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  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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  • 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
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  • C07C271/06—Esters of carbamic acids
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  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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  • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
  • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
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  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
  • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
  • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
  • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Definitions

• tetracyclines became known as "broad spectrum" antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes.
• this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., pneumococci and Salmonella).
• the rise of tetracycline-resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice.
• the invention pertains, at least in part, to prodrugs of 9-substituted aminomethyl
• E oxygen, nitrogen, or a covalent bond
• G is alkyl; heterocyclicalkyl; aryl; alkylcarbonyloxyalkyl; arylcarbonyloxyalkyl; alkyloxycarbonyloxyalkyl; arylalkylcarbonyloxyalkyl; alkyloxyalkylcarbonyloxyalkyl; alkoxyalkoxycarbonyloxyalkyl, and pharmaceutically acceptable salts thereof.
• the invention also pertains, at least in part, to tetracycline compounds of formula
• Q' is a prodrug moiety and pharmaceutically acceptable salts thereof.
• the invention also pertains, at least in part, to tetracycline compounds of the formula
• Q is a prodrug moiety, and pharmaceutically acceptable salts thereof.
• the invention also pertains, at least in part, to tetracycline compounds of the formula (IV):
• the invention includes a method for treating a tetracycline responsive state in a subject, by administering to the subject a tetracycline compound of the invention.
• the tetracycline compound is metabolized in vivo.
• the invention also pertains to pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier.
• the invention pertains, at least in part, to prodrugs of tetracycline compounds. These compounds may be metabolized in vivo, to yield a desired tetracycline compound.
• the invention pertains, at least in part, to the tetracycline compounds described herein, to methods of using the tetracycline compounds, and pharmaceutical compositions comprising the tetracycline compounds. h one embodiment, the invention pertains to tetracycline compounds of formula
• E oxygen, nitrogen, or a covalent bond
• G is alkyl; heterocyclicalkyl; aryl; alkylcarbonyloxyalkyl; arylcarbonyloxyalkyl; alkyloxycarbonyloxyalkyl; arylalkylcarbonyloxyalkyl; alkyloxyalkylcarbonyloxyalkyl; alkoxyalkoxycarbonyloxyalkyl, and pharmaceutically acceptable salts thereof.
• E is a covalent bond.
• G is alkyl, e.g., methyl.
• E is nitrogen or NH.
• G is aryl, e.g., substituted or unsubstituted phenyl.
• G is substituted with, for example, a substituent which allows it to perform its intended function.
• substituents include alkyl (including substituted alkyl such as halogenated alkyl), nitro, halogen, or alkoxy.
• E is oxygen.
• G is alkylcarbonyloxyalkyl.
• R 1 may be substituted or unsubstituted alkyl.
• R 1 may be branched, straight, or cyclic.
• g is 1 or 2 and R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, -(CH 2 ) 10 -CH 3 , or -(CH 2 ) ⁇ CH 3 .
• G is alkyl, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, -(CH 2 ) 10 -CH 3 , or -(CH 2 ) ⁇ CH 3 .
• G is arylcarbonyloxyalkyl.
• f is 1.
• R 2 is substituted or unsubstituted phenyl.
• substituents include, for example, halogen, alkoxy, or alkyl
• G is alkyloxycarbonyloxyalkyl.
• R 3 is methyl, ethyl, propyl, butyl or pentyl.
• G is arylalkylcarbonyloxyalkyl.
• G is of the formula wherein h is 1-5, h' is 1- 5, and R 4 is aryl.
• h' is 1 and h is 1 or 2.
• R is substituted or unsubstituted phenyl.
• G is alkyloxyalkylcarbonyloxyalkyl.
• i' is 1 and i is 1, 2, or 3.
• R 5 is methyl.
• G is alkoxyalkoxyalkylcarbonyloxyalkyl.
• the compounds of the invention do not include the compounds described in U.S.S.N. 10/384,855 or U.S.S.N. 10/412,656.
• E and G are selected such that after administration of the tetracycline compound to the subject, the tetracycline compound is metabolized in vivo to a compoxmd of the formula:
• the term "metabolized” includes any and all processes within a subject which would yield a compound of formula (la).
