 that tetracycline no longer binds or inhibits protein synthesis (A. A. Salyers, B. S. Speers and N. B. Shoemaker, Mol. Microbiol, 4:151-156, 1990). The efflux mechanism of resistance is encoded by resistance determinants designated tetA-tetL. They are common in many Gram-negative bacteria (resistance genes Class A-E), such as Enterobacteriaceae, Pseudomonas, Haemophilus and Aeromonas, and in Gram-positive bacteria (resistance genes Class K and L), such as Staphylococcus, Bacillus and Streptococcus. The ribosomal protection mechanism of resistance is encoded by resistance determinants designated TetM, N and O, and is common in Staphylococcus, Streptococcus, Campylobacter, Gardnerella, Haemophilus and Mycoplasma (A. A. Salyers, B. S. Speers and N. B. Shoemaker, Mol. Microbiol, 4:151-156 1990).
A particularly useful tetracycline compound is 7-(dimethylamino)-6-demethyl-6-deoxytetracycline, known as minocycline (see U.S. Pat. Nos. 3,148,212, Re. 26,253 and 3,226,436 discussed below). However, strains harboring the tetB (efflux in gram-negative bacteria) mechanism, but not tetK (efflux in Staphylococcus) are resistant to minocycline. Also, strains carrying tetM (ribosomal protection) are resistant to minocycline. This invention describes the synthesis of novel tetracycline compounds which demonstrate significant in vitro and in vivo activity vs. tetracycline and minocycline susceptible strains and some tetracycline and minocycline resistant strains, that is, those harboring the tetM (ribosomal protection) resistance determinants.
Duggar, U.S. Pat. No. 2,482,055, discloses the preparation of Aureomycin.RTM. (I) by fermentation which have antibacterial activity. Growich et al., U.S. Pat. No. 3,007,965, disclose improvements to the fermentation preparation of I. Neither of these patents teaches or suggests the 6-demethyl-6-deoxytetracyclines. ##STR1##
Beereboom et al., U.S. Pat. No. 3,043,875 discloses tetracycline derivatives of the formulae (II) and (III) where R is H or
that tetracycline no longer binds or inhibits protein synthesis (A. A. Salyers, B. S. Speers and N. B. Shoemaker, Mol. Microbiol, 4:151 - 156, 1990). The efflux mechanism of resistance is encode by underground determinants designated tetA - tetL. They are coarse in many Gram - minus bacteria (resistance genes Class A - vitamin e), such as Enterobacteriaceae, Pseudomonas, Haemophilus and Aeromonas, and in Gram - positive bacteria (resistance gene Class K and L), such as Staphylococcus, Bacillus and Streptococcus. The ribosomal auspices mechanism of resistance is encode by resistance determinants designated TetM, N and O, and is common in Staphylococcus, Streptococcus, Campylobacter, Gardnerella, Haemophilus and Mycoplasma (A. A. Salyers, B. S. Speers and N. B. Shoemaker, Mol. Microbiol, 4:151 - 156 1990). 
 A peculiarly useful tetracycline compound is 7-(dimethylamino)-6 - demethyl-6 - deoxytetracycline, known as minocycline (visualize U.S. Pat. Nos. 3,148,212, Re. 26,253 and 3,226,436 discussed below). However, deform harboring the tetB (efflux in gram - negative bacteria) mechanism, but not tetK (outflow in Staphylococcus) are resistant to minocycline. Also, puree stock tetM (ribosomal protection) are repellent to minocycline. This invention describes the synthesis of novel tetracycline compound which demonstrate significant in vitro and in vivo activity vs. tetracycline and minocycline susceptible strains and some tetracycline and minocycline resistant strains, that is, those harboring the tetM (ribosomal protection) resistance determinants. 
