US2011086822A1PendingUtilityA1
Substituted Tetracycline Compounds
Est. expiryMar 21, 2022(expired)· nominal 20-yr term from priority
Inventors:Mark L. NelsonKwasi OhemengRoger FrechettePaul AbatoVictor AmooUpul K. BandarageJoel BerniacBeena BhatiaJackson ChenMohamed Y. IsmailOak K. KimLaura HoneymanRachid MechicheAndre Lee PearsonLaxma Reddy NagavelliPaul SheahanAtul K. VermaPeter ViskiTadeusz Warchol
A61P 35/04A61P 9/12A61P 9/10A61P 3/10A61P 9/04A61P 43/00A61P 29/00A61P 25/00A61P 25/14A61P 25/28A61P 25/02A61P 25/18A61P 3/04A61P 27/02A61P 31/12A61P 25/06A61P 25/16A61P 33/06A61P 25/08A61P 35/00A61P 31/04A61P 31/10A61P 25/22A61P 31/00A61P 25/24C07D 207/16C07C 271/44C07D 295/108A61P 1/10C07D 317/54C07D 213/65C07D 261/18C07D 239/42A61P 1/04C07C 323/60C07C 275/34C07D 295/155A61P 19/02C07D 401/04C07C 237/26C07C 255/58C07C 251/08C07C 239/18A61P 1/14C07D 239/30C07D 307/52C07C 323/32C07C 251/48C07D 213/30C07C 311/21C07C 255/59A61P 13/10C07C 279/18C07D 295/215C07D 261/10C07D 211/58A61P 19/10C07C 255/25C07C 281/14C07C 317/48C07D 239/26A61P 21/04C07C 311/19A61P 17/02A61P 11/08C07C 2603/46C07D 307/68C07D 213/75C07C 309/61A61P 1/02C07D 213/61A61P 15/08C07C 255/43C07C 271/28C07D 307/28C07C 49/755C07C 49/683
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Claims
Abstract
The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
wherein:
X is CHC(R 13 Y′Y), CR 6′ R 6 , C═CR 6′ R 6 , S, NR 6 , or O;
R 2 , R 2′ , R 4′ , and R 4″ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 4 is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;
R 2′ , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety;
R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R 6 and R 6′ are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7 is nitro, heterocyclic, alkyl, aminoalkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, carbonyl, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ;
R 8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 NR 8c C(=E′)ER 8a ;
R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a ;
R 7a , R 7b , R 7c , R 7d , R 7e , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 8f are each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
E is CR 8d R 8e , S, NR 8b or O;
E′ is O, NR 8f , or S;
Z is CR 9d R 9e , S, NR 9b or O;
Z′ is O, S, or NR 9f ;
W is CR 7d R 7e , S, NR 7b or O;
W′ is O, NR 7 S;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 4 is NR 4′ R 4″ ; X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen; R 4′ and R 4″ are lower alkyl; and R 5 is hydroxy or hydrogen.
3 . The compound of claim 2 , wherein R 4′ and R 4″ are each methyl and R 5 is hydrogen.
4 . A compound of Formula II:
wherein:
X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O;
R 2 , R 2′ , R 4′ , and R 4″ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 4 is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
R 2′ , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety;
R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R 6 and R 6′ are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7 is —CH 2 NR 7a R 7b , halogen, —CH 2 OR 7a , substituted alkenylfuranyl, pyrazinyl, pyridinyl, alkyl, acyl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ;
R 8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 9 is —CH 2 SR 9a , —CH 2 S(═O)R 9a , —CH 2 S(═O) 2 R 9a , —CH 2 NR 9a R 9b , SO 3 H, aminoalkyl, furanyl, substituted alkyl, —(CH 2 ) 0-3 (NR 9c ) 0-1 C(═Z′)(Z) 0-1 R 9a , nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso, or —(CH 2 ) 0-3 (NR 9c ) 0-1 C(═Z′)(Z) 0-1 R 9a ;
Z is CR 9d R 9e , S, NR 9b or O;
Z′ is O, S, or NR 9f ;
W is CR 7d R 7e , S, NR 7b or O;
W′ is O, NR 7 S;
R 7a , R 7b , R 7c , R 7d , R 7e , R 9a , R 9b , R 9c , R 9d , and R 9e are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, or a pharmaceutically acceptable salt thereof, provided that R 7 and R 9 are not both unsubstituted phenyl.