• the mechanisms may include, for example, enzymatic degradation, hydrolysis, cleavage by esterases, etc.
• E and G are selected such that together they consist of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 atoms selected from the group consisting of oxygen, carbon, and nitrogen.
• E and G may further comprise hydrogen atoms or halogen atoms.
• the invention pertains to tetracycline compounds of the formula (II):
• prodrug moiety includes moieties which may be metabolized in vivo to form a desired tetracycline compound (e.g., a compound of formula la, Ha, IHa, or IVa).
• prodrug moieties include carbonyl moieties, carbamates, amides, and the like, hi one embodiment, the prodrug moiety consist of 3, 4, 5, 6, 7, 8, 9, 10, 1.1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 atoms selected from the group consisting of oxygen, carbon, and nitrogen.
• the prodrug moiety may further comprise hydrogen atoms, halogen atoms, or other substituents which allow the tetracycline compound to perform its intended function.
• Q' is of the formula ⁇ (OOJ-E'-G 1 wherein E 1 is oxygen, nitrogen, or a covalent bond; G 1 is alkyl; heterocyclicalkyl; aryl; alkylcarbonyloxyalkyl; arylcarbonyloxyalkyl; alkyloxycarbonyloxyalkyl; arylalkylcarbonyloxyalkyl; alkyloxyalkylcarbonyloxyalkyl; or alkoxyalkoxycarbonyloxyalkyl.
• E 1 is oxygen.
• G 1 is alkylcarbonyloxyalkyl.
• m is 1.
• R 7 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, -(CH 2 ) 10 -CH 3 , or -(CH 2 ) ⁇ CH 3 .
• Q' is selected such that after administration of the tetracycline compound to the subject, the tetracycline compound is metabolized in vivo to a compound of the
• the invention pertains to tetracycline compound of the formula (ID):
• Q is a prodrug moiety, and pharmaceutically acceptable salts thereof.
• G 2 is is alkyl; heterocyclicalkyl; aryl; alkylcarbonyloxyalkyl; arylcarbonyloxyalkyl; alkyloxycarbonyloxyalkyl; arylalkylcarbonyloxyalkyl; alkyloxyalkylcarbonyloxyalkyl; ' or aUcoxyalkoxycarbonyloxyalkyl.
• G is alkyloxycarbonylalkyl or alkyl.
• the tetracycline compound of formula m is:
• Q is selected such that after admi- ⁇ istration of the tetracycline compound to the subject, the tetracycline compound is metabolized in vivo to a compoxmd of the formula (Ilia):
• the invention also pertains, at least in part, to tetracycline compounds of the formula (IV):
• Q" is a prodrug moiety and pharmaceutically acceptable salts thereof.
• E 3 is oxygen.
• G 3 is substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, etc.) or substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl, etc.).
• the compounds of the invention include:
• Q" is selected such that after administration of the tefracycUne compound to the subject, the tetracycline compound is metabolized in vivo to a compoxmd of the
• 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 can further include 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 ⁇ 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 t -C ⁇ 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, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylami ⁇ o, and alkylarylamino), acylamino (including aUcylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarbox
• Cycloalkyls can be ftirther substituted, e.g., with the substituents described above.
• An "alkylaryl” or an “arylalkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
• the term “alkyl” also includes the side chains of natural and unnatural amino acids.
• aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
• aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
• aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
• the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarb ⁇ nyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including a--kylc- ⁇ rbonyl--mino, aryl
• Aryl groups can also be fused or bridged with alicyclic or heteracyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
• alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
• alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
• alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonen
• 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., C2-C ⁇ for straight chain, C3-C6 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, phosphonat ⁇ , phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylarnino), 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.
• 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., C2-Cg for straight chain, C3-C6 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 alkyl amino, ⁇ -iaUcylamino, arylamino, diarylamino, and alkylarylarnino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thio
• lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
• Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
• acyl includes compounds and moieties which contain the acyl radical (CH 3 CO-) or a carbonyl group.
• substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dial-kylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfonyl, acyl
• 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 alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
• halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
• amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
• alkyl amino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
• dialkyl amino 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 refers to an amino group which is boxind 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.
• amide or "aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
• alkaminocarbonyl or "alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl or alkynyl groups bound to an amino group bound to a carbonyl group. It includes a-rylaminocarbonyl groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
• alkylaminocarbonyl alkenylaminocarbonyl
• alkynylaminocarbonyl alkynylaminocarbonyl
• arylaminocarbonyl alkylcarbonylamino
• alkenylcarbonylamino alkynylcarbonylamino
• arylcarbonylamino alkylcarbonylamino
• alkenylcarbonylamino alkynylcarbonylamino
• moieties which contain a carbonyl include aldehydes, ketones, carboxyUc acids, amides, esters, anhydrides, etc.
• thiocarbonyl or thiocarboxy includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
• 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.
• 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.
• thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
• 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.
• hydroxy or “hydroxyl” includes groups with an -OH or -O " .
• halogen includes fluorine, bromine, chlorine, iodine, etc.
• perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
• polycyclyl or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalk nyls, aryls and or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
• Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbox3(late, alkylcarbonyl, alkoxycarbonyl, alkylaininoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, m ⁇ lkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carb
• heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
• prodrug moiety includes moieties which can be metabolized in vivo to an active group and moieties which may advantageously remain attached in vivo. Preferably, the prodrugs moieties are metabolized in vivo by enzymes, e.g., 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).
• prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound with a sxiitable agent. Hydroxyl groups can be converted into esters via treatment with a carboxyUc 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,
• prodrug moieties are propionoic acid esters and acyl esters.
• 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) 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.
• the invention also pertains to methods for treating a tetracycline responsive states in subjects, by administering to a subject an effective amount of a compound of the invention (e.g., a compound of Formula (I), (II), (IQ), (IN) or otherwise described herein), such that the tetracycline responsive state is treated.
• a compound of the invention e.g., a compound of Formula (I), (II), (IQ), (IN) or otherwise described herein
• the invention also pertains, at least in part, to administering to a subject an effective amount of a tetracycline compoxmd of formula (I), (II), (HI), or (IV) which is metabolized in vivo to a compoxmd of formula (la), (Ila), (Ilia), or (IVa).
• Tetracycline compound responsive state includes states which can be treated, prevented, or otherwise ameliorated by the administration of a compound of the invention, e.g., a compound of Formula (I), (IT), (HI), (IV) or otherwise described herein.
• Tetracycline compound responsive states include bacterial, viral, and fungal infections (including those which are resistant to other tetracycline compounds), cancer (e.g., prostate, breast, colon, lung melanoma and lymph cancers and other disorders characterized by unwanted cellular proliferation, including, but not limited to, those described in U.S.
• 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.
• tetracycline responsive state is not a bacterial infection.
• Other tetracycline compound responsive itates include, for example, those described in U.S.S.N. 10/196,010.
• Tetracycline compound responsive states also include inflammatory process associated states (IP AS).
• the term "inflammatory process associated state” includes states in which inflammation or inflammatory factors (e.g., matrix metalloproteinases (MMPs), nitric oxide (NO), TNF, interleukins, plasma proteins, cellular defense systems, cytokines, lipid metabolites, proteases, toxic radicals, adhesion molecules, etc.) are involved or are present in an area in aberrant amounts, e.g., in amounts which may be advantageous to alter, e.g., to benefit the subject.
• MMPs matrix metalloproteinases
• NO nitric oxide
• TNF interleukins
• plasma proteins e.g., in amounts which may be advantageous to alter, e.g., to benefit the subject.
• the inflarnmatory process is the response of living tissue to damage.
• the cause of inflammation may be due to physical damage, chemical substances, micro-organisms, tissue necrosis, cancer or other agents.
• Acute inflammation is short-lasting, lasting only a few days.
• IPAS's include inflammatory disorders. Inflammatory disorders are generally characterized by heat, redness, swelling, pain and loss of function. Examples of causes of inflammatory disorders include, but are not limited to, microbial infections (e.g., bacterial and fungal infections), physical agents (e.g., burns, radiation, and trauma), chemical agents (e.g., toxins and caustic substances), tissue necrosis and various types of immx ologic reactions.