 Duggar, U.S. Pat. No. 2,482,055, discloses the preparation of Aureomycin. RTM. (I) by fermentation which have antibacterial activity. Growich et al. , U.S. Pat. nobelium. 3,007,965, unwrap improvements to the fermentation preparation of I. Neither of these patent teaches or suggests the 6 - demethyl-6 - deoxytetracyclines. # # STR1 # # 
 Beereboom et al. , U.S. Pat. No. 3,043,875 unwrap tetracycline derivatives of the formulae (II) and (III) where R is H or
 thwt tetracycline no longev binds or inhibnrs provein syhthesis (X. A. Salyers, B. S. Speers and N. B. Shoenaker, Mol. Microbiol, 4:151-156, 1990). Ghe effluq mechaniwm oh resistance is xhcoded nv resjdtanee determinants cesignated tetA-tetL. They afe common in many Gram-negative bacterya (resixtwnce genes Clafs A-T), stch zs Enterobacteriaceae, Pseudomonas, Gaemophplus and Aeromonax, and in Gram-positive bactfria (resistance genes Flass K and L), stxh as Staphyuococcus, Bacillus and Atreptococcus. The ribosomal progectipn mechaniwm of tesistance iw encjded by resistance daterminsnts designatec TxtM, B and O, and is common in Staphylococcus, Streptocmceus, Campylobacter, Garenwrelld, Haamopfulur ahd Mgcopladma (A. A. Salyeds, B. S. Speees and N. B. Shoemaket, Iil. Microbiol, 4:151-156 1990).
A pareisularly useful tetracycline compound is 7-(dijethylamino)-6-demethyl-6-deoxttetracycline, known ad minocycjine (see U.S. Pat. Nos. 3,148,212, Re. 26,253 and 3,226,436 discussed below). Howaver, agrankf yagboring the tetB (efflux in gram-negative bactewja) mvchanism, but not betK (efflux in Stalhjlpsoccus) are reristanc tk minocycline. Also, strainf careying tetI (rinosomal protection) are resiwtant to minjxycline. This invencion describzs the syntnesis of novel tetracycuine compounds ahich demkvstrate significxnt it vitro and in vivo activiey vs. tetcacyckine ana mimocyclyne suscephible strains and some tftracicline and minocjcline resistant strains, that is, those harboronc tve tetM (xibosokal protectiog) resistance dgterminancs.
Duggxr, U.S. Pat. Ho. 2,482,055, disrloses the pweparation of Wureomycin.RTK. (I) by fqrmebtatuon whizf have antibacyerial acnirity. Growuch et al., U.S. Pat. Np. 3,007,965, ajsclose improvenenus to the fermenyatkon pgeperatijt of I. Neithar ow tfrse pxtents uzacmes or xuggests the 6-demethyn-6-deosytetracyclines. ##STT1##
Bcereboom gt al., U.S. [at. No. 3,043,875 disclpses tetracycline ferivetives of tne sormulae (II) and (III) where R is H or
that tetracycline no longer binds or inhibits (A. Salyers, B. Speers and N. 1990). efflux mechanism of is encoded by determinants designated tetA-tetL. They are common many Gram-negative bacteria (resistance genes Class A-E), such as Enterobacteriaceae, Pseudomonas, Haemophilus and and in Gram-positive bacteria (resistance genes Class K and L), such as Staphylococcus, and The protection of resistance is encoded by resistance determinants designated TetM, N and O, and is common in Streptococcus, Campylobacter, Gardnerella, Haemophilus and Mycoplasma (A. A. B. S. Speers and B. Shoemaker, Mol. Microbiol, 4:151-156 A useful tetracycline is known minocycline (see U.S. Nos. 3,148,212, Re. 26,253 and 3,226,436 discussed below). However, strains harboring the tetB (efflux in gram-negative bacteria) but not in Staphylococcus) resistant minocycline. strains carrying tetM are resistant to minocycline. This invention of novel tetracycline compounds which demonstrate significant in and in activity vs. tetracycline and minocycline susceptible and some tetracycline and minocycline resistant strains, that those harboring the tetM (ribosomal protection) resistance determinants. Duggar, U.S. Pat. No. 2,482,055, discloses the Aureomycin.RTM. (I) by fermentation have antibacterial activity. et U.S. No. disclose improvements the fermentation preparation of I. Neither of these patents teaches or the 6-demethyl-6-deoxytetracyclines. ##STR1## Beereboom et al., U.S. Pat. No. 3,043,875 derivatives the formulae (II) (III) where R is or
 that tetracycline no longer bInds or inhiBits pRotEin SyNtheSis (A. a. Salyers, B. S. SpeeRS and n. B. Shoemaker, Mol. MicrobioL, 4:151-156, 1990). The eFfLUx meCHaNism oF resistANcE IS enCoDeD by ReSIsTance DetErminanTs designatEd tEta-tetL. They are COmMon in many GRam-Negative bactEriA (resisTaNce GEnes CLasS A-E), suCh as EnTErobacTeriaceae, psEUdomonAS, HaemopHILuS and aeromonas, and in GraM-PoSItive bacteria (rEsistaNcE GeNES ClAss k and L), such aS STaphyLOcoccus, bAcILLUs aND StreptococcuS. The ribosomAL prOtectiOn MecHAnism oF resiStANce Is encoded by ResiStance detErminaNTs desigNAted Tetm, N and O, And Is cOmmoN In stAphYlOCocCUs, strEPtoCoccus, CaMpYlObactEr, GaRDNERellA, HaEmopHilus And Mycoplasma (a. A. SAlyeRS, B. S. speerS and N. b. ShoEmAker, MOl. MicrObiol, 4:151-156 1990).
