • R and R are each independently hydrogen, methyl, or hydroxyl
  • R 7 is hydrogen, or dimethylamino
  • R 8 is phenyl, nitrophenyl, halo, or lower alkynyl
  • R 9 is hydrogen or amino, and pharmaceutically acceptable salts thereof.
  • the tetracycline compound of the invention is a doxycycline derivative, i.e., wherein R 5 is hydroxyl, R 6 is methyl, and R 6 is hydrogen.
  • the invention also pertains to a method for treating a tetracycline responsive state in a mammal, by administering to a mammal a compound of formula I.
  • the invention relates to the use of a compound of formula I to treat a tetracycline responsive state.
  • the present invention relates to the use of a compound of formula I as an antibiotic.
  • the invention also pertains to pharmaceutical compositions comprising a compound of formula I, and to the use of a compound of formula I in the manufacture of a medicament to treat a tetracycline responsive state.
  • the invention pertains to, at least in part, to 8-substituted tetracycline compounds of the formula: wherein:
  • R 4 and R 4 are each methyl
  • R 5 is hydrogen or hydroxyl
  • R 6 and R 6 are each independently hydrogen, methyl, or hydroxyl
  • R 7 is hydrogen or dimethylamino
  • R 8 is phenyl, nitrophenyl, halo, or lower alkynyl
  • R 9 is hydrogen or amino, and pharmaceutically acceptable salts thereof.
  • tetracycline compound includes compounds with a similar ring structure to tetracycline, such as those included in formula I.
  • Some examples of tetracycline compounds which can be modified include a substituent at position 8 include doxycycline; however, other derivatives and analogues comprising a similar ring structure are also included.
  • the structures of tetracycline and doxycycline are shown below.
  • 8-substituted tetracycline compounds includes tetracycline compounds with a substituent at the 8 position, as described in formula I.
  • the substituted tetracycline compound is a substituted doxycycline derivative (e.g., wherein R 4 and R 4 are methyl, R >5 i •s hydroxyl, R is methyl, and R is hydrogen).
  • doxycycline derivatives of tetracycline compounds of the invention include compounds wherein R 7 is hydrogen, R 8 is halo, phenyl, or nitrophenyl, and R 9 is hydrogen.
  • R is hydrogen
  • R is phenyl or lower alkynyl (e.g., ethynyl)
  • R 9 is amino.
  • Examples of such tetracycline compounds which are doxycycline derivatives include 8- phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, and 8-phenyl-9-amino doxycycline.
  • Compounds of the invention can be synthesized by transition metal catalyzed coupling of tetracyclines halogenated at the 8- position.
  • transition metal catalysis many reactions between aryl halides and various reactive species have been developed using transition metal catalysis.
  • Coupling of aryl halides or triflates with main group organometallics with oxidate addition- transmetallation-reductive elimination reactions has been developed and occurs using a wide range of catalysts, such as Pd(Pd 3 ) 4 , Pd(dba) 2 , PdCl 2 , Pd(OAc) 2 , and PdCl 2 (CH 3 CN) 2 .
  • Ligands such as PPh 3 or AsPh may be added to form catalysts in situ with palladium species such as Pd(dba) 2 or PdCl 2 .
  • copper salts such as CuCN or Cul may also be added to further enhance the reaction.
  • Scheme 1 An example of a coupling using a halogenated tetracycline compound is shown in Scheme 1.
  • X is bromine or iodine.
  • the substituted tetracycline compounds of the invention can be synthesized using organotin reagents, halogenated or triflate tetracycline compounds, and an appropriate catalyst (e.g., palladium).
  • organotin reagents include, for example, ethenyl tributyltin, ethynyl tributyltin, phenyl tributyltin, ethenyl trimethyl tin, ethynyl trimethyl tin, etc.
  • Stille type couplings are run by adding the transition metal (e.g., palladium) catalyst to a solution of the halogenated or triflate tetracycline compound and the organotin reagent in polar solvents.
  • transition metal e.g., palladium
  • Stille type couplings with alkynyl and alkenyl tin reagents are shown in Scheme 2, wherein X is a halogen or a triflate group.
  • 8-halogenated tetracycline compounds can be synthesized via azidotetracyclines.