5 . The compound of claim 4 , wherein X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 8 , R 10 , R 11 , and R 12 are each hydrogen; R 4 is NR 4′ R 4″ ; R 4′ and R 4″ are lower alkyl; and R 5 is hydroxy or hydrogen.
6 . The compound of claim 5 , wherein R 4′ and R 4″ are each methyl and R 5 is hydrogen.
7 . A compound of formula III:
wherein:
X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O;
R 2 , R 4′ , R 4″ , R 7′ and R 7″ are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 4 is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;
R 2′ , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety;
R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R 6 and R 6′ are independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7 is NR 7′ R 7″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;
R 8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 9 is —C(═Z′)R 9a , CH 2 S(═O)R 9a , —CH 2 OR 9a , alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, heterocyclic, arylalkenyl, arylalkynyl, thionitroso,substituted alkyl, or —(CH 2 ) 0-3 (NR 9c ) 0-1 C(═Z′)(Z) 0-1 R 9a ;
Z is CR 9d R 9e , S, NR 9b or O;
Z′ is NR 9f , O or S;
R 9a , R 9b , R 9c , R 9d , R 9e and R 9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, or a pharmaceutically acceptable salt, ester or prodrug thereof.
8 . The compound of claim 7 , wherein R 4 is NR 4′ R 4″ ; X is CR 6 R 6′ ; R 7 is NR 7′ R 7″ ; R 2 , R 2′ , R 5 , R 6 , R 6′ , R 8 , R 10 , R 11 , and R 12 are each hydrogen; and, R 4′ , R 4″ , R 7′ , and R 7″ are each lower alkyl.
9 . The compound of claim 8 , wherein R 4′ , R 4″ , R 7′ , and R 7″ are each methyl.
10 . A compound of formula IV:
wherein:
X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O;
R 2 , R 4′ , R 4″ , R 7′ and R 7″ are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
R 4 is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;
R 2′ , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety;
R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R 6 and R 6′ are independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 (NR 7c ) 0-1 C(═W′)WR 7a ;
R 8 is hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 (NR 8c ) 0-1 C(=E′)ER 8a ;
R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a ;
R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , 8 8a , R 8b , R 8c , R 8d , R 8e , R R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 8f are each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
E is CR 8d R 8e , S, NR 8b or O;
E′ is O, NR 8f , or S;
W is CR 7d R 7e , S, O or NR 7b ;
W′ is O, NR 7f , or S;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, or a pharmaceutically acceptable salt, ester or prodrug thereof.
11 . The compound of claim 10 , wherein X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 10 , R 11 , and R 12 are each hydrogen; R 4 is NR 4′ R 4″ ; R 4′ and R 4″ are lower alkyl; and R 5 is hydroxy or hydrogen.
12 . A compound selected from the group consisting of:
and pharmaceutically acceptable esters, enantiomers, amides, prodrugs, and salts thereof.
13 . A method for treating a tetracycline responsive state in a subject, comprising administering to said subject a compound of claim 1 , such that said subject is treated.
14 . The method of claim 13 , wherein said tetracycline responsive state is a bacterial infection.
15 . The method of claim 14 , wherein said bacterial infection is associated with E. coli.
16 . The method of claim 14 , wherein said bacterial infection is associated with S. aureus.
17 . The method of claim 14 , wherein said bacterial infection is associated with E. faecalis.
18 . The method of claim 14 , wherein said bacterial infection is resistant to other tetracycline antibiotics.
19 . The method of claim 13 , wherein said subject is a human.
20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.Cited by (0)
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