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US 11,124,479 B2Granted
Oligopyrroles as antagonists of islet amyloid polypeptide oligomerization
AssigneeNew York University
InventorsAndrew D. Hamilton, Sunil Kumar
Life of this patent
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Abstract
The invention relates to compounds and pharmaceutical compositions capable of treating amyloid diseases and other diseases characterized by oligomerization and/or fibrillation of amyloidogenic peptides such as islet amyloid polypeptide (IAPP).
Claims16
A compound according to formula (IV):
- wherein Ra is independently selected at each occurrence from hydrogen, C1-C12 hydrocarbons, —F;
- —Cl;
- —Br;
- —I;
- —OH, —OR*;
- —SO3H;
- —NO;
- —NO2;
- —NO3;
- —O—NO;
- —N3;
- —NH2;
- —NHR*;
- and —N(R*)2;
- X is independently at each occurrence selected from —O—;
- —S—;
- —NH—;
- —NR*—;
- and C(R*)2;
- R1 is selected from hydrogen or a straight chained C2-C20 hydrocarbon, or branched or cyclic aliphatic C3-C20 hydrocarbon;
- an aromatic C6-C20 hydrocarbon;
- a heteroaromatic C2-C20 hydrocarbon;
- and a C2-C12 perfluorocarbon, or a combination thereof, each of which is optionally substituted with one or more of —F;
- —Cl;
- —Br;
- —I;
- —OH, —NO;
- —NO2;
- —NO3;
- —O—NO;
- —N3;
- —NH2;
- —NHR*;
- —N(R*)2;
- —N(R*)3+;
- —N(R*)—OH;
- —O—N(R*)2;
- —N(R*)—O—R*;
- —CN;
- —NC;
- —(C═O)—R*;
- —CHO;
- —CO2H;
- —CO2R*;
- —(C═O)—S—R*;
- —O—(C═O)—H;
- —O—(C═O)—R*;
- —S—(C═O)—R*;
- —(C═O)—NH2;
- —(C═O)—N(R*)2;
- —(C═O)—NHNH2;
- —O—(C═O)—NHNH2;
- —(C═S)—NH2;
- —(C═S)—N(R*)2;
- —N(R*)—CHO;
- —N(R*)—(C═O)—R*;
- —SCN;
- —NCS;
- —NSO;
- —SSR*;
- —SO2R*;
- —SO3H;
- —SO2—N(R*)2;
- —S(═O)—OR*;
- —S(═O)—R*;
- —Si(R*)3;
- —CF3;
- —O—CF3;
- —P(R*)2;
- —O—P(═O)(OR*)2;
- and —P(═O)(OR*)2;
- or combinations thereof;
- R2 is independently at each occurrence selected from hydrogen or a straight chained C2-C20 hydrocarbon, or branched or cyclic aliphatic C3-C20 hydrocarbon;
- an aromatic C6-C20 hydrocarbon;
- a heteroaromatic C2-C20 hydrocarbon;
- and a C2-C12 perfluorocarbon, or a combination thereof, each of which is optionally substituted with one or more of —F;
- —Cl;
- —Br;
- —I;
- —OH, —NO;
- —NO2;
- —NO3;
- —O—NO;
- —N3;
- —NH2;
- —NHR*;
- —N(R*)2;
- —N(R*)3+;
- —N(R*)—OH;
- —O—N(R*)2;
- —N(R*)—O—R*;
- —CN;
- —NC;
- —(C═O)—R*;
- —CHO;
- —CO2H;
- —CO2R*;
- —(C═O)—S—R*;
- —O—(C═O)—H;
- —O—(C═O)—R*;
- —S—(C═O)—R*;
- —(C═O)—NH2;
- —(C═O)—N(R*)2;
- —(C═O)—NHNH2;
- —O—(C═O)—NHNH2;
- —(C═S)—NH2;
- —(C═S)—N(R*)2;
- —N(R*)—CHO;
- —N(R*)—(C═O)—R*;
- —SCN;
- —NCS;
- —NSO;
- —SSR*;
- —SO2R*;
- —SO3H;
- —SO2—N(R*)2;
- —S(═O)—OR*;
- —S(═O)—R*;
- —Si(R*)3;
- —CF3;
- —O—CF3;
- —P(R*)2;
- —O—P(═O)(OR*)2;
- and —P(═O)(OR*)2;
- or combinations thereof;
- R3 is selected from hydrogen or a straight chained C2-C20 hydrocarbon, or branched or cyclic aliphatic C3-C20 hydrocarbon;
- an aromatic C6-C20 hydrocarbon;
- a heteroaromatic C2-C20 hydrocarbon;