• microbial infections e.g., bacterial and fungal infections
• physical agents e.g., burns, radiation, and trauma
• chemical agents e.g., toxins and caustic substances
• inflammatory disorders include, but are not limited to, osteoarthritis, rheumatoid arthritis, acute and chronic infections (bacterial and fungal, including diphtheria and pertussis); acute and chronic bronchitis, sinusitis, and upper respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; acute and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendinitis); uremic pericarditis; acute and chronic cholecystis; acute and chronic vaginitis; acute and chronic uveitis; drug reactions; insect bites; burns (thermal, chemical, and electrical); and sunburn.
• osteoarthritis bacterial and fungal, including diphtheria and pertussis
• acute and chronic bronchitis sinusitis, and upper respiratory infections, including the common cold
• Tetracycline compound responsive states also include NO associated states.
• NO associated state includes states which involve or are associated with nitric oxide (NO) or inducible nitric oxide synthase (iNOS).
• NO associated state includes states which are characterized by aberrant amounts of NO and or iNOS.
• the NO associated state can be treated by administering tetracycline compounds of the invention, e.g., compounds of formula I, ⁇ , HI, IV, or otherwise described herein.
• the disorders, diseases and states described in U.S. Patents Nos. 6,231,894; 6,015,804; 5,919,774; and 5,789,395 are also included as NO associated states.
• NO associated states include, but are not limited to, malaria, senescence, diabetes, vascular stroke, neurodegenerative disorders (Alzheimer's disease, Huntington's disease), cardiac disease ( reperfusion-associated injury following infarction), juvenile diabetes, inflammatory disorders, osteoarthritis, rheumatoid arthritis, acute and chronic infections (bacterial, viral, and fungal); cystic fibrosis, acute and chronic bronchitis, sinusitis, and respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; acute and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendinitis); uremic pericarditis; acute and chronic cholecystis; acute and chronic vaginitis; acute and chronic u
• MMPAS matrix metalloproteinase associated states
• MMPAS include states characterized by aberrant amounts ofMMPs or MMP activity. These are also include as tetracycline compound responsive states which may be treated using compounds of the invention, e.g., in formula (I), (II), (IH), (IV) or otherwise described herein.
• MJyiPAS's matrix metalloproteinase associated states
• MMPAS include those described in U.S. Pat. Nos. 5,459,135; 5,321,017; 5,308,839; 5,258,371; 4,935,412; 4,704,383, 4,666,897, and RE 34,656, incorporated herein by reference in their entirety.
• the tefracycline compoxmd responsive state is cancer.
• cancers which the tetracycline compounds of the invention may be useful to treat include all solid tumors, i.e., carcinomas e.g., adenocarcinomas, and sarcomas.
• Adenocarcinomas are carcinomas derived from glandular tissue or in which the tumor cells form recogmzable glandular structures.
• Sarcomas broadly include tumors whose cells are embedded in a fibrillar or homogeneous substance like embryonic connective tissue.
• carcinomas which maybe treated using the methods of the invention include, but are not limited to, carcinomas of the prostate, breast, ovary, testis, lung, colon, and breast.
• the methods of the invention are not limited to the freatment of these tumor types, but extend to any solid tumor derived from any organ system.
• treatable cancers include, but are not limited to, colon cancer, bladder cancer, breast cancer, melanoma, ovarian carcinoma, prostatic carcinoma, lung cancer, and a variety of other cancers as well.
• the methods of the invention also cause the inhibition of cancer growth in adenocarcinomas, such as, for example, those of the prostate, breast, kidney, ovary, testes, and colon.
• the tetracycline responsive state of the invention is cancer.
• the invention pertains to a method for treating a subject suffering or at risk of suffering from cancer, by administering an effective amount of a substituted tetracycline compoxmd, such that inhibition cancer cell growth occurs, i.e., cellular proliferation, invasiveness, metastasis, or tumor incidence is decreased, slowed, or stopped.
• the inhibition may result from inhibition of an inflammatory process, down-regulation of an inflammatory process, some other mechanism, or a combination of mechanisms.
