9-aminomethyl minocycline compounds and methods of use thereof in urinary tract infection (uti) treatment

Abstract

The invention disclosed herein provides a method for treating urinary tract infection (UTI) using 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, in either oral or IV doses or a combination of both.

We claim: 
     
         1 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an oral dose of 300-600 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, such that said subject is treated. 
     
     
         2 . The method of  claim 1 , wherein the oral dose is 300-450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof. 
     
     
         3 . The method of  claim 1 , comprising administering to said subject one oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof once every 24 hours, for a total of 4 or 5 days. 
     
     
         4 . The method of  claim 1 , comprising administering to said subject one oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof once every 24 hours, for a total of 5-14 days. 
     
     
         5 . The method of  claim 1 , comprising administering to said subject one oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof once every 24 hours, for a total of 5-14 days. 
     
     
         6 . The method of  claim 1 , comprising administering to said subject one oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof once every 24 hours, for a total of 5 days, and further comprising administering to said subject an additional oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof about 12 hours after the first oral dose. 
     
     
         7 . The method of  claim 1 , comprising administering to said subject one oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof once every 24 hours, for a total of 5-14 days, and further comprising administering to said subject an additional oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof about 12 hours after the first oral dose. 
     
     
         8 . The method of  claim 1 , comprising administering to said subject one oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof once every 24 hours, for a total of 5 days, and further comprising administering to said subject an additional oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof about 12 hours after the first oral dose. 
     
     
         9 . The method of  claim 1 , comprising administering to said subject one oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof once every 24 hours, for a total of 5-14 days, and further comprising administering to said subject an additional oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof about 12 hours after the first oral dose. 
     
     
         10 . The method of  claim 1 , comprising administering to said subject:
 (1) one or more loading doses of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof at the first day of treatment; followed by,   (2) one or more maintenance doses of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, wherein the maintenance doses are administered about 24 hours apart.   
     
     
         11 . The method of  claim 10 , wherein said one or more loading doses are two intravenous (IV) doses of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hours apart. 
     
     
         12 . The method of  claim 10 , wherein said one or more loading doses is one intravenous (IV) dose of about 200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof. 
     
     
         13 . The method of  claim 10 , wherein said one or more loading doses are two intravenous (IV) doses of about 200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hours apart. 
     
     
         14 . The method of  claim 10 , wherein said one or more loading doses is one oral dose of about 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof. 
     
     
         15 . The method of  claim 10 , wherein said one or more loading doses are two oral doses of about 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hours apart. 
     
     
         16 . The method of  claim 10 , wherein said one or more loading doses are two oral doses of about 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hours apart. 
     
     
         17 . The method of  claim 10 , wherein said one or more loading doses are one intravenous (IV) dose of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, and one oral dose of about 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hours apart. 
     
     
         18 . The method of  claim 17 , wherein said one IV dose is administered before said one oral dose. 
     
     
         19 . The method of any one of  claims 10 - 18 , wherein each of said one or more maintenance doses comprises about 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof. 
     
     
         20 . The method of any one of  claims 10 - 18 , wherein each of said one or more maintenance doses comprises about 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof. 
     
     
         21 . The method of any one of  claims 10 - 18 , wherein said one or more maintenance doses comprise one or more intravenous (IV) maintenance doses of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, and one or more oral maintenance doses of about 300 mg or 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof. 
     
     
         22 . The method of  claim 21 , wherein the IV maintenance doses are administered before the oral maintenance doses. 
     
     
         23 . The method of any one of  claims 10 - 22 , wherein said one or more maintenance doses are administered on the 2 nd -5 th  day of treatment. 
     
     
         24 . The method of any one of  claims 10 - 22 , wherein said one or more maintenance doses are administered on the 2 nd -14 th  day of treatment. 
     
     
         25 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an intravenous (IV) dose of about 200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, followed by four oral doses of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, such that said subject is treated, wherein said IV dose and said four oral doses are administered about 24 hrs apart from one another. 
     
     
         26 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an intravenous (IV) dose of about 200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, followed by 4-13 oral doses of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, such that said subject is treated, wherein said IV dose and said 4-13 oral doses are administered about 24 hrs apart from one another. 
     
     
         27 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject two intravenous (IV) doses administered 12 hours apart, each about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, followed by 4-13 oral doses of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, such that said subject is treated, wherein the first of said two IV doses and said 4-13 oral doses are administered about 24 hrs apart from one another. 
     
     
         28 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an intravenous (IV) dose of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, followed by 4-13 oral doses of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, wherein said IV dose and said 4-13 oral doses are administered about 24 hrs apart from one another; further comprising administering to said subject an additional oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hrs from said IV dose, such that said subject is treated. 
     
     
         29 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an intravenous (IV) dose of about 200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, followed by four oral doses of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, such that said subject is treated, wherein said IV dose and said four oral doses are administered about 24 hrs apart from one another. 
     
     
         30 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an intravenous (IV) dose of about 200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, followed by 4-13 oral doses of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, such that said subject is treated, wherein said IV dose and said 4-13 oral doses are administered about 24 hrs apart from one another. 
     
