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US 7,067,526 B1Granted
28-epirapalogs
AssigneeARIAD Gene Therapeutics, Inc.
InventorsWu Yang, Cheryl A. Digits, Leonard Rozamus, Dennis A. Holt
Life of this patent
Estimating the term…
Abstract
Rapamycin derivatives containing substituents at C-28 in the epi orientation relative to rapamycin are disclosed, together with methods for their preparation and use, e.g. for regulation of biological phenomena in engineered cells. The compounds may contain optional additional modifications relative to rapamycin, as disclosed herein.
Claims42
A compound of the formula I or II:
- wherein
- n is 1 or 2;
- R28 and R43 are independently selected from the group consisting of H and an aliphatic or acyl moiety;
- one of R7a and R7b is H and the other is halo, —RA, —ORA, —SRA, —OC(O)RA, —OC(O)NRARB—NRARB, —NRBC(O)RA, —NRBC(O)ORA, —NRBSO2RA, —NRBSO2NRARB′ or —NRBC(O)NRARB′;
- or
- R7a and R7b taken together, are H in the tetraene moiety:
- where RA is H or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where RB is H, OH or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where each aliphatic moiety is an independently chosen saturated or unsaturated, branched or unbranched, cyclic or polycyclic, aliphatic hydrocarbon containing 1–8 contiguous aliphatic carbon atoms;
- where each heteroaliphatic moiety is an independently chosen 2–8-membered non-cyclic or 3–10-membered cyclic aliphatic moiety which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms;
- where each aryl moiety is an independently chosen 6–14-membered mono- or polycyclic unsaturated moiety;
- where each heteroaryl moiety is an independently chosen 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- and
- where each acyl moiety is an independently chosen —OCR group where R is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- or a pharmaceutically acceptable salt thereof.
12 more elements
A compound of the formula I or II:
- wherein
- n is 1 or 2;
- R28 and R43 are independently selected from the group consisting of H and an aliphatic or acyl moiety;
- one of R7a and R7b is H and the other is halo, —RA, ORA, SRA, OC(O)RA, —OC(O)NRARB, —NRARB, —NRBC(O)RA, —NRBC(O)ORA, —NRBSO2RA, —NRBSO2NRARB′ or —NRBC(O)NRARB′;
- or
- R7a and R7b taken together, are H in the tetraene moiety:
- where RA is H or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where RB is H, OH or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where each aliphatic moiety is an independently chosen saturated or unsaturated, branched or unbranched, cyclic or polycyclic, aliphatic hydrocarbon containing 1–8 contiguous aliphatic carbon atoms;
- where each heteroaliphatic moiety is an independently chosen 2–8-membered non-cyclic or 3–10-membered cyclic aliphatic moiety which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms;
- where each aryl moiety is an independently chosen 6–14-membered mono- or polycyclic unsaturated moiety;
- where each heteroaryl moiety is an independently chosen 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- where each acyl moiety is an independently chosen —OCR group where R is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- wherein each aliphatic, acyl, heteroaliphatic, aryl, or heteroaryl moiety contains one or more optional substituents selected from the group consisting of —OH, —OR2, —SH, —SR2, —CHO, ═O, —COOH (or ester, carbamate, urea, oxime or carbonate thereof), —NH2 (or substituted amine, amide, urea, carbamate or guanidino derivative thereof), halo, trihaloalkyl, cyano, —SO2—CF3, —OSO2F, —OS(O)2R11, —SO2—NHR11, —NHSO2—R11, sulfate, sulfonate, aryl and heteroaryl moieties;
- where R2 is an aliphatic, heteroaliphatic, aryl, heteroaryl or alkylaryl moiety;
- and
- where R11 is H or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
- or a pharmaceutically acceptable salt thereof.