  • the protonolysis of the aryl azides produces 8-halo-9-amino tetracycline in good yield.
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • alkyl further includes alkyl groups, which comprise oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C] . -C 6 for straight chain, C 3 -C 6 for branched chain), and more preferably 4 or fewer.
  • preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C C 6 includes alkyl groups containing 1 to 6 carbon atoms.
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids.
  • aryl includes groups with aromaticity, including 5- and 6-membered single- ring aromatic groups that may include from zero to four heteroatoms as well as polycyclic systems with at least one aromatic ring.
  • aryl groups include phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).
  • heteroaryl refers to pyrazinyl, pyridinyl, furanyl, and dioxenyl groups.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond, e.g., a -C-C double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, de
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both "unsubstituted alkenyls" and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond, e.g., a -C-C triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure, e.g., branched or unbranched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl.
  • “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms, e.g., ethenyl, ethynyl, propenyl, propynyl, butenyl, butynyl, pentenyl, and pentynyl.
  • acyl includes compounds and moieties which contain the acyl radical
  • substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
  • amide or “aminocarboxy” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group.
  • arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy alkenylaminocarboxy
  • alkynylaminocarboxy and “arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • alkylamino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkylamino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
  • moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • dioxenyl refers to moieties of the formula:
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • halo includes, for example, substituents such as chlorine, fluorine, bromine, or iodine, as well as mono-, di- or tri- halogenated lower alkyl group, e.g., mono-, di- or tri- halogenated methyl groups.
  • substituents such as chlorine, fluorine, bromine, or iodine
  • mono-, di- or tri- halogenated lower alkyl group e.g., mono-, di- or tri- halogenated methyl groups.
  • halo substitution of the phenyl substituent enhances the ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states.
  • heteroatom includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O " .
  • polycyclyl or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers), as well as racemic mixtures thereof, are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • Prodrugs are compounds which are converted in vivo to active forms (see, e.g., R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8). Prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular compound. For example, a hydroxyl group, can be esterified, e.g., with a carboxylic acid group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the hydroxyl group.
  • prodrug moiety includes moieties which can be metabolized in vivo to a hydroxyl group and moieties which may advantageously remain esterified in vivo.
  • the prodrugs moieties are metabolized in vivo by esterases or by other mechanisms to hydroxyl groups or other advantageous groups.
  • Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
  • Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di- lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di
  • the invention also features a method for treating a tetracycline compound responsive state in a subject, by administering to the subject a 8- substituted tetracycline compound of the invention, e.g., a compound of formula I. Preferably, an effective amount of the tetracycline compound is administered.
  • 8 substituted tetracycline compounds of the invention include 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl- 9-amino doxycycline, and 8-phenyl-9-amino doxycycline.
  • tetracycline compound responsive state includes states which can be treated, prevented, or otherwise ameliorated by the administration of a tetracycline compound of the invention. Tetracycline compound responsive states include bacterial infections
  • Compounds of the invention can be used to prevent or control important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure, ear, nose and throat infections, wound infection, mastitis and the like.
  • methods for treating neoplasms using tetracycline compounds of the invention are also included (van der Bozert et al., Cancer Res., 48:6686-6690 (1988)).
  • Bacterial infections may be caused by a wide variety of gram positive and gram negative bacteria.
  • the compounds of the invention are useful as antibiotics against organisms which are resistant to other tetracycline compounds.
  • the antibiotic activity of the tetracycline compounds of the invention may be determined using the method discussed in Example 2, or by using the in vitro standard broth dilution method described in Waitz, J.A., National Commission for Clinical Laboratory Standards, Document M7-A2, vol. 10, no. 8, pp. 13-20, 2 nd edition, Villanova, PA (1990).
  • the tetracycline compounds of the present invention may also be used to treat infections traditionally treated with tetracycline compounds such as, for example, rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, psittacosis.
  • the tetracycline compounds may be used to treat infections of, e.g., K. pneumoniae, Salmonella, E. hirae, A. baumanii, B. catarrhalis, H. influenzae, P. aeruginosa, E.faecium, E. coli, S. aureus or E.faecalis.
  • the tetracycline compound may be used to treat a bacterial infection that is resistant to other tetracycline antibiotic compounds.
