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US 2024/0197726 A1Published application
Novel tetrahydroisoquinoline alkaloid compound containing macrocycle
AssigneeThe University of Tokyo
InventorsHiroki OGURI, Ryo TANIFUJI
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Abstract
[Problem] To provide: a novel tetrahydroisoquinoline (THIQ) alkaloid compound having a macrocyclic structure; an intermediate of the compound; and a method for producing the compound. [Solution] Provided is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. The present invention also provides: a method for synthesizing this compound; and an intermediate compound useful in this synthesis.
Claims23
A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
- wherein A is a single bond or an optionally substituted C1-C6 alkylene group;
- X1 is a divalent group selected from the group consisting of an optionally substituted alkylene group, an optionally substituted alkenylene group, —NRbC(O)—, —C(O)NRb—, —C(O)O—, —OC(O)—, —NRbC(O)O—, —OC(O)NRb—, —OC(O)O—, a carbonyl group, —C(═S)—, —C(═NRb)—, —NRb—, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof;
- Y1 is a divalent group selected from the group consisting of a single bond, an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and —NRb—;
- Y2 is a divalent group selected from the group consisting of an optionally substituted alkylene group, an optionally substituted alkenylene group, —NRbC(O)—, —C(O)NRb—, —C(O)O—, —OC(O)—, —NRbC(O)O—, —OC(O)NR—, —OC(O)O—, a carbonyl group, —C(═S)—, —C(═NRb)—, —NRb—, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof;
- X2 is selected from the group consisting of -L1-C(═CRf2)—CRf═CRf-L2-, -L1-CRf═CRf—C(═CRf2)-L2-, -L1-CRf═CRf-L2-, -L1-CR═CRf—CR═CRf-L2-, -L1-NRb—CRf2—C C-L2-, -L1-C═C—CRf2—NRb-L2-, -L1-C≡C-L2-, and -L1-C≡C—C≡C-L2-,
- L1 and L2 each independently represent a single bond or a C1-C6 alkylene group,
- Rf each independently represents a hydrogen atom, an optionally substituted C1-C20 alkyl group or an optionally substituted aryl group,
- Z1 and Z2 each independently represent —NRc— or —CRdRe—, Rc, Rd, and Re are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group, or Rc and Rd together with Z1 and Z2 to which they are bonded form a 5- or 6-membered ring structure, and the ring structure may be substituted with 1 to 4 substituents;
- Ra is each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group or respective Ra's may be taken together to form a ring structure containing an oxygen atom to which they are bonded;
- Rb is each independently selected from among a hydrogen atom, an optionally substituted C1-C20 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group,
- R1 is a methyl group;
- R2 is a hydrogen atom or an optionally substituted C1-C6 alkyl group;
- R3 is a methyl group;
- R4 is selected from among a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group, and
- R5 represents CN, a hydroxyl group or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom.
12 more elements
A compound represented by the following formula (IIIc) or a pharmaceutically acceptable salt thereof:
- wherein
- X1c is selected from among a hydrogen atom, an optionally substituted C1-C20 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group,
- X1d is selected from among a hydrogen atom, a methyl group, and substituents corresponding to various natural/unnatural amino acid side chains,
- LX2a and LX2b each independently represent a hydrogen atom, an optionally substituted C1-C20 alkyl group or an optionally substituted aryl group,
- Y1 is a divalent group selected from the group consisting of an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and —NRb—;
- Y2 is a divalent group selected from the group consisting of an optionally substituted alkylene group, an optionally substituted alkenylene group, —NRbC(O)—, —C(O)NRb—, —C(O)O—, —OC(O)—, —NRbC(O)O—, —OC(O)NRb—, —OC(O)O—, a carbonyl group, —C(═S)—, —C(═NRb)—, —NRb—, a sulfonyl group, an ether group, a thioether group, and an amino acid residue,
- R4 is selected from among a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group,
- R5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom,
- Rb is selected from among a hydrogen atom, an optionally substituted C1-C20 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group, and
- Me represents a methyl group.
7 more elements
A compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof:
- wherein
- A is a single bond or an optionally substituted C1-C6 alkylene group;
- X1 is a divalent group selected from the group consisting of an optionally substituted alkylene group, an optionally substituted alkenylene group, —NRbC(O)—, —C(O)NRb—, —C(O)O—, —OC(O)—, —NRbC(O)O—, —OC(O)NRb—, —OC(O)O—, a carbonyl group, —C(═S)—, —C(═NRb)—, —NRb—, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof;
- Y1 is a divalent group selected from the group consisting of a single bond, an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and —NRb—;
- Y2 is a divalent group selected from the group consisting of an optionally substituted alkylene group, an optionally substituted alkenylene group, —NRbC(O)—, —C(O)NR—, —C(O)O—, —OC(O)—, —NRbC(O)O—, —OC(O)NRb—, —OC(O)O—, a carbonyl group, —C(═S)—, —C(═NRb)—, —NRb—, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof;
- M1 is selected from among a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, —N(Rb)2, an optionally substituted alkylene-N(Rb)2, a hydroxyl group, a carbonyl group, a thiol group, and a halogen atom;
- M2 is selected from among a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, —N(Re)2, an optionally substituted alkylene-N(Rb)2, a hydroxyl group, a carbonyl group, a thiol group, and a halogen atom;
- Rb is each independently selected from among a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group,
- Ra is each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group, or respective R's may be taken together to form a ring structure containing an oxygen atom to which they are bonded;
- R1 is a methyl group;
- R2 is a hydrogen atom or an optionally substituted C1-C6 alkyl group;
- R3 is a methyl group;
- R4 is selected from among a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group, and
- R5 represents CN, a hydroxyl group or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom.
11 more elements
A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, the method including the following step (F):
- step (F):
- reacting a compound represented by the following formula (IIf) with a compound represented by formula (IVb) in the presence of a copper catalyst and a ligand to obtain a compound represented by formula (IIIc):
Dependencies are inferred from the claim text.