Inhibitors of hedgehog signaling pathways, compositions and uses related thereto
AssigneeJohn Hopkins University School of Medicine
InventorsPhilip A. Beachy, Michael K. Cooper, Jeffrey A. Porter
Life of this patent
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Abstract
The present invention makes availables assays and reagents inhibiting paracrine and/or autocrine signals produced by a hedgehog protein or aberrant activation of a hedgehog signal transduction pathway, e.g., which involve the use of a steroidal alkaloid or other small molecule.
Claims17
A method for inhibiting mitotic cell proliferation in an animal, wherein the mitotic cell proliferation is associated with a cancer, comprising administering to the animal a purified compound represented in the general formula (I), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof:
- wherein, as valence permits,
- R2, R3, R4, and R5 independently for each occurrence, represent one or more substituents selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R6 is absent or is selected from halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R7 and R′7, taken together with the carbon atom to which they are attached, form a furo[3,2-b]piperidine ring system, wherein the carbon atom to which R7 and R′7 are attached is the carbon atom at the 2-position of the furo[3,2-b]piperidine ring system;
- R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
- and
- m is an integer in the range 0 to 8 inclusive.
A method for inhibiting mitotic cell proliferation in an animal, wherein the mitotic cell proliferation is associated with a cancer, comprising administering to the animal a purified compound represented in the general formula (II), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof:
- wherein, as valence permits,
- R2 and R4, independently for each occurrence, are selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R3, independently for each occurrence, is selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R5, independently for each occurrence, is absent or represents a substituent selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R6 is absent or is selected from halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R7 and R′7, taken together with the carbon atom to which they are attached, form a furo[3,2-b]piperidine ring system, wherein the carbon atom to which R7 and R′7 are attached is the carbon atom at the 2-position of the furo[3,2-b]piperidine ring system;
- R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
- X represents O or S;
- and
- m is an integer in the range 0 to 8 inclusive.
Dependencies are inferred from the claim text.