15 more elements
A compound of the formula I or II:
- wherein
- n is 1 or 2;
- R28 and R43 are independently selected from the group consisting of H and an aliphatic or acyl moiety;
- one of R7a and R7b is H and the other is halo, —RA, —ORA, —SRA, —OC(O)RA, —OC(O)NRARB′, —NRARB, —NRBC(O)RA, —NRBC(O)ORA, —NRBSO2RA, —NRBSO2NRARB′ or NRBC(O)NRARB′;
- or
- R7a and R7b taken together, are H in the tetraene moiety:
- where RA is H or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where RB is H, OH or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where each aliphatic moiety is an independently chosen saturated or unsaturated, branched or unbranched, cyclic or polycyclic, aliphatic hydrocarbon containing 1–8 contiguous aliphatic carbon atoms;
- where each heteroaliphatic moiety is an independently chosen 2–8-membered non-cyclic or 3–10-membered cyclic aliphatic moiety which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms;
- where each aryl moiety is an independently chosen 6–14-membered mono- or polycyclic unsaturated moiety;
- where each heteroaryl moiety is an independently chosen 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- where each acyl moiety is an independently chosen —OCR group where R is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- wherein each aryl or heteroaryl moiety contains one or more optional substituents selected from the group consisting of hydroxy, C1–C8 alkoxy, C1–C8 branched or straight-chain alkyl, acyloxy, carbamoyl, amino, N-acylamino, nitro, halo, trihalomethyl, cyano, and carboxyl;
- or a pharmaceutically acceptable salt thereof.
12 more elements
A compound of the formula I or II:
- wherein
- n is 1 or 2;
- R28 is selected from the group consisting of H and an aliphatic or acyl moiety;
- R43 is an alkyl, alkenyl or acyl moiety;
- one of R7a and R7b is H and the other is halo, —RA, —ORA, —SRA, —OC(O)RA, —OC(O)NRARB, —NRARB, —NRBC(O)RA, —NRBC(O)ORA, —NRBSO2RA, —NRBSO2NRARB′ or —NRBC(O)NRARB′;
- or
- R7a and R7b taken together, are H in the tetraene moiety:
- where RA is H or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where RB is H, OH or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where each aliphatic moiety is an independently chosen saturated or unsaturated, branched or unbranched, cyclic or polycyclic, aliphatic hydrocarbon containing 1–8 contiguous aliphatic carbon atoms;
- where each heteroaliphatic moiety is an independently chosen 2–8-membered non-cyclic or 3–10-membered cyclic aliphatic moiety which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms;
- where each aryl moiety is an independently chosen 6–14-membered mono- or polycyclic unsaturated moiety;
- where each heteroaryl moiety is an independently chosen 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- where each acyl moiety is an independently chosen —OCR group where R is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- wherein each alkyl, alkenyl or acyl moiety contains one or more optional substituents selected from the group consisting of —OH, —OR2, —SH, —SR2, —CHO, ═O, —COOH (or ester, carbamate, urea, oxime or carbonate thereof), —NH2 (or substituted amine, amide, urea, carbamate or guanidino derivative thereof), halo, trihaloalkyl, cyano, —SO2—CF3, —OSO2F, —OS(O)2R11, —SO2—NHR11, —NHSO2—R11, sulfate, sulfonate, aryl and heteroaryl moieties;
- where R2 is an aliphatic, heteroaliphatic, aryl, heteroaryl or alkylaryl moiety;
- and
- where R11 is H or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
- or a pharmaceutically acceptable salt thereof.
16 more elements
28-epirapamycin or a pharmaceutically acceptable salt thereof.
29-epirapamycin or a pharmaceutically acceptable salt thereof.
28,29-bis-epirapamycin or a pharmaceutically acceptable salt thereof.
A compound having the structure of 28-epirapamycin, 29-epirapamycin or 28,29-bis-epirapamycin except that the hydroxyl group at position 43 is replaced with OR43 wherein R43 is an aliphatic or acyl moiety;
- where an aliphatic moiety is a saturated or unsaturated, branched or unbranched, cyclic or polycyclic, aliphatic hydrocarbon containing 1–8 contiguous aliphatic carbon atoms;
- where an acyl moiety is an —OCR group where R is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where a heteroaliphatic moiety is a 2–8-membered non-cyclic or 3–10-membered cyclic aliphatic moiety which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms;
- where an aryl moiety is a 6–14-membered mono- or polycyclic unsaturated moiety;
- where a heteroaryl moiety is a 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- and
- or a pharmaceutically acceptable salt thereof.
