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US 2004/0023949 A1Published application
Mediators of hedgehog signaling pathways, compositions and uses related thereto
AssigneeCuris, Inc.
InventorsAnthony David Baxter, Edward Andrew Boyd, Oivin 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.
Claims103
A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with a hedgehog antagonist in a sufficient amount to inhibit hedgehog signalling, wherein the hedgehog antagonist is a organic molecule represented in the general formula (I):
- 34
- 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 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 O, S, or NR5, wherein R5 represents LR8 or —(C═O)LR8.
- 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 method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with a hedgehog antagonist in a sufficient amount to inhibit hedgehog signalling, wherein the hedgehog antagonist is a organic molecule 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-, —(CH2O(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;
- 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 preparation comprising a sterile pharmaceuti cal excipient and a compound represented by the general formula (I):
- 36
- wherein, as valence and stability permit,
- R1, R2, R3, and R4, independently for each occurrence, represent H, lower alky, —(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 O, S, or NR5, wherein R5 represents LR8 or —(C═O)LR8.
- 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 preparation comprising a sterile pharmaceuti cal excipient and a compound represented by the general formula (II):
- 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;
- 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 method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with a hedgehog antagonist in a sufficient amount to inhibit hedgehog signalling, wherein the hedgehog antagonist is a organic molecule represented in the general formula (E):
- 38
- 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 method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with a hedgehog antagonist in a sufficient amount to inhibit hedgehog signalling, wherein the hedgehog antagonist is a organic molecule represented in the general formula (IV):
- 39
- 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 preparation comprising a sterile pharmaceuti cal excipient and a compound represented by the general formula (III):
- 40
- 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 preparation comprising a sterile pharmaceuti cal excipient and a compound represented by the general formula (IV):
- 41
- 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 preparation comprising a sterile pharmaceuti cal excipient and a compound represented by the general formula (V):
- 42
- 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 from 0 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 preparation comprising a sterile pharmaceuti cal excipient and a compound represented by the general formula (VI):
- 43
- 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 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.
11 more elements
A method for preparing an exocyclic amine, comprising transforming a compound having a structure of Formula X according to the following scheme:
- 44
- wherein q, s, and r each represent, independently, an integer in the range of 0 to 2, such that the sum of q+s+r is an integer in the range of 2-4;
- LG represents a leaving group, such as a halogen or a sulfonate;
- A represents an oxygen or sulfur bound to an acid-protecting group or a group having the formula XLR4;
- B represents a nitrogen-protecting group or a group having the formula MR3;
- R3 and R4, independently for each occurrence, represent H, lower alkyl, —(CH2)naryl (substituted or unsubstituted), or —(CH2)nheteroaryl (substituted or unsubstituted);
- Y can be selected from O and S;
- X is be selected f rom —N(R8)—, —O—, —S—, or a direct bond ;
- M is absent or represents L, —SO2L—, or —(C═O)L—;
- L, independently for each occurrence, is absent or represents —(CH2)nalkyl-, -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—;
- R8, independently for each occurrence, represents H, lower alkyl, —(CH2)naryl (e.g., substituted or unsubstituted), —(CH2)nheteroaryl (e.g., substituted or unsubstituted), or two R8 taken together may form a 4- to 8-membered ring;
- p represents, independently for each occurrence, an integer from 0 to 10, preferably from 0 to 3;
- and
- n, individually for each occurrence, represents an integer from 0 to 10, preferably from 0 to 5,
- and wherein step A includes converting the hydroxyl to a leaving group,
- step B includes displacing the leaving group with an azide, and
- step C includes reducing the azide to an amine.
14 more elements
A method for preparing an exocyclic amine, comprising transforming a compound of Formula XIV according to the following scheme:
- 45
- wherein q and r each represent, independently, an integer in the range of 0 to 2, such that the sum of q+r is an integer in the range of 2-4;
- LG represents a leaving group, such as a halogen or a sulfonate ester;
- A represents an oxygen or sulfur bound to an acid-protecting group or a group having the formula NJ2N(R9)2;
- B represents a nitrogen-protecting group or a group having the formula GR6;
- G is absent or represents —C(═O)—, —C(═S)—, 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;
- R6 represents substituted or unsubstituted aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, including polycyclic groups;
- and
- Y can be selected from O and S;
- and wherein step A includes converting the hydroxyl to a leaving group,
- step B includes displacing the leaving group with an azide, and
- step C includes reducing the azide to an amine.
11 more elements
Dependencies are inferred from the claim text.