Pharmaceutically active compounds and methods of use thereof

1 . A 5,9-substituted tetracycline.

2 . A compound of claim 1 of the following Formula I:

wherein R is alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl;

alkylsulfonyl; alkylamino; or an aryalkyl;

R 2 is alkanoyl; aroyl; alkaroyl; carbocyclic aryl, heteroaromatic, alkyl;

alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl;

Z is hydrogen, alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; aryalkyl, carbocyclic aryl, heteroalicyclic or heteroaromatic group; and pharmaceutically acceptable salts thereof.

3 . A compound of claim 1 that is

5-propionate-9-t-butyl doxycycline;

9-chloro-t-butyl-5-propionate doxycycline;

9-t-butyl-6-alpha-deoxy-5-oxy-tetracycline;

9-t-butyl-5-oxytetracycline;

9-t-butyl-6-alpha-deoxy-5-formyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-acetoxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-propionyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-phenylcarbonyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-benzylcarbonyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-dimethylaminocarbonyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-cyclopentylcarbonyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-cyclobutylcarbonyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-cyclohexylcarbonyloxy-tetracycline;

9-t-butyl-6-alpha-deoxy-5-cycloheptylcarbonyloxy-tetracycline;

9-(chloro-t-butyl)-6-alpha-deoxy-5-oxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-oxy-tetracycline;

9-(amino)-t-butyl-6-alpha-deoxy-5-oxy-tetracycline;

9-[(piperidino)-t-butyl]-6-alpha-deoxy-5-oxy-tetracycline;

9-[(diethylamino)-t-butyl]-6-alpha-deoxy-5-oxy-tetracycline;

9-[(dipropylamino)-t-butyl]-6-alpha-deoxy-5-oxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-formyloxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-acetoxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-propionylcarbonyloxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-phenylcarbonyloxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-benzylcarbonyloxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-dimethylaminocarbonyloxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cyclopentylcarbonyloxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cyclobutylcarbonyloxy-tetracycline;

9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cyclohexylcarbonyloxy-tetracycline; or 9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cycloheptylcarbonyloxy-tetracycline; and pharmaceutically acceptable salts thereof.

4 . The compound of claim 2 wherein R is alkyl having 1 to about 20 carbon atoms; alkenyl having 2 to about 20 carbon atoms; alkynyl having 2 to about 20 carbon atoms; alkoxy having 1 to about 20 carbon atoms; alkylthio having 1 to about 20 carbon atoms; alkylsulfinyl having from 1 to about 20 carbon atoms; alkylsulfonyl having from 1 to about 20 carbon atoms; alkylamino having from 1 to about 20 carbon atoms; or aryalkyl;

R 2 is alkyl having 1 to about 20 carbon atoms; alkenyl having 2 to about 20 carbon atoms; alkynyl 2 to about 20 carbon atoms; alkoxy 1 to about 20 carbon atoms; alkylthio having 1 to about 20 carbon atoms; alkylsulfinyl having from 1 to about 20 carbon atoms; alkylsulfonyl having from 1 to about 20 carbon atoms; alkylamino having from 1 to about 20 carbon atoms; or aryalkyl; alkanoyl from 1 to about 20 carbon atoms; aroyl; alkaroyl; carbocyclic aryl, heteroaromatic; and

Z is hydrogen, alkyl having 1 to about 20 carbon atoms; alkenyl having 2 to about 20 carbon atoms; alkynyl 2 to about 20 carbon atoms; alkoxy 1 to about 20 carbon atoms; alkylthio having 1 to about 20 carbon atoms; alkylsulfinyl having from 1 to about 20 carbon atoms; alkylsulfonyl having from 1 to about 20 carbon atoms; alkylamino having from 1 to about 20 carbon atoms; aryalkyl; carbocyclic aryl, or an heteroalicyclic group.