  • the tetracycline compounds of the invention may be administered with a pharmaceutically acceptable carrier.
  • the language "effective amount" of the compound is that amount necessary or sufficient to treat or prevent a tetracycline compound responsive state.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular tetracycline compound. For example, the choice of the tetracycline compound can affect what constitutes an "effective amount".
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the tetracycline compound without undue experimentation.
  • the invention also pertains to methods of treatment against microorganism infections and associated diseases.
  • the methods include administration of an effective amount of one or more tetracycline compounds to a subject.
  • the subject can be either a plant or, advantageously, an animal, e.g., a mammal, e.g., a human.
  • one or more tetracycline compounds of the invention may be administered alone to a subject, or more typically a compound of the invention will be administered as part of a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • the pharmaceutical compositions of the invention comprise a 8- substituted tetracycline compound of the invention, e.g., of formula I.
  • the 8- substituted tetracycline compound is 8-phenyl doxycycline, 8-bromo doxycycline, $>-(p- nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, or 8-phenyl-9-amino doxycycline.
  • pharmaceutically acceptable carrier includes substances capable of being coadministered with the tetracycline compound(s), and which allow both to perform their intended function, e.g., treat or prevent a tetracycline compound responsive state.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
  • the tetracycline compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of the tetracycline compounds of the invention that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • salts must be pharmaceutically acceptable-for administration to a subject, e.g., a mammal, it is often desirable in practice to initially isolate a tetracycline compound of the invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
  • the tetracycline compounds of the invention that are acidic in nature are capable of forming a wide variety of base salts.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those tetracycline compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • the pharmaceutically acceptable base addition salts of tetracycline compounds of the invention that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods.
  • these salts may be readily prepared by treating the tetracycline compound of the invention with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure.
  • a lower alkyl alcohol solution of the tetracycline compound of the invention may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness.
  • tetracycline compounds of the invention can be administered via either oral, parenteral or topical routes.
  • these compounds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of administration chosen. Nariations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • compositions of the invention may be administered alone or in combination with other known compositions for treating tetracycline responsive states in a mammal.
  • Preferred mammals include pets (e.g., cats, dogs, ferrets, etc.), farm animals (e.g., cows, sheep, pigs, horses, goats), lab animals (e.g., rats, mice, monkeys), and primates (e.g., chimpanzees, humans, gorillas).
  • the language "in combination with" a known composition is intended to include simultaneous administration of the composition of the invention and the known composition, administration of the composition of the invention first, followed by the known composition and administration of the known composition first, followed by the composition of the invention. Any of the therapeutic compositions known in the art for treating tetracycline responsive states can be used in the methods of the invention.
  • the compounds of the invention may be administered in various dosage forms. They may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously mentioned, and the administration may be carried out in single or multiple doses.
  • the novel therapeutic agents of this invention can be administered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non- toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a therapeutic compound of the present invention e.g., in either sesame or peanut oil, or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Therapeutic compounds may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline or 5% saline dextrose solutions commonly used with injectables.
  • topical administration examples include transdermal, buccal or sublingual application.
  • therapeutic compounds can be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream.
  • topical carriers include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.
  • topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodium lauryl sulfate 5% in water, and the like.
  • materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired.
  • tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like are particularly suitable, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys and the like; horses; and pets such as dogs and cats.
  • livestock such as cattle, sheep, goats, cows, swine and the like
  • poultry such as chickens, ducks, geese, turkeys and the like
  • horses such as dogs and cats.
  • the compounds of the invention may be used to treat non-animal subjects, such as plants.
  • compounds of the invention for treatment can be administered to a subject in dosages used in prior tetracycline therapies. See, for example, the Physicians' Desk Reference.
  • a suitable effective dose of one or more compounds of the invention will be in the range of from about 0.01 to 100 milligrams per kilogram of body (or subject) weight of recipient per day, preferably in the range of from about 0.1 to 50 milligrams per kilogram body weight of recipient per day, more preferably in the range of about 1 to 20 milligrams per kilogram body weight of recipient per day.
  • the desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
  • the invention also pertains to the use of a tetracycline compound of formula I, for the preparation of a medicament.