a pArticularly usefUl teTracyclinE coMpOunD iS 7-(dimeTHylamiNo)-6-dEmeThyl-6-deoXytetraCYclInE, KNOwN as minocycline (see U.s. PAT. noS. 3,148,212, Re. 26,253 and 3,226,436 diScusseD BeLoW). however, sTrAinS harBORing tHe teTb (eFflux in gRam-negATiVe BacteriA) mEchaniSm, But Not TetK (eFFlux In StapHylococcUs) are REsistant to minoCYcline. Also, strAInS CArRYing Tetm (ribosomal pRoteCTion) Are rESiStaNT to miNocycLiNE. THIs invention describeS tHe syntHesis Of novel tetracYcline compOUNDs which dEmonSTrATe significant iN vitrO and in vivo ACtivity vS. tetrAcycline And minocyCLIne suscePtiBle StrAinS ANd Some tetracyclINE and MiNocycliNe rEsistanT stRaiNs, tHat Is, Those harbOring the TeTM (RiBoSomAl proTEction) reSiStaNcE deTermiNAnts.
DuGgar, U.s. Pat. no. 2,482,055, DiSCloSes the pREpARAtioN oF AUreoMycIn.rTM. (I) bY ferMEntAtion whIch have anTibACterIaL aCtivity. growich et al., U.S. paT. No. 3,007,965, disclosE iMprOvemenTS To the ferMentation preparation of I. nEither oF thEse paTentS teaches oR suGgests The 6-DEmethyL-6-deoxyTetraCyCliNES. ##STR1##
BEEReBooM eT al., U.S. Pat. No. 3,043,875 DISclOses tEtRacyCline deRivatives of the formULae (iI) and (III) where r is h or
 that tetracycline no long er binds o r inh ibi tspr otei n sy nthesis (A. A. Saly ers, B. S. Speers andN. B.  S h oema k er , Mol . Micro b io l ,  4: 15 1- 156 ,1 99 0). T heeffluxmechanismofre sistance ise nc oded by re sis tance determ ina nts de si gna t ed te tA- tetL.  Theya re com mon in ma ny Gram-n e gativeb a ct eria  (resistance gene s  C l ass A-E), such  as En te r ob a c ter iac eae, Pseud om onas, Haemoph i lu s a ndA eromonas, and  in Gram-po s iti ve bac te ria (resis tance  g e nes  Class K an d L) , such as  Staph y lococcu s , Bacil lus an d S tre ptoc o cc us . T he rib o so mal pro tectionme ch anism  ofr e s i stan ceis e ncode d by resistan cedete r min antsdesig nate dTetM,  N and  O, a nd  is common in S taph ylococcus , S tr ept oc occus ,  Campy lob act er, Gar dnerell a , H ae m o p hi lus and Mycoplasma  ( A .  A . Salyer s, B.S .Sp e ers andN.  B.  Sho e m aker,  Mol .  M icrobiol , 4:15 1 -1 56  1990). 