• the tetracycline compounds may be useful for preventing cancer recurrence, for example, to treat residual cancer following surgical resection or radiation therapy.
• the tetracycline compounds useful according to the invention are especially advantageous as they are substantially non-toxic compared to other cancer treatments.
• the compounds of the invention are administered in combination with standard cancer therapy, such as, but not limited to, chemotherapy.
• standard cancer therapy such as, but not limited to, chemotherapy.
• the language "in combination with" another therapeutic agent or treatment includes co-administration of the tetracycline compound and with the other therapeutic agent or treatment, administration of the tetracycline compound first, followed by the other therapeutic agent or treatment and administration of the other therapeutic agent or treatment first, followed by the tetracycline compound.
• the other therapeutic agent may be any agent which is known in the art to treat, prevent, or reduce the symptoms of a tetracycline responsive state.
• the other therapeutic agent may be any agent of benefit to the patient when administered in combination with the administration of an tefracycline compound.
• the cancers treated by methods of the invention include those described in U.S. Patent Nos. 6,100,248; 5,843,925; 5,837,696; or 5,668,122, incorporated herein by reference in their entirety.
• the tefracycUne compound responsive state is diabetes, e.g., juvenile diabetes, diabetes mellitus, diabetes type I, diabetes type Et, diabetic ulcers, or other diabetic complications.
• protein glycosylation is not affected by the administration of the tetracycline compounds of the invention.
• the tetracycline compoxmd of the invention is administered in combination with standard diabetic therapies, such as, but not limited to insulin therapy.
• the IP AS includes disorders described in U.S. Patents Nos. 5,929,055; and 5,532,227, incorporated herein by reference in their entirety.
• the tetracycline compound responsive state is a bone mass disorder. Bone mass disorders include disorders where a subjects bones are disorders and states where the formation, repair or remodeling of bone is advantageous.
• bone mass disorders include osteoporosis (e.g., a decrease in bone strength and density), bone fractures, bone formation associated with surgical procedures (e.g., facial reconstruction), osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, and the depletion of calcium in bone, such as that which is related to primary hyperpa athyroidism.
• Bone mass disorders include all states in which the formation, repair or remodeling of bone is advantageous to the subject as well as all other disorders associated with the bones or skeletal system of a subject which can be treated with the tetracycline compounds of the invention.
• the bone mass disorders include those described in U.S. Patents Nos.
• the tetracycline compound responsive state is acute lung injury.
• Acute lung injuries include adult respiratory distress syndrome (A -DS), post-pump syndrome (PPS), and trauma. Trauma includes any injury to Uving tissue caused by an extrinsic agent or event. Examples of frauma include, but are not limited to, crush injuries, contact with a hard surface, or cutting or other damage to the lungs.
• the invention also pertains to a method for treating acute lung injury by administering a tetracycline compound of the invention.
• the tetracycline responsive states of the invention also include chronic lung disorders.
• the invention pertains to methods for treating chronic lung disorders by administering a tetracycline compound, such as those described herein.
• the method includes administering to a subject an effective amount of a substituted tetracycline compound such that the chronic lung disorder is treated.
• chronic lung disorders include, but are not limited, to asthma, cystic fibrosis, and emphysema.
• the tetracycline compounds of the invention used to treat acute and/or chronic lung disorders such as those described in U.S. Patents No.
• the tetracycline compound responsive state is ischemia, stroke, or ischemic stroke.
• the invention also pertains to a method for treating ischemia, stroke, or ischemic stroke by administering an effective amount of a substituted tetracycline compound of the invention.
• the compounds of the invention are used to treat such disorders as described in U.S. Patents No. 6,231,894; 5,773,430; 5,919,775 or 5,789,395, incorporated herein by reference.
• the tetracycline compound responsive state is a skin wound.
• the invention also pertains, at least in part, to a method for improving the healing response of the epithelialized tissue (e.g., skin, mucosae) to acute traumatic injury (e.g., cut, burn, scrape, etc.).
• the method may include using a tefracycline compound of the invention (which may or may not have antibacterial activity) to improve the capacity of the epithelialized tissue to heal acute wounds.
