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US 7,256,218 B2Granted
Biguanide and dihydrotriazine derivatives
AssigneeJacobus Pharmaceutical Company, Inc.
InventorsDavid P. Jacobus, Guy A. Schiehser, Hong-Ming Shieh, Norman P. Jensen, Jacek Terpinski
Life of this patent
Estimating the term…
Abstract
Biguanide and dihydrotriazine derivatives, preferably substituted asymmetrical imidodicarbonimidic diamides derived from hydroxylamines, and compositions containing biguanide and dihydrotriazine derivatives are disclosed. In addition, methods of using the biguanide and dihydrotriazine derivatives, inter alia, as antimicrobial agents and methods of using the dihydrotriazine derivatives in biological assays are disclosed. Methods of making the biguanide and dihydrotriazine derivatives are also disclosed.
Claims91
A compound of formula I or a pharmaceutically acceptable salt thereof:
- wherein:
- R1 is Rx, substituted aryl, substituted alkyl, substituted fused cycloalkylaryl, substituted aralkyl, substituted cycloalkylarylalkyl, substituted heteroaryl, or substituted heteroarylalkyl, wherein the latter seven groups are substituted with at least one substituent selected from the group consisting of —CN, —OCF3, haloalkoxy, —SR4, —OCF3, —SCF3, haloalkylthio, —NR5R6, —SO2R4, —SO2NR5R6a, heteroaryl, heterocyclyl or R10O—(CH2CH2O)j—, or combinations thereof;
- Rx is substituted or unsubstituted:
- wherein each R1a and R1b are independently H, alkyl or fluoro;
- R2 is branched or straight chain lower alkylidene, or lower alkylene;
- R3a and R3b are each independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or taken together form a cycloalkyl group;
- each R4 is independently hydrogen, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, aryl, substituted aryl, haloaryl, acyl, or heterocyclyl;
- each R5 is independently hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl substituted aryl, or acyl;
- each R6 is independently hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl substituted aryl, acyl, —SO2R5, or SO2NR5R5;
- or R5 and R6 taken together with the atom to which they are attached form a heterocycle;
- each R6a is independently hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl substituted aryl, acyl;
- or R5 and R6a taken together with the atom to which they are attached form a heterocycle;
- R7 and R8 are each, independently, hydrogen, alkyl, or acyl;
- D is lower alkylidene, lower alkylene, —O—, —S—, or —N(R9)—;
- R9 is hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl-substituted aryl, or acyl;
- R10 is alkyl or haloalkyl;
- j is an integer from 1 to 20;
- and
- k is an integer from 1 to 4.
16 more elements
A process for preparing antimicrobial compounds, comprising the steps of:
- contacting a compound of formula II:
- with a compound of formula III:
- to provide a compound of formula I:
- wherein:
- R1 is Rx, substituted aryl, substituted alkyl, substituted fused cycloalkylaryl, substituted aralkyl, substituted cycloalkylarylalkyl, substituted heteroaryl, or substituted heteroarylalkyl, wherein the latter seven groups are substituted with at least one substituent selected from the group consisting of —CN, —OCF3, haloalkoxy, —SR4, —OCF3, —SCF3, haloalkylthio, —NR5R6, —SO2R4, —SO2NR5R6a, heteroaryl, heterocyclyl or R10O—(CH2CH2O)j—, or combinations thereof;
- Rx is substituted or unsubstituted:
- wherein each R1a and R1b bare independently H, alkyl or fluoro;
- R2 is branched or straight chain lower alkylidene, or lower alkylene;
- R3a and R3b are each independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or taken together form a cycloalkyl or spiroalkyl group;
- each R4 is independently hydrogen, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, aryl, substituted aryl, haloaryl, acyl, or heterocyclyl;
- each R5 is independently hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl substituted aryl, or acyl;
- each R6 is independently hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl substituted aryl, acyl, —SO2R5, or SO2NR5R5;
- or R5 and R6 taken together with the atom to which they are attached form a heterocycle;
- each R6a is independently hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl substituted aryl, acyl;
- or R5 and R6a taken together with the atom to which they are attached form a heterocycle;
- R7 and R8 are each, independently, hydrogen, alkyl, or acyl;
- D is lower alkylidene, lower alkylene, —O—, —S—, or —N(R9)—;
- R9 is hydrogen, alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, alkyl-substituted aryl, or acyl;
- R10 is alkyl or haloalkyl;
- j is an integer from 1 to 20;
- and
- k is an integer from 1 to 4;
- or a pharmaceutically acceptable salt thereof.
20 more elements
Dependencies are inferred from the claim text.