4 more elements
A compound having the structure of 28-epirapamycin, 29-epirapamycin or 28,29-bis-epirapamycin except that the hydroxyl group at position 43 is replaced with OR43 wherein R43 is an aliphatic or acyl moiety;
- where an aliphatic moiety is a saturated or unsaturated, branched or unbranched, cyclic or polycyclic, aliphatic hydrocarbon containing 1–8 contiguous aliphatic carbon atoms;
- where an acyl moiety is an —OCR group where R is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where a heteroaliphatic moiety is a 2–8-membered non-cyclic or 3–10-membered cyclic aliphatic moiety which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms;
- where an aryl moiety is a 6–14-membered mono- or polycyclic unsaturated moiety;
- where a heteroaryl moiety is a 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- wherein each aliphatic or acyl, moiety contains one or more optional substituents selected from the group consisting of —OH, —OR2, —SH, —SR2, —CHO, ═O, —COOH (or ester, carbamate, urea, oxime or carbonate thereof), —NH2 (or substituted amine, amide, urea, carbamate or guanidino derivative thereof), halo, trihaloalkyl, cyano, —SO2—CF3, —OSO2F, —OS(O)2R11, —SO2—NHR11, —NHSO2—R11, sulfate, sulfonate, aryl and heteroaryl moieties;
- where R2 is an aliphatic, heteroaliphatic, aryl, heteroaryl or alkylaryl moiety;
- and
- where R11 is H or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
- or a pharmaceutically acceptable salt thereof.
7 more elements
A compound having the structure of 28-epirapamycin, 29-epirapamycin or 28,29-bis-epirapamycin except that the hydroxyl group at position 43 is replaced with OR43 wherein R43 is an aroyl or heteroaroyl moiety;
- where an aroyl moiety is an —OCR group where R is an aryl moiety;
- where a heteroaroyl moiety is an —OCR group where R is a heteroaryl moiety;
- where an aryl moiety is a 6–14-membered mono- or polycyclic unsaturated moiety;
- where a heteroaryl moiety is a 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- and
- wherein each aroyl or heteroaroyl moiety contains one or more optional substituents selected from the group consisting of hydroxy, C1–C8 alkoxy, C1–C8 branched or straight-chain alkyl, acyloxy, carbamoyl, amino, N-acylamino, nitro, halo, trihalomethyl, cyano, and carboxyl;
- or a pharmaceutically acceptable salt thereof.
4 more elements
A compound having the structure of 28-epirapamycin, 29-epirapamycin or 28,29-bis-epirapamycin except that the hydroxyl group at position 43 is replaced with OR43 wherein R43 is an acyl moiety;
- where an acyl moiety is an —OCR group where R is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety;
- where an aliphatic moiety is a saturated or unsaturated, branched or unbranched, cyclic or polycyclic, aliphatic hydrocarbon containing 1–8 contiguous aliphatic carbon atoms;
- where a heteroaliphatic moiety is a 2–8-membered non-cyclic or 3–10-membered cyclic aliphatic moiety which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms;
- where an aryl moiety is a 6–14-membered mono- or polycyclic unsaturated moiety;
- where a heteroaryl moiety is a 5–6-membered monocyclic or 9–14-membered polycyclic unsaturated moiety which contains one or more oxygen, sulfur or nitrogen atoms;
- wherein each acyl moiety contains one or more optional substituents selected from the group consisting of —OH, —OR2, —SH, —SR2, —CHO, ═O, —COOH (or ester, carbamate, urea, oxime or carbonate thereof), —NH2 (or substituted amine, amide, urea, carbamate or guanidino derivative thereof), halo, trihaloalkyl, cyano, —SO2—CF3, —OSO2F, —OS(O)2R11, —SO2—NHR11, —NHSO2—R11, sulfate, sulfonate, aryl and heteroaryl moieties;
- where R2 is an aliphatic, heteroaliphatic, aryl, heteroaryl or alkylaryl moiety;
- and
- where R11 is H or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
- or a pharmaceutically acceptable salt thereof.
7 more elements
Dependencies are inferred from the claim text.