Bryostatin compounds and methods of preparing the same

Patent metadata

Field	Value
Publication number	US-2019292172-A1
Application number	US-201716337221-A
Country	US
Kind code	A1
Filing date	Sep 28, 2017
Priority date	Oct 5, 2016
Publication date	Sep 26, 2019
Grant date	—

Abstract

Methods for preparing a variety of bryostatin compounds are provided. The subject methods provide for preparation of bryostatin 1 in multi-gram quantities in a low and unprecedented number of convergent synthetic steps from commercially available materials. The subject methods are scalable with low estimated material costs and can provide enough material to meet clinical needs. Also provided are a variety of bryostatin analog compounds, and prodrug forms thereof, which are synthetically accessible via the subject methods and pharmaceutical compositions including the same.

First claim

What is claimed is:

1 . A method of preparing a bryostatin compound, wherein the method comprises:
(a) preparing a compound of formula (X) from a starting material of formula (I) or a synthon thereof or a synthetic equivalent thereof:

wherein:
P 1 and P 2 are independently a hydroxyl protecting group or synthetic equivalent thereof;
each R and R 1 -R 2 is independently an alkyl or a substituted alkyl;
R 12 is an alkyl or a substituted alkyl; and
R 11 is an acyl, a substituted acyl, an alkyl, a substituted alkyl, —CO-aryl, —CO(substituted aryl), —CO-heteroaryl, or -CO(substituted heteroaryl); and

(b) preparing a compound of formula (XX) from a starting material of formula (XI) or a synthon thereof or a synthetic equivalent thereof:

wherein:
Z 1 is an alkynyl, a substituted alkynyl, an allenyl, a substituted allenyl an alkyl or a substituted alkyl (e.g., including one or more O or N atoms in the carbon chain, or substituted with a cycloalkyl, substituted cycloalkyl, cyclic alkenyl, substituted cyclic alkenyl, aryl, substituted aryl, heteroaryl, or substituted hereoaryl);
R 12 , R 13 and R 16 are independently an alkyl or a substituted alkyl; and
P 3 is H or a hydroxyl protecting group.

2 . The method of claim 1 , wherein step (a) comprises 10 synthetic steps or fewer; step (b) comprises 13 synthetic steps or fewer; and the starting material of formula (XI) or a synthon thereof or a synthetic equivalent thereof is selected from one of the following:

3 . The method of any one of claims 1 - 2 , wherein Z 1 comprises 4-10 carbons.

4 . The method of claim 3 , wherein Z 1 is:

5 . The method of any one of claims 1 - 4 , further comprising:
(c) coupling the compound of formula (X) and the compound of formula (XX) via esterification and macrocyclization (or vice versa) to produce a macrocyclic compound; and (d) preparing a compound of formula (XXII) from the macrocyclic compound (e.g., via an oxidative cleavage, such as an osmylation/diol cleavage, or an ozonolysis reaction):

wherein:
R 4 is an alkyl or a substituted alkyl;
Z 2 is =CR 5 R 6 or =NR 7 when the covalent bond designated “b” is a double bond;
Z 2 is —OR 8 or —N(R 7 ) 2 when the covalent bond designated “b” is a single bond; and
R 5 , R 6 , R and R 8 are each independently H, alkyloxycarbonyl, substituted alkyloxycarbonyl, alkyl or substituted alkyl;
P 1 and P 3 are independently H or a hydroxyl protecting group;
R 11 is H, an acyl, a substituted acyl, an alkyl or a substituted alkyl;
R 12 is H, an alkyl or a substituted alkyl; and
R 16 is H, an alkyl or a substituted alkyl.

6 . The method of claim 5 , further comprising deprotecting a protected hydroxy group to produce a bryostatin compound having a free hydroxyl group.

7 . The method of claim 6 , further comprising preparing a prodrug of the bryostatin compound.

8 . The method of claim 5 , wherein the macrocyclic compound is of formula (XXI):

9 . The method of any one of claims 5 - 8 , wherein the bryostatin compound has the structure of formula (XXIII);

wherein:
R 13 is an alkyl or a substituted alkyl; and
R 14 is H, a hydroxyl protecting group or a promoiety.

10 . The method of any one of claims 5 - 8 , wherein the bryostatin compound has the structure of formula (XXXII):

wherein:
R 13 is an alkyl or a substituted alkyl; and
R 14 is H, a hydroxyl protecting group or a promoiety.

11 . The method of any one of claims 1 - 10 , wherein step (a) comprises a method of preparing the compound of formula (X) from a compound of formula (III):

wherein:
P 1 and P 2 are independently H or a hydroxyl protecting group;
R 4 is H, an alkyl or a substituted alkyl; each R and R 12 is an alkyl or a substituted alkyl; and
R 11 is an acyl, a substituted acyl, an alkyl or a substituted alkyl.

12 . The method of any one of claims 1 - 11 , wherein step (a) comprises preparing a compound of formula (VII) from a compound of formula (VI):

wherein R 3 is H, an alkyl or a substituted alkyl.

13 . The method of any one of claims 1 - 12 , wherein step (a) comprises reacting a compound of formula (VII) with a compound of formula (VIII) to stereoselectively produce a compound of formula (IX):

wherein:
each R and R 3 is alkyl or a substituted alkyl; and
each X is a leaving group.

14 . The method of any one of claims 1 - 13 , wherein step (b) comprises preparing a compound of formula (XIVb) from compounds of formula (XII) and (XIII) via intermediate (XIVa):

15 . The method of any one of claims 1 - 13 , wherein step (b) comprises preparing a compound of formula (XIV) from a compound of formula (XIVb) via a metathesis reaction:

wherein R 3 is an alkyl comprising at least two carbons or a substituted alkyl.

16 . A method of preparing a bryostatin compound or a precursor thereof, wherein the method comprises one or more steps according to any one of the steps depicted in FIG. 1 to