  • the medicament may include a pharmaceutically acceptable carrier and the tetracycline compound is an effective amount, e.g., an effective amount to treat a tetracycline responsive state.
  • the invention also pertains to the use of a tetracycline compound of formula I to treat a tetracycline responsive state, e.g., in a subject, e.g., a mammal, e.g., a human.
  • 9-NO 2 doxycycline (lg) was dissolved in methanol (50 ml) and poured into a Pan- apparatus with 100 mg of 10% Pd/C. The reaction was charged with H 2 and shaken for 2 hours. The 9-amino doxycycline was separated by preparative apic purification to produce 9- NH 2 doxycycline and 7-NH 2 doxycycline in a 7:2 ratio.
  • the final cell density should be approximately 5xl0 5 CFU/ml. These plates are incubated at 35°C in an ambient air incubator for approximately 18 hr. The plates are read with a microplate reader and are visually inspected when necessary.
  • the MIC is defined as the lowest concentration of the tetracycline compound that inhibits growth. Compounds of the invention indicate good inhibition of growth.

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Abstract

L'invention concerne des composés de tétracycline substitués en 8, des procédés de traitement d'états réagissant à la tétracycline et des compositions renfermant des composés de tétracycline substitués en 8.
PCT/US2000/021366 2000-07-07 2000-08-04 Composes de tetracycline substitues en 8 WO2002012170A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU2000265203A AU2000265203A1 (en) 2000-08-04 2000-08-04 8-substituted tetracycline compounds
PCT/US2000/021366 WO2002012170A1 (fr) 2000-08-04 2000-08-04 Composes de tetracycline substitues en 8
US09/894,805 US6624168B2 (en) 2000-07-07 2001-06-29 7,8 and 9-substituted tetracycline compounds
CA002415086A CA2415086A1 (fr) 2000-07-07 2001-06-29 Composes de tetracycline substitues en 7, 8 et 9
EP01950582A EP1303479B1 (fr) 2000-07-07 2001-06-29 Composes de tetracycline substitues en 7, 8 et 9
AT01950582T ATE504562T1 (de) 2000-07-07 2001-06-29 7-, 8- und 9-substitutierte tetracyclinverbindungen
PCT/US2001/020558 WO2002004404A2 (fr) 2000-07-07 2001-06-29 Composes de tetracycline substitues en 7, 8 et 9
JP2002509072A JP4963771B2 (ja) 2000-07-07 2001-06-29 ７、８および９−置換テトラサイクリン化合物
EP09175818A EP2166000A1 (fr) 2000-07-07 2001-06-29 Composés de tétracycline 7-,8-et 9 substitué
DE60144375T DE60144375D1 (de) 2000-07-07 2001-06-29 7-, 8- und 9-substitutierte tetracyclinverbindungen
AU2001271556A AU2001271556A1 (en) 2000-07-07 2001-06-29 7,8 and 9-substituted tetracycline compounds

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PCT/US2000/021366 WO2002012170A1 (fr) 2000-08-04 2000-08-04 Composes de tetracycline substitues en 8

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US8486921B2 (en) 2006-04-07 2013-07-16 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
AU2012202559B2 (en) * 2004-05-21 2014-07-17 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
US9073829B2 (en) 2009-04-30 2015-07-07 President And Fellows Of Harvard College Synthesis of tetracyclines and intermediates thereto

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SUM P.-E.; LEE V.L.; TALLY F.P.: "Synthesis of Novel Tetracycline Derivatives with Substitution at the C-8 Position", TETRAHEDRON LETTERS, vol. 35, no. 12, 1994, pages 1835 - 1836, XP000983725 *

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EP2329828A1 (fr) 2001-07-13 2011-06-08 Paratek Pharmaceuticals, Inc. Tetracyclines pour le traitement de l'ischémie
EP2327409A1 (fr) 2001-07-13 2011-06-01 Paratek Pharmaceuticals, Inc. Tetracycline avec activité pharmacéutique
EP2332548A1 (fr) 2001-07-13 2011-06-15 Paratek Pharmaceuticals, Inc. Tetracyclines pour le traitement des accidents cérebrovasculaires