• the method may increase the rate of collagen accumulation of the healing tissue.
• the method may also decrease the proteolytic activity in the epthithelialized tissue by decreasing the collagenolytic and/or gelatinolytic activity of MMPs.
• the tefracycline compound of the invention is administered to the surface of the skin (e.g., topically).
• the tetracyclme compound of the invention is used to treat a skin wound, and other such disorders as described in, for example, U.S. Patent Nos. 5,827,840; 4,704,383; 4,935,412; 5,258,371; 5,308,8391 5,459,135; 5,532,227; and 6,015,804; each of which is incorporated herein by reference in its entirety.
• Examples of tetracycline responsive states also include neurological disorders which include both neuropsychiatric and neurodegenerative disorders, but are not limited to, such as Alzheimer's disease, dementias related to Alzheimer's disease (such as Pick's disease), Parkinson's and other Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de la Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, epilepsy, and Creutzfeldt- Jakob disease; autonomic function disorders such as hypertension and sleep disorders, and neuropsychiatric disorders, such as depression, schizophrenia, schizoaffective disorder, Korsakoff s psychosis, mania, anxiety disorders, or phobic disorders; learning or memory disorders, e.g., amnesia or age-related memory loss, attention deficit disorder, dysthymic disorder, major depressive disorder, mania, obsessive-compulsive disorder, psychoactive substance use disorders, anxiety, phobia
• the tetracycline compound responsive state is an aortic or vascular aneurysm in vascular tissue of a subject (e.g., a subject having or at risk of having an aortic or vascular aneurysm, etc.).
• the tetracycline compound may by effective to reduce the size of the vascular aneurysm or it may be administered to the subject prior to the onset of the vascular aneurysm such that the aneurysm is prevented.
• the vascular tissue is an artery, e.g., the aorta, e.g., the abdominal aorta.
• the tetracycline compounds of the invention are used to treat disorders described in U.S. Patent Nos. 6,043,225 and 5,834,449, incorporated herein by reference in their entirety.
• 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 may be resistant to other tetracycline compounds.
• the antibiotic activity of the tefracycline 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 aitz, 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 compounds of the invention may also be used as antiinfectives and have antiparasitic, antiviral, antifungal, and/or antibiotic activities.
• the tetracycline compounds of the 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 is used to treat a bacterial infection that is resistant to other tetracycline antibiotic compounds.
• the tetracycline compound of the invention may be administered with a pharmaceutically acceptable carrier.
• the language "effective amoxint" of the compoxmd 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 compound. For example, the choice of the compoxmd 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 compoxmds 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.
• conventional excipient i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
• the invention also pertains to pharmaceutical compositions comprising a therapeutically effective amount of a tetracycline compound and, optionally, a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier includes substances capable of being coadministered with the tetracycline compound(s), and which allow both to perform their intended function, e.g. , treat or prevent a tetracycline responsive state.
• Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
• the pharmaceutical preparations can be steriUzed and if desired mixed with auxihary 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.
• auxihary 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.
• auxihary 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 delete
• 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, fximarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methahesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and palmoate [i.e., 1,1 - methylene-bis-(2-
• salts must be pharmaceutically acceptable for administration to a subject, e.g., a mammal
• the acid addition salts of the base compoxmds 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.
• the desired soUd salt is readily obtained.
• the preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
• the preparation of other tefracycline 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 r soluble amine addition salts such as N-methylglucamine-(meglx ⁇ mine), 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.
• the preparation of other tefracycUne 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 compounds of the invention and pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes.
• these compoxmds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of administration chosen. Variations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
• the pharmaceutical compositions of the invention may be administered alone or in combination with other known compositions for treating tetracycline responsive states in a subject, e.g., a mammal.
• Preferred mammals include pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows, sheep, pigs, horses, goats, etc.), lab animals (rats, mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas).
• the language "in combination with" a known composition is intended to include simultaneous administration of the composition of the invention and the known composition, administration of the composition of the invention first, followed by the known composition and administration of the known composition first, followed by the composition of the invention. Any of the therapeutically composition known in the art for treating tefracycUne responsive states can be used in the methods of the invention.