5 . The compound of claim 2 wherein R is alkyl having 1 to about 12 carbon atoms; alkenyl having 2 to 12 about carbon atoms; alkynyl having 2 to 12 about carbon atoms; alkoxy having 1 to about 12 carbon atoms; alkylthio having 1 to about 12 carbon atoms; alkylsulfinyl having 1 to about 12 carbon atoms; alkylsulfonyl having 1 to about 12 carbon atoms; alkylamino having 1 to about 12 carbon atoms; or benzyl;

R 2 is alkyl having 1 to about 12 carbon atoms; alkenyl having 2 to 12 about carbon atoms; alkynyl having 2 to 12 about carbon atoms; alkoxy having 1 to about 12 carbon atoms; alkylthio having 1 to about 12 carbon atoms; alkylsulfinyl having 1 to about 12 carbon atoms; alkylsulfonyl having 1 to about 12 carbon atoms; alkylamino having 1 to about 12 carbon atoms; benzyl; aroyl; alkaroyl; carbocyclic aryl, heteroaromatic; and Z is hydrogen.

6 . The compound of claim 2 wherein R and/or R 2 is selected from the group consisting of t-butyl; chloro-t-butyl; (dimethylamino)-t-butyl; propionate; piperidinoethyl; formyloxy; acetoxy; propionyloxy; phenylcarbonyloxy; benzylcarbonyloxy; piperidino; amino; diethylamino; dipropylamino; acetylcarbonyloxy; propionylcarbonyloxy; phenylcarbonyloxy; benzylcarbonyloxy; dimethylaminocarbonyloxy; cyclopentylcarbonyloxy; cyclobutylcarbonyloxy; cyclohexylcarbonyloxy; cycloheptylcarbonyloxy; and Z is hydrogen.

7 . The compound of claim 1 , wherein said compound is selected from the group consisting of 5-propionate-9-t-butyl doxycycline; 9-t-butyl-6-deoxy-5-propionylcarbonyloxytetracycline, 9-t-butyl-6-deoxy-5-acetylcarbonyloxytetracycline, 9-t-butyl-6-deoxy-5-cyclobutylcarbonyloxytetracycline, and pharmaceutically acceptable salts thereof.

8 . A 9,13-substituted tetracycline compound.

9 . A compound of claim 8 that is of the following Formula II:

wherein R is alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl;

R 1 is hydrogen, hydroxy, alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl;

X and Y are each independently hydrogen; halogen; hydroxyl; cyano, sulfhydryl; amino; alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl;

Z is hydrogen, alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; aryalkyl, carbocyclic aryl, heteroalicyclic or heteroaromatic group; and pharmaceutically acceptable salts thereof.

10 . A compound of claim 8 that is:

13-cyclopentylthio-9-t-butyl-5-oxy-tetracycline;

13-methylthio-9-t-butyl-5-oxy-tetracycline;

13-ethylthio-9-t-butyl-5-oxy-tetracycline;

13-propylthio-9-t-butyl-5-oxy-tetracycline;

13-isopropylthio-9-t-butyl-5-oxy-tetracycline;

13-butylthio-9-t-butyl-5-oxy-tetracycline;

13-isobutylthio-9-t-butyl-5-oxy-tetracycline;

13-pentylthio-9-t-butyl-5-oxy-tetracycline;

13-isopentylthio-9-t-butyl-5-oxy-tetracycline;

13-cyclobutylthio-9-t-butyl-5-oxy-tetracycline;

13-cyclopentylthio-9-t-butyl-5-oxy-tetracycline;

13-cyclohexylthio-9-t-butyl-5-oxy-tetracycline;

13-phenylthio-9-t-butyl-5-oxy-tetracycline;

13-(3,4-dichlorophenyl)thio-9-t-butyl-5-oxy-tetracycline;

13-benzylthio-9-t-butyl-5-oxy-tetracycline;

13-(4-chlorobenzyl)thio-9-t-butyl-5-oxy-tetracycline;

13-(3,4-dichlorobenzyl)thio-9-t-butyl-5-oxy-tetracycline;

13-(4-methoxybenzyl)thio-9-t-butyl-5-oxy-tetracycline;

13-(2,3-dihydroxypropyl)thio-9-t-butyl-5-oxy-tetracycline; and

5-propionate-13-cyclopentylthio-9-t-butyl oxytetracycline;

5-propionate-13-cyclopentylthio-9-piperidinoethyl oxytetracycline;

and pharmaceutically acceptable salts thereof.

11 . A 5,9,13-substituted tetracycline.

12 . A compound of claim 11 that is of the following Formula III:

wherein R is alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl;

R 2 is alkanoyl; aroyl; alkaroyl; carbocyclic aryl, heteroaromatic, alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl such as benzyl;

X and Y are each independently hydrogen; halogen; hydroxyl; cyano, sulfhydryl; amino; alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl;

Z is hydrogen, alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; aryalkyl, carbocyclic aryl, heteroalicyclic or heteroaromatic group; and pharmaceutically acceptable salts thereof.

13 . A compound of claim 11 that is:

13-cyclopentylthio-9-t-butyl-5-formyloxy-tetracycline;

13-methylthio-9-t-butyl-5-acetoxy-tetracycline;

13-ethylthio-9-t-butyl-5-propionylcarbonyloxy-tetracycline;

13-propylthio-9-t-butyl-5-butanylcarbonyloxy-tetracycline;

13-isopropylthio-9-t-butyl-5-cyclopentylcarbonyloxy-tetracycline;

13-butylthio-9-t-butyl-5-cyclohexylcarbonyloxy-tetracycline;

13-isobutylthio-9-t-butyl-5-cycloheptylcarbonyloxy-tetracycline;

13-pentylthio-9-t-butyl-5-formyloxy-tetracycline;

13-isopentylthio-9-t-butyl-5-acetoxy-tetracycline;

13-cyclobutylthio-9-t-butyl-5-propionylcarbonyloxy-tetracycline;

13-cyclopentylthio-9-t-butyl-5-cyclopentanylcarbonyloxy-tetracycline;

13-cyclohexylthio-9-t-butyl-5-cyclohexylcarbonyloxy-tetracycline;

13-phenylthio-9-t-butyl-5-phenylacetylcarbonyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-formyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-acetoxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-propionylcarbonyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-phenylcarbonyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-benzylcarbonyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-dimethylamino carbonyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cyclopentyl carbonyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cyclobutyl carbonyloxy-tetracycline;

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cyclohexyl carbonyloxy-tetracycline; or

13-cyclopentylthio-9-[(dimethylamino)-t-butyl]-6-alpha-deoxy-5-cycloheptyl carbonyloxy-tetracycline; and pharmaceutically acceptable salts thereof.

14 . A compound of the following Formula IV:

wherein R 3 is alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; or an aryalkyl;

Z is hydrogen, alkyl; alkenyl; alkynyl; alkoxy; alkylthio; alkylsulfinyl; alkylsulfonyl; alkylamino; aryalkyl, carbocyclic aryl, heteroalicyclic or heteroaromatic group; and pharmaceutically acceptable salts thereof.

15 . A compound of claim 14 which is

9-t-butyl tetracycline;

9-t-butyl anhydrotetracycline;

9-t-butyl minocycline; and pharmaceutically acceptable salts thereof.

16 . The compound of claim 14 wherein R 3 is alkyl having 1 to about 20 carbon atoms; alkenyl having 2 to about 20 carbon atoms; alkynyl having 2 to about 20 carbon atoms; alkoxy having 1 to about 20 carbon atoms; alkylthio having 1 to about 20 carbon atoms; alkylsulfinyl having from 1 to about 20 carbon atoms; alkylsulfonyl having from 1 to about 20 carbon atoms; alkylamino having from 1 to about 20 carbon atoms; or aryalkyl; and

Z is hydrogen, alkyl having 1 to about 20 carbon atoms; alkenyl having 2 to about 20 carbon atoms; alkynyl 2 to about 20 carbon atoms; alkoxy 1 to about 20 carbon atoms; alkylthio having 1 to about 20 carbon atoms; alkylsulfinyl having from 1 to about 20 carbon atoms; alkylsulfonyl having from 1 to about 20 carbon atoms; alkylamino having from 1 to about 20 carbon atoms; aryalkyl; carbocyclic aryl, or an heteroalicyclic group.

17 . The compound of claim 14 wherein R 3 is alkyl having 1 to about 12 carbon atoms; alkenyl having 2 to 12 about carbon atoms; alkynyl having 2 to 12 about carbon atoms; alkoxy having 1 to about 12 carbon atoms; alkylthio having 1 to about 12 carbon atoms; alkylsulfinyl having 1 to about 12 carbon atoms; alkylsulfonyl having 1 to about 12 carbon atoms; alkylamino having 1 to about 12 carbon atoms; or benzyl; and Z is hydrogen.

18 . The compound of claim 14 wherein R 3 is selected from the group consisting of t-butyl; chloro-t-butyl; (dimethylamino)-t-butyl; methylcyclohexyl; methylcyclobutyl; methylpentyl; bromomethylpentyl; nitromethylpentyl; and acetoxymethylpentyl.

19 . The compound of claim 14 , wherein said compound is selected from the group consisting of 9-t-butyl-6-deoxy-5-hydroxytetracycline, 9-[1′-(1′-methyl)cyclohexyl]-6-deoxy-5-hydroxytetracycline, 9-[1′-(1′-methyl)cyclopentyl]-6-deoxy-5-hydroxytetracycline, 9-[1′-(1′-methyl)cyclobutyl]-6-deoxy-5-hydroxytetracycline, 9-[2′-(2′-methyl)pentyl]-6-deoxy-5-hydroxytetracycline, 9-[4′-(1′-bromo-4′-methyl)pentyl]-6-deoxy-5-hydroxytetracycline, 9-[4′-(1′-dimethylamino-4′-methyl)pentyl]-6-deoxy-5-hydroxytetracycline, 9-[4′-(1′-pyrrolidinyl-4′-methyl)pentyl]-6-deoxy-5-hydroxytetracycline, 9-[4′-(1′-cyano-4′-methyl)pentyl]-6-deoxy-5-hydroxytetracycline, 9-[4′-(1′-nitro-4′-methyl)pentyl]-6-deoxy-5-hydroxytetracycline, 9-[4′-(1′-acetoxy-4′-methyl)pentyl]-6-deoxy-5-hydroxytetracycline); 9-t-butyl tetracycline; 9-t-butyl anhydrotetracycline; 9-t-butyl minocycline; and pharmaceutically acceptable salts thereof.

20 . A method for treating against a targeted microogranism comprising administering to the microorganism a compound of claim 1 .

21 . A method for treating against bacteria comprising administering to the bacteria a compound of claim 1 .

22 . A method for treating a mammal suffering from or susceptible to a microorganism infection or disease associated therewith comprising administering to the mammal a compound of claim 1 .

23 . A method for treating a mammal suffering from or susceptible to bacteria infection comprising administering to the mammal a compound of claim 1 .

24 . The method of claim 22 wherein the mammal is a human.

25 . The method of claim 22 wherein the microorgansim or bacteria is tetracycline sensitive.

26 . The method of claim 22 wherein the microorgansim or bacteria is tetracycline resistant.

27 . The method of claim 21 wherein the bacteria is E. coli, S. aureus or E. faecalis.

28 . A method for converting tetracycline resistant bacteria into tetracycline resistant bacteria, comprising

a) contacting the resistant bacteria with a predetermined quantity of a compound of claim 1 , and

b) concomitantly administering to the bacteria a predetermined quantity of a tetracycline-type compound that is different than the compound of step a).

29 . A pharmaceutical composition of claim 1.