EP2332549A1 (fr) 2001-07-13 2011-06-15 Paratek Pharmaceuticals, Inc. Nouvelle tetracyclines et leur utilisation en médicine
EP2332550A1 (fr) 2001-07-13 2011-06-15 Paratek Pharmaceuticals, Inc. Composés de tétracycline pour le traitement des maladies neurodégénératives
EP2329826A1 (fr) 2001-07-13 2011-06-08 Paratek Pharmaceuticals, Inc. Tetracyclines pour le traitement de la sclérose en plaques
EP2332546A1 (fr) 2001-07-13 2011-06-15 Paratek Pharmaceuticals, Inc. Tetracyclines pour le traitement des accidents cérebrovasculaires
EP2301550A1 (fr) 2001-07-13 2011-03-30 Paratek Pharmaceuticals, Inc. Composés de tétracycline dotés d'activités thérapeutiques
WO2003005971A2 (fr) 2001-07-13 2003-01-23 Paratek Pharmaceuticals, Inc. Composes de tetracycline a activites therapeutiques cibles
EP2301915A1 (fr) 2001-07-13 2011-03-30 Paratek Pharmaceuticals, Inc. Tétracycline avec groupe 7-(diethylamino)methyl doté d'activités thérapeutiques
EP2332904A2 (fr) 2004-01-15 2011-06-15 Paratek Pharmaceuticals, Inc. Derives des composes de tetracycline
US7786099B2 (en) 2004-01-15 2010-08-31 Paratek Pharmaceuticals, Inc. Aromatic a-ring derivatives of tetracycline compounds
US7807842B2 (en) 2004-05-21 2010-10-05 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
US9884830B2 (en) 2004-05-21 2018-02-06 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
US8598148B2 (en) 2004-05-21 2013-12-03 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
US10669244B2 (en) 2004-05-21 2020-06-02 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
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AU2005244988B2 (en) * 2004-05-21 2012-02-02 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
EP1753713A2 (fr) * 2004-05-21 2007-02-21 The President and Fellows of Harvard College Synthese de tetracyclines et d'analogues de tetracyclines
EP1753713A4 (fr) * 2004-05-21 2009-07-08 Harvard College Synthese de tetracyclines et d'analogues de tetracyclines
US9365493B2 (en) 2004-05-21 2016-06-14 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
AU2005244988C1 (en) * 2004-05-21 2012-06-28 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
AU2012202559B2 (en) * 2004-05-21 2014-07-17 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
EP2301912A2 (fr) 2004-10-25 2011-03-30 Paratek Pharmaceuticals, Inc. 4-aminotétracyclines et procédés d'utilisation associés
EP2301916A2 (fr) 2004-10-25 2011-03-30 Paratek Pharmaceuticals, Inc. 4-aminotétracyclines et procédés d'utilisation associés
US7879828B2 (en) 2005-03-14 2011-02-01 Wyeth Llc Tigecycline compositions and methods of preparation
US10588975B2 (en) 2005-03-14 2020-03-17 Wyeth Llc Tigecycline compositions and methods of preparation
US9694078B2 (en) 2005-03-14 2017-07-04 Wyeth Llc Tigecycline compositions and methods of preparation
US8975242B2 (en) 2005-03-14 2015-03-10 Wyeth Llc Tigecycline compositions and methods of preparation
US9254328B2 (en) 2005-03-14 2016-02-09 Wyeth Llc Tigecycline compositions and methods of preparation
US8486921B2 (en) 2006-04-07 2013-07-16 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
EP2431469A2 (fr) 2006-05-15 2012-03-21 Paratek Pharmaceuticals, Inc. Procédés de régulation de l'expression des gènes ou produits génétiques utilisant des composés tétracyclines substitués
EP2537934A2 (fr) 2006-05-15 2012-12-26 Paratek Pharmaceuticals, Inc. Procédés de régulation de lýexpression des gènes ou produits génétiques utilisant des composés tétracyclines substitués
EP2218785A2 (fr) 2006-05-15 2010-08-18 Paratek Pharmaceuticals, Inc. Procédés de régulation de l'expression de gènes ou de produits génétiques utilisant des composés tétracyclines substitués
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US9688644B2 (en) 2009-04-30 2017-06-27 President And Fellows Of Harvard College Synthesis of Tetracyclines and intermediates thereto

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