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US 7,268,124 B2Granted
Geranylgeranyl pyrophosphate synthase inhibitors
AssigneeUniversity of Iowa Research Foundation
InventorsDavid F. Wiemer, Raymond J. Hohl
Life of this patent
Estimating the term…
Abstract
The invention provides novel pyrophosphate synthase inhibitors of formula I as well as compositions comprising such inhibitors and methods for their use.
Claims57
An unsymmetrical bisphosphonate compound of formula I:
- wherein:
- R1 is a saturated or unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, —P(═O)(ORa)2, or —NRbRc;
- R2 is a saturated or unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, P(═O)(ORa)2, or —NRbRc;
- each R3, R4, R5 and R6 is independently OH or (C1-C6)alkoxy;
- each Ra is independently H, (C1-C6)alkyl, or aryl;
- and
- each Rb and Rc is independently H, (C1-C6)alkyl, or aryl;
- or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
- wherein any aryl is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NRdRe, or S(O)2NRdRe, wherein each Rd and Re is independently H or (C1-C6)alkyl;
- and
- wherein R1 is not equal to R2;
- or a pharmaceutically acceptable salt or prodrug thereof.
9 more elements
A compound of formula I:
- wherein:
- R1 is a saturated or unsaturated (C5-C20)alkyl chain tat comprises one or more aryl rings in the chain;
- R2 is a saturated or unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, —P(═O)(ORa)2, or —NRbRc;
- each R3, R4, R5, and R6 is independently OH or (C1-C6)alkoxy;
- each Ra is independently H, (C1-C6)alkyl, or aryl;
- and
- each Rb and Rc is independently H, (C1-C6)alkyl, or aryl;
- or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
- wherein any aryl is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NRdRc, or S(O)2NRdRe, wherein each Rd and Re is independently H or (C1-C6)alkyl;
- or a pharmaceutically acceptable salt or prodrug thereof.
7 more elements
A compound of formula I:
- wherein:
- R1 is a saturated or unsaturated (C5-C20)alkyl chain that is substituted with one or more halo, trifluoromethyl, ORa or NRbRc;
- R2 is a saturated or unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, —P(═O)(ORa)2, or —NRbRc;
- each R3, R4, R5, and R6 is independently OH or (C1-C6)alkoxy;
- each Ra is independently H, (C1-C6)alkyl, or aryl;
- and
- each Rb and Rc is independently H, (C1-C6)alkyl, or aryl;
- or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
- wherein any aryl is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NRdRe, or S(O)2NRdRe, wherein each Rd and Re is independently H or (C1-C6)alkyl;
- or a pharmaceutically acceptable salt or prodrug thereof.
7 more elements
A compound of formula I:
- wherein:
- R1 is of the formula,
- wherein n is 0, 1, or 3;
- and each bond designated by - - - is independently either present or is absent;
- R2 is a saturated or unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, —P(═O)(ORa)2, or —NRbRc;
- each R3, R4, R5, and R6 is independently OH or (C1-C6)alkoxy;
- each Ra is independently H, (C1-C6)alkyl, or aryl;
- and
- each Rb and Rc is independently H, (C1-C6)alkyl, or aryl;
- or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
- wherein any aryl is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NRdRe, or S(O)2NRdRe, wherein each Rd and Re is independently H or (C1-C6)alkyl;
- or a pharmaceutically acceptable salt or prodrug thereof.
9 more elements
A compound of formula I:
- wherein:
- R1 is a saturated or unsaturated (C5-C20)alkyl chain terminally substituted with ORa or NRbRc;
- wherein Ra is aryl;
- and each Rb, and Rc is independently H, (C1-C6)alkyl, or aryl;
- wherein any aryl is optionally substituted with one or more carboxy or S(O)2NRdRe, wherein each Rd and Re is independently H or (C1-C6)alkyl;
- R2 is a saturated or unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, —P(═O)(ORa)2, or —NRbRc;
- each R3, R4, R5, and R6 is independently OH or (C1-C6)alkoxy;
- each Ra is independently H, (C1-C6)alkyl, or aryl;
- and
- each Rb and Rc is independently H, (C1-C6)alkyl, or aryl;
- or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
- wherein any aryl is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NRdRe, or S(O)2NRdRe, wherein each Rd and Re is independently H or (C1C6)alkyl;
- or a pharmaceutically acceptable salt or prodrug thereof.
10 more elements
A compound of formula I:
- wherein:
- R1 is an unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, —P(═O)(ORa)2, or —NRbRc;
- R2 is a saturated or unsaturated (C5-C20)alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —ORa, —P(═O)(ORa)2, or —NRbRc;
- each R3, R4, R5, and R6 is (C1-C6)alkoxy;
- each Ra is independently H, (C1-C6)alkyl, or aryl;
- and
- each Rb and Rc is independently H, (C1-C6)alkyl, or aryl;
- or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
- wherein any aryl is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NRdRe, or S(O)2NRdRe, wherein each Rd and Re is independently H or (C1-C6)alkyl;
- or a pharmaceutically acceptable salt or prodrug thereof.
7 more elements
The compound tetramethyl (E)-1,1-bis(4,8-dimethyl-nona-3,7-dienyl)-1,1-bisphosphonate;
- tetraethyl 4,8-dimethyl-3,7-nonadienyl-1,1-bisphosphonate;
- tetraethyl (2E,6E)-1-(3-methyl-but-2-enyl)-3,7,11-trimethyl-dodeca-2,6,10-trienyl-1,1-bisphosphonate;
- 1-(3,7-dimethyl-octa-2,6-dienyl)-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic;
- acid or a salt thereof;
- tetrapivaloyloxymethyl (E)-1,1-bis(4,8-dimethyl-nona-3,7-dienyl)-1,1-bisphosphonate;
- (2E,6E)-1-(3-methyl-but-2-enyl)-3,7,11-trimethyl-dodeca-2,6,10-triene-1,1-bisphosphonate or a salt thereof;
- or a compound of the following formula:
4 more elements
Dependencies are inferred from the claim text.