Amino-methyl substituted tetracycline compounds
Aminomethyl substituted tetracycline compounds, pharmaceutical compositions, and methods of use thereof are discussed.
1 . A tetracycline compound of the formula (I):
wherein
R 1 and R 2 are linked to form a ring, or pharmaceutically acceptable salts, prodrugs and esters thereof.
2 . The tetracycline compound of claim 1 , wherein R 1 and R 2 are linked to form a five membered ring.
3 . The tetracycline compound of claim 1 , wherein R 1 and R 2 are linked to form a six membered ring.
4 . The tetracycline compound of claim 3 , wherein R 1 and R 2 are linked to form a piperidine ring, morpholine ring, pyridine ring, or a pyrazinyl ring.
5 . The tetracycline compound of claim 4 , wherein said compound is:
6 . A tetracycline compound of the formula:
pharmaceutically acceptable salts, esters or prodrugs thereof.
7 . A tetracycline compound of the formula (II):
wherein:
J 1 and J 2 are each independently hydrogen, aryl, sulfonyl, acyl, or linked to form a ring, provided that at least one of J 1 or J 2 is not hydrogen;
J 3 and J 4 are each alkyl, halogen, or hydrogen;
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 9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso, or —(CH 2 ) 0-3 NR 9c C(=Z′)ZR 9a ;
Z is CR 9d R 9e , NR 9b or O;
Z′ is O, S, or NR 9f ;
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 8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
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, and pharmaceutically acceptable salts, esters, and prodrugs thereof.
8 . The tetracycline compound of claim 7 , 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.
9 . The tetracycline compound of claim 8 , wherein R 4′ and R 4″ are each methyl and R 5 is hydrogen.
10 . The tetracycline compound of claim 7 , wherein J 3 and J 4 are hydrogen.
11 . The tetracycline compound of claim 7 , wherein J 1 is substituted or unsubstituted alkyl.
12 . The tetracycline compound of claim 7 , wherein J 1 is sulfonyl.
13 . The tetracycline compound of claim 7 , wherein J 1 and J 2 are linked to form a ring.
14 . The tetracycline compound of claim 7 , wherein J 1 is heteroaryl.
15 . A tetracycline compound, wherein said compound is selected from the group consisting of:
wherein
R is substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, alkoxy; and Y is N, O, or S, or pharmaceutically acceptable salts, esters, or prodrugs thereof.
16 . A tetracycline compound of formula (III):
wherein:
J 5 and J 6 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, sulfonyl, acyl, alkoxycarbonyl, alkaminocarbonyl, alkaminothiocarbonyl, substituted thiocarbonyl, substituted carbonyl, alkoxythiocarbonyl, or linked to form a ring;
J 7 and J 8 are each alkyl, halogen, or hydrogen;
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 hydrogen;
R 8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
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, and pharmaceutically acceptable salts thereof.
17 . The tetracycline compound of claim 16 , 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 10 , R 11 , and R 12 are each hydrogen; R 4′ and R 4″ are lower alkyl; and R 5 is hydroxy or hydrogen.
18 . The tetracycline compound of claim 17 , wherein R 4′ and R 4″ are each methyl and R 5 is hydrogen.
19 . The tetracycline compound of claim 16 , wherein J 7 and J 8 are hydrogen.
20 . The tetracycline compound of claim 16 , wherein J 5 is substituted or unsubstituted alkyl.
21 . The tetracycline compound of claim 16 , wherein J 5 is sulfonyl.
22 . The tetracycline compound of claim 16 , wherein J 5 and J 6 are linked to form a ring.
23 . The tetracycline compound of claim 16 , wherein J 5 is heteroaryl.
24 . The tetracycline compound of claim 16 , wherein J 5 is substituted carbonyl.
25 . The tetracycline compound of claim 16 , wherein said compound is selected from the group consisting of:
wherein
R is substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, alkoxy; and Y is N, O, or S, or pharmaceutically acceptable salts or prodrugs thereof.
26 . A tetracycline compound of Table 1, or a pharmaceutically acceptable salt thereof.
27 . A pharmaceutical composition comprising an effective amount of a tetracycline compound of any one of claims 1 , 15 , 16 , 25 or 26 , and a pharmaceutically acceptable carrier.
28 . The pharmaceutical composition of claim 27 , wherein said effective amount is effective to treat a tetracycline responsive state.
29 . A method for treating a tetracycline responsive state in a subject, comprising administering to said subject a tetracycline compound of any one of claims 1 , 15 , 16 , 25 or 26 , such that said subject is treated.
30 . The method of claim 29 , wherein said tetracycline responsive state is an inflammatory process associated state.
31 . The method of claim 29 , wherein said tetracycline responsive state is cancer, a lung injury, an eye disorder, neurological disorder or stroke.
32 . The method of claim 29 , wherein said tetracycline responsive state is a bacterial infection.
33 . The method of claim 32 , wherein said bacterial infection is associated with E. coli.
34 . The method of claim 32 , wherein said bacterial infection is associated with S. aureus.
35 . The method of claim 32 , wherein said bacterial infection is associated with E. faecalis.
36 . The method of claim 32 , wherein said bacterial infection is resistant to other tetracycline antibiotics.
37 . The method of claim 32 , wherein said bacterial infection is associated with gram positive bacteria.
38 . The method of claim 32 , wherein said bacterial infection is associated with gram negative bacteria.
39 . The method of claim 29 , wherein said tetracycline responsive state is a viral or fungal infection.
40 . The method of claim 29 , wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.
41 . The method of claim 29 , wherein said subject is a human.