     
         31 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject two intravenous (IV) doses, each about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof administered 12 hours apart, followed by 4-13 oral doses of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, such that said subject is treated, wherein the first of said two IV doses and said 4-13 oral doses are administered about 24 hrs apart from one another. 
     
     
         32 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an intravenous (IV) dose of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, followed by 4-13 oral doses of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, wherein said IV dose and said 4-13 oral doses are administered about 24 hrs apart from one another; further comprising administering to said subject an additional oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hrs from said IV dose, such that said subject is treated. 
     
     
         33 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject five oral doses of about 300 mg each of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, administered about 24 hrs apart from one another; and further comprising administering to said subject an additional oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hrs from the first of said five oral doses, such that said subject is treated. 
     
     
         34 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject 5-14 oral doses of about 300 mg each of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, administered about 24 hrs apart from one another; and further comprising administering to said subject an additional oral dose of 300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hrs from the first of said 5-14 oral doses, such that said subject is treated. 
     
     
         35 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject five oral doses of about 450 mg each of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, administered about 24 hrs apart from one another; and further comprising administering to said subject an additional oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hrs from the first of said five oral doses, such that said subject is treated. 
     
     
         36 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject 5-14 oral doses of about 450 mg each of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, administered about 24 hrs apart from one another; and further comprising administering to said subject an additional oral dose of 450 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, administered about 12 hrs from the first of said 5-14 oral doses, such that said subject is treated. 
     
     
         37 . The method of any one of  claims 1 - 36 , wherein said UTI is uncomplicated urinary tract infection (uUTI) or cystitis. 
     
     
         38 . The method of any one of  claims 1 - 36 , wherein said UTI is complicated urinary tract infection (cUTI) or pyelonephritis. 
     
     
         39 . The method of any one of  claims 1 - 38 , wherein said UTI is community-acquired. 
     
     
         40 . The method of any one of  claims 1 - 38 , wherein said UTI is hospital-acquired or healthcare-associated (e.g., acquired during urinary catheterization). 
     
     
         41 . The method of any one of  claims 1 - 40 , wherein said UTI is characterized by the presence of a pathogen selected from the group consisting of:  Escherichia coli  (ESBL + , ESBL − , FQS, FQR, Carbapenem-resistant, Carbapenem-susceptible),  Staphylococcus saprophyticus, Klebsiella pneumoniae  (ESBL + , ESBL − , FQS, FQR), and  Enterococcus  ( E. faecalis  VS,  E. faecalis  VNS,  E. faecalis  Vancomycin-Resistant (VRE),  E. faecium  VS,  E. faecium  VNS,  E. faecium  Vancomycin-Resistant (VRE)), MSSA, MRSA, MSCoNS, MRCoNS,  Streptococcus agalactiae  (group B streptococci),  K. oxytoca, E. cloacae  CeftazS,  E. cloacae  CeftazR,  Citrobacter  spp.,  S. marcescens , and  Acinetobacter.    
     
     
         42 . The method of  claim 41 , wherein the pathogen comprises extended spectrum beta-lactamase (ESBL)-producing  E. coli  (e.g., those that are resistant to multiple antibiotics). 
     
     
         43 . The method of  claim 41  or  42 , wherein said pathogen has a titer of ≥10 5  CFU/mL in a urine culture from said subject. 
     
     
         44 . The method of any one of  claims 1 - 43 , wherein said subject is treated as demonstrated by a post treatment reduction of at least 10-fold in pathogen titer of a urine culture from said subject. 
     
     
         45 . The method of any one of  claims 1 - 44 , wherein said subject has a post treatment pathogen titer of less than 10 4  CFU/mL on the urine culture from said subject. 
     
     
         46 . The method of any one of  claims 1 - 45 , wherein said subject is a female. 
     
     
         47 . The method of  claim 46 , wherein the female is diabetic, has multiple sclerosis, and/or has a condition that affects urine flow (such as kidney stones, stroke, and spinal cord injury). 
     
     
         48 . The method of any one of  claims 1 - 47 , wherein each of said oral dose is administered independently as two or three 150-mg tablets. 
     
     
         49 . The method of any one of  claims 1 - 48 , wherein each of said IV dose is administered continuously over about 30 minutes (e.g., at least 30 minutes and not more than 45 minutes). 
     
     
         50 . A method of treating urinary tract infection (UTI) in a subject in need of treatment thereof, comprising administering to said subject an IV dose of about 100-200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, such that said subject is treated. 
     
     
         51 . The method of  claim 50 , wherein the subject is not administered oral dose of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof. 
     
     
         52 . The method of  claim 50  or  51 , wherein the IV dose is about 100 mg or about 200 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof. 
     
     
         53 . The method of any one of  claims 50 - 52 , comprising administering to said subject one IV dose of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, once every 24 hours, for a total of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. 
     
     
         54 . The method of any one of  claims 50 - 52 , comprising administering to said subject one IV dose of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, once every 24 hours, for a total of 5-14 days. 
     
     
         55 . The method of  claim 53  or  54 , further comprising administering to said subject an additional IV dose of about 100 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof, about 12 hours after the first IV dose. 
     
     
         56 . The method of any one of  claims 50 - 55 , wherein the UTI is cUTI or pyelonephritis.