• the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously ' mentioned, and the administration may be carried out in single or multiple doses.
• 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 microcrystalUne 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 polyvinylpyrroUdone, 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 polyvinylpyrroUdone, 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 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 infraarticular, 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% sahne dextrose solutions commonly used with injectables. Additionally, it is also possible to administer the compoxmds of the present invention topically when treating inflammatory conditions of the skin. Examples of methods of topical administration 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, hi addition, materials such as anti-oxidants, humectants, viscosity stabiUzers and the like also may be added if desired.
• materials such as anti-oxidants, humectants, viscosity stabiUzers and the like also may be added if desired.
• enteral application particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
• a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
• Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
• the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of
• Uvestock 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.
• the compounds of the invention may be used to treat non-animal subjects, such as plants. It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compoxmd being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of aclministration can be readily ascertained by those skilled in the art using conventional dosage, determination tests conducted with regard to the foregoing guidelines.
• 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 0.01 to 100 milligrams per kilogram of body weight of recipient per day, preferably in the range of from 0.1 to 50 milligrams per kilogram body weight of recipient per day, more preferably in the range of 1 to 20 milligrams per kilogram body weight of recipient per day.
• the desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
• the medicament may include a pharmaceutically acceptable carrier and the compoxmd is an effective amount, e.g., an effective amount to treat a tefracycline responsive state.
• the compoxmd is an effective amount, e.g., an effective amount to treat a tefracycline responsive state.
• Example 1 Synthesis of 9-Ammomethyl Minocycline and derivatives thereof Trifluoroacetic acid (1L) was charged into a 2L flask under argon and tefracycUne. HC1 (200g, 1 eq) and N-hydroxymethylphthalimide (lOOg) were added to the flask while stirring. Once the entire sohd dissolved, H 2 SO (200 mL) was added to the reaction. The reaction was heated to 40-50°C for 5-6 hours. N-hydroxymethylamine (lOOg) was added portionwise.
• 2,9-bis-aminomethylphthalimideminocycline (lOOg) was suspended in 2M solution of methylamine in methanol (10 eq). The reaction was stirred at room temperature for 2-3 hours, at which point HPLC analysis confirmed total conversion of the starting material to 2,9-bis aminomethyltetracycline. The reaction mixture was poured into t-BME (5 volumes), and stirred for thirty minutes. Next, the suspension was filtered and washed with t-BME (200 mL) to isolate the desired product, 2,9-bis- aminomethyltetracycline.
• 2,9-bis-aminomethylminocycline (40g) was slxirried in 200 mL water/methanol 1/9 and the pH was adjusted to 3 by the dropwise addition of trifluoroacetic acid. The mixture was heated to 40°C for 1-2 hours.
• HPLC analysis confirmed the hydrolysis of 2,9-bis-aminomethylminocycline to 9-aminomethyltetracycline, the reaction was allowed to return to room temperature and the pH was adjusted to 7 using triethylamine. Isopropyl alcohol (200 mL) was added to precipitate out the solid.
• Example 5 In vitro Minimum Inhibitory Concentration (MIC) Assay The following assay is used to determine the efficacy of compounds against common bacteria. 2 mg of each compound is dissolved in 100 ⁇ l of DMSO. The solution is then added to cation-adjusted Mueller Hinton broth (CAMHB), which results in a final compound concentration of200 ⁇ g per ml. The compound solutions are diluted to 50 ⁇ h volumes, with a test compoxmd concentration of .098 ⁇ g/ml. Optical density (OD) determinations are made from fresh log-phase broth cultures of the test strains. Dilutions are made to achieve a final cell density of lxl0 6 CFU/ml.
• MIC In vitro Minimum Inhibitory Concentration
• cell densities for different genera should be approximately: E. coli lxlO 9 CFU/ml S. aureus 5x10 8 CFU/ml Enterococcus sp. 2.5x 10 9 CFU/ml 50 ⁇ l of the cell suspensions are added to each well of microtiter plates. The final cell density should be approximately 5 l0 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 compoxmd that inhibits growth.

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