- and a C2-C12 perfluorocarbon, or a combination thereof, each of which is optionally substituted with one or more of —F;
- —Cl;
- —Br;
- —I;
- —OH, —NO;
- —NO2;
- —NO3;
- —O—NO;
- —N3;
- —NH2;
- —NHR*;
- —N(R*)2;
- —N(R*)3+;
- —N(R*)—OH;
- —O—N(R*)2;
- —N(R*)—O—R*;
- —CN;
- —NC;
- —(C═O)—R*;
- —CHO;
- —CO2H;
- —CO2R*;
- —(C═O)—S—R*;
- —O—(C═O)—H;
- —O—(C═O)—R*;
- —S—(C═O)—R*;
- —(C═O)—NH2;
- —(C═O)—N(R*)2;
- —(C═O)—NHNH2;
- —O—(C═O)—NHNH2;
- —(C═S)—NH2;
- —(C═S)—N(R*)2;
- —N(R*)—CHO;
- —N(R*)—(C═O)—R*;
- —SCN;
- —NCS;
- —NSO;
- —SSR*;
- —SO2R*;
- —SO3H;
- —SO2—N(R*)2;
- —S(═O)—OR*;
- —S(═O)—R*;
- —Si(R*)3;
- —CF3;
- —O—CF3;
- —P(R*)2;
- —O—P(═O)(OR*)2;
- and —P(═O)(OR*)2;
- or combinations thereof;
- wherein at least one of R1, R2, and R3 is substituted with one or more of —F;
- —Cl;
- —Br;
- —I;
- —OH, —NO;
- —NO2;
- —NO3;
- —O—NO;
- —N3;
- —NH2;
- —NHR*;
- —N(R*)2;
- —N(R*)3+;
- —N(R*)—OH;
- —O—N(R*)2;
- —N(R*)—O—R*;
- —CN;
- —NC;
- —(C═O)—R*;
- —CHO;
- —CO2H;
- —CO2R*;
- —(C═O)—S—R*;
- —O—(C═O)—H;
- —O—(C═O)—R*;
- —S—(C═O)—R*;
- —(C═O)—NH2;
- —(C═O)—N(R*)2;
- —(C═O)—NHNH2;
- —O—(C═O)—NHNH2;
- —(C═S)—NH2;
- —(C═S)—N(R*)2, —N(R*)—CHO;
- —N(R*)—(C═O)—R*;
- —SCN;
- —NCS;
- —NSO;
- —SSR*;
- —SO2R*;
- —SO3H;
- —SO2—N(R*)2;
- —S(═O)—OR*;
- —S(═O)—R*;
- —Si(R*)3;
- —CF3;
- —O—CF3;
- —P(R*)2;
- —O—P(═O)(OR*)2;
- and —P(═O)(OR*)2;
- or combinations thereof;
- A is selected from —OH, —OR*;
- —NO;
- —NO2;
- —NO3;
- —O—NO;
- —N3;
- —CN;
- —NC;
- —(C═O)—R*;
- —CHO;
- —CO2H;
- —CO2R*;
- —(C═O)—S—R*;
- —O—(C═O)—H;
- —O—(C═O)—R*;
- —S—(C═O)—R*;
- —(C═O)—NH2;
- —(C═O)—N(R*)2;
- —(C═O)—NHNH2;
- —O—(C═O)—NHNH2;
- —(C═S)—NH2;
- —(C═S)—N(R*)2;
- —SCN;
- —NCS;
- —NSO;
- —SSR*;
- —SO2R*;
- —SO3H;
- —SO2—N(R*)2;
- —S(═O)—OR*;
- —S(═O)—R*;
- —Si(R*)3;
- —CF3;
- —O—CF3;
- —P(R*)2;
- —O—P(═O)(OR*)2;
- —P(═O)(OR*)2;
- C1-C8 perfluorocarbon;
- an aliphatic C1-C12 hydrocarbon;
- an aromatic C3-C12 hydrocarbon;
- and a C2-C12 heteroaryl, with a proviso that A is not —N(R*)—(C═O)—H or —N(R*)—(C═O)—CH3;
- B is selected from hydrogen, —F;
- —Cl;
- —Br;
- —I;
- —OH, —OR*;
- —NO;
- —NO2;
- —NO3;
- —O—NO;
- —N3;
- —NH2;
- —NHR*;
- —N(R*)2;
- —N(R*)3+;
- —N(R*)—OH;
- —O—N(R*)2;
- —N(R*)—O—R*;
- —CN;
- —NC;
- —(C═O)—R*;
- —CHO;
- —CO2H;
- —CO2R*;
- —(C═O)—S—R*;
- —O—(C═O)—H;
- —O—(C═O)—R*;
- —S—(C═O)—R*;
- —(C═O)—NH2;
- —O—(C═O)—NHNH2;
- —(C═S)—NH2;
- —(C═S)—N(R*)2;
- —N(R*)—CHO;
- —N(R*)—(C═O)—R*;
- —SCN;
- —NCS;
- —NSO;
- —SSR*;
- —SO2R*;
- —SO3H;
- —SO2—N(R*)2;
- —S(═O)—OR*;
- —S(═O)—R*;
- —Si(R*)3;
- —CF3;
- —O—CF3;
- —P(R*)2;
- —O—P(═O)(OR*)2;
- —P(═O)(OR*)2;
- C1-C8 perfluorocarbon;
- an aliphatic C1-C12 hydrocarbon;
- an aromatic C3-C12 hydrocarbon;
- and a C2-C12 heteroaryl;
- R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S;
- or combinations thereof,
- or a pharmaceutically acceptable salt thereof.
320 more elements
A compound having the structure of formula:
- or a pharmaceutically acceptable salt thereof.
A compound having the structure of formula:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.