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US 2002/0165221 A1Published application
Mediators of hedgehog signaling pathways, compositions and uses related thereto
OwnerAnthony David Baxter, Edward Andrew Boyd +3inventors
InventorsAnthony David Baxter, Edward Andrew Boyd, Oivin M. Guicherit, Stephen Price, Lee L. Rubin
Life of this patent
Estimating the term…
Abstract
The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.
Claims92
A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (I):
- 34
- wherein, as valence and stability permit,
- R1 and R4, independently for each occurrence, represent H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl;
- L, independently for each occurrence, is absent or represents —(CH2)n—, -alkenyl-, -alkynyl-, —(CH2)nalkenyl-, —(CH2)nalkynyl-, —(CH2)nO(CH2)p—, —(CH2)nNR8(CH2)p—, —(CH2)nS(CH2)p—, —(CH2)nalkenyl(CH2)p—, —(CH2)nalkynyl(CH2)p—, —O(CH2)n—, —NR8(CH2)n—, or —S(CH2)n—;
- X and D, independently, are selected from —N(R8)—, —O—, —S—, —(R8)N—N(R8)—, —ON(R8)—, and a direct bond;
- Y and Z, independently, are selected from O and S;
- E represents NR5, wherein R5 represents LR8 or an ammonium salt thereof;
- R8, independently for each occurrence, represents H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl, or two R8 taken together may form a 4- to 8-membered ring;
- p represents, independently for each occurrence, an integer from 0 to 3;
- n, individually for each occurrence, represents an integer from 0 to 5;
- and
- q and r represent, independently for each occurrence, an integer from 0 to 2.
9 more elements
A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (II):
- 35
- wherein, as valence and stability permit,
- R1 R2, R3, and R4, independently for each occurrence, represent H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl;
- L, independently for each occurrence, is absent or represents —(CH2)n—, -alkenyl-, -alkynyl-, —(CH2)nalkenyl-, —(CH2)nalkynyl-, —(CH2)nO(cH2)p—, —(CH2)nNR8(CH2)p—, —(CH2)nS(CH2)p—, —(CH2)nalkenyl(CH2)p—, —(CH2)nalkynyl(CH2)p—, —O(CH2)n—, —NRs(CH2)n—, or —S(CH2)n—;
- X is selected, independently, from —N(R8)—, —O—, —S—, —(R8)N—N(R8)—, —ON(R8)—, and a direct bond;
- Y and Z, independently, are selected from O and S;
- R8, independently for each occurrence, represents H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl, or two R8 taken together may form a 4- to 8-membered ring;
- M is absent or represents L, —SO2L—, or —(C═O)L—;
- p represents, independently for each occurrence, an integer from 0 to 3;
- n, individually for each occurrence, represents an integer from 0 to 5;
- and
- q, r, and s represent, independently for each occurrence, an integer from 0 to 2.
9 more elements
A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (III):
- 36
- wherein, as valence and stability permit,
- R1, R2, R3, and R4, independently for each occurrence, represent H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl;
- L, independently for each occurrence, is absent or represents —(CH2)n—, -alkenyl-, -alkynyl-, —(CH2)nalkenyl—, —(CH2)nalkynyl-, —(CH2)nO(CH2)p—, —(CH2)nNR8(CH2)p—, —(CH2)nS(CH2)p—, —(CH2)nalkenyl(CH2)p—, —(CH2)nalkynyl(CH2)p—, —O(CH2)n—, —NR8(CH2)n—, or —S(CH2)n—;
- X is selected from —N(R8)—, —O—, —S—, —(R8)N—N(R8)—, —ON(R8)—, and a direct bond;
- Y and Z, independently, are selected from O and S;
- R8, independently for each occurrence, represents H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl, or two R8 taken together may form a 4- to 8-membered ring;
- M is absent or represents L, —SO2L—, or —(C═O)L—;
- p represents, independently for each occurrence, an integer from 0 to 3;
- n, individually for each occurrence, represents an integer from 0 to 5;
- and
- q and r represent, independently for each occurrence, an integer from 0 to 2.
9 more elements
A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (IV):
- 37
- wherein, as valence and stability permit,
- R1, R2, R3, and R4, independently for each occurrence, represent H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl;
- L, independently for each occurrence, is absent or represents —(CH2)n—, -alkenyl-, -alkynyl-, —(CH2)nalkenyl-, —(CH2)nalkynyl-, —(CH2)nO(CH2)p—, —(CH2)nNR8(CH2)p—, —(CH2)nS(CH2)p—, —(CH2)nalkenyl(CH2)p—, —(CH2)nalkynyl(CH2)p—, —O(CH2)n—, —NR8(CH2)n—, or —S(CH2)n—;
- X is selected, independently, from —N(R8)—, —O—, —S—, —(R8)N—N(R8)—, —ON(R8)—, and a direct bond;
- R8, independently for each occurrence, represents H, lower alkyl, —(CH2)naryl, or —(CH2)nheteroaryl, or two R8 taken together may form a 4- to 8-membered ring;
- M is absent or represents L, —SO2L—, or —(C═O)L—;
- p represents, independently for each occurrence, an integer from 0 to 3;
- and
- n, individually for each occurrence, represents an integer from 0 to 5.
7 more elements
A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented by the general formula (V):
- 38
- wherein, as valence and stability permit,
- Y is O or S;
- Z′ is SO2, —(C═S)—, or—(C═O)—;
- p represents, independently for each occurrence, an integer from 0 to 3;
- n, individually for each occurrence, represents an integer from 0 to 5;
- q and r represent, independently for each occurrence, an integer fLrom C to 2;
- V is absent or represents O, S, or NR8;
- G is absent or represents —C(═O)— or —SO2—;
- J, independently for each occurrence, represents H or substituted or unsubstituted lower alkyl or alkylene attached to NC(═Y), such that both occurrences of N adjacent to J are linked through at least one occurrence of J, and
- R9, independently for each occurrence, is absent or represents H or lower alkyl, or two occurrences of J or one occurrence of J taken together with one occurrence of R9, forms a ring of from 5 to 7 members, which ring includes one or both occurrences of N;
- R5 represents substituted or unsubstituted alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, or cycloalkylalkyl;
- R6 represents substituted or unsubstituted aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, including polycyclic groups;
- and
- R7 represents substituted or unsubstituted aryl, aralkyl, heteroaryl, or heteroaralkyl.
12 more elements
A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented by the general formula (VI):
- 39
- wherein, as valence and stability permit,
- Y is O or S;
- Z′ is SO2, —(C═S)—, or —(C═O)—;
- p represents, independently for each occurrence, an integer from 0 to 3;
- n, individually for each occurrence, represents an integer from 0 to 5;
- V is absent or represents 0, S, or NR8;
- G is absent or represents—C(═O)— or —SO2—;
- J, independently for each occurrence, represents H or substituted or unsubstituted lower alkyl or alkylene attached to NC(═Y), such that both occurrences of N adjacent to J are linked through at least one occurrence of J, and
- R9, independently for each occurrence, is absent or represents H or lower alkyl, or two occurrences of J or one occurrence of J taken together with one occurrence of R9, forms a ring of from 5 to 7 members, which ring includes one or both occurrences of N;
- R5 represents substituted or unsubstituted alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, or cycloalkylalkyl;
- R6 represents substituted or unsubstituted aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, including polycyclic groups;
- and
- R7 represents substituted or unsubstituted aryl, aralkyl, heteroaryl, or heteroaralkyl.
11 more elements
Dependencies are inferred from the claim text.