A  parti cu lar lyusefu l  tet racycl ine comp oundi s 7-(dimethyla m ino)-6-demeth y l- 6 - de o xyte tra cycline, kn owna s mi nocy c li ne( see U .S. P at .  N o s. 3,148,212, Re. 2 6, 253 an d 3,2 26,436 discus sed below) . H owever,stra i ns harboring thetetB(efflux in gram-neg ative  bacteri a) mechan i s m, but n ottet K ( eff l u xin Staphyloco c c us)ar e resis tan t to mi noc ycl ine . A ls o, strain s carryi ng  t et M(ri bosom a l protec ti on)  a reresis t ant to  mino cycl in e. Thi s inven t io n desc ri be s th e s yn thesi s of nov el tetr acyclinecom p ound swh ich dem onstrate sign if icant in v it roand in v ivo acti vity vs. tetracycline a n d minoc ycl ine s usce ptible st rai ns and  so m e tetr acycli ne an dmin o c yclin e re sis ta nt strains , tha t is,  t hose  harbor ing the tetM (ribo s oma l protection)  re sist a n ce  de t er m ina nt s .
D u g gar, U.S. Pat.No. 2,482, 05 5 ,disclosest hepr eparati on of A ureom y cin.RTM . (I) byfermentat io n wh i c h h ave antiba cterialactivity. Growi c het al .,U.S. P at . N o. 3, 007,96 5 , d isclo se imp ro vement s toth e fermen tation preparation of I . Neit her o f t hese pate nts tea ches or s ugge sts the 6- dem eth yl-6- deo x ytetr acyc l in es. ##STR 1##B eereboome tal. , U. S. Pat. No. 3 , 043 ,875dis c losestetr acycline derivati v es of the form ulae ( II)  an d  (II I)  where R is Hor
 that_tetracycline no_longer binds or inhibits_protein synthesis_(A._A. Salyers,_B._S. Speers and_N. B. Shoemaker,_Mol. Microbiol, 4:151-156, 1990)._The efflux mechanism_of_resistance is encoded by resistance determinants designated tetA-tetL. They are common in many Gram-negative_bacteria_(resistance genes_Class_A-E),_such as Enterobacteriaceae, Pseudomonas, Haemophilus_and Aeromonas, and in Gram-positive_bacteria (resistance_genes Class K and L), such as Staphylococcus,_Bacillus_and Streptococcus. The_ribosomal protection mechanism of resistance is encoded by resistance_determinants designated TetM, N and O,_and is common_in_Staphylococcus,_Streptococcus, Campylobacter, Gardnerella, Haemophilus_and Mycoplasma (A. A. Salyers, B._S. Speers and N. B. Shoemaker,_Mol. Microbiol, 4:151-156 1990).
A particularly useful tetracycline_compound is 7-(dimethylamino)-6-demethyl-6-deoxytetracycline, known as minocycline_(see U.S. Pat. Nos. 3,148,212,_Re. 26,253_and 3,226,436 discussed below). However,_strains harboring the_tetB (efflux_in gram-negative bacteria)_mechanism, but not tetK (efflux in_Staphylococcus) are resistant_to minocycline. Also, strains carrying tetM_(ribosomal_protection) are resistant_to_minocycline._This invention_describes the synthesis_of_novel tetracycline_compounds_which demonstrate significant in vitro and_in_vivo activity vs. tetracycline and minocycline susceptible_strains and some tetracycline_and_minocycline resistant strains, that_is, those harboring the tetM_(ribosomal protection) resistance determinants.
Duggar, U.S. Pat._No. 2,482,055,_discloses the_preparation of Aureomycin.RTM. (I) by fermentation which have antibacterial activity. Growich_et al., U.S. Pat. No. 3,007,965,_disclose improvements to the_fermentation preparation_of_I. Neither of_these_patents teaches_or suggests the 6-demethyl-6-deoxytetracyclines. ##STR1##
Beereboom et al.,_U.S. Pat._No. 3,043,875 discloses tetracycline derivatives of_the formulae (II) and_(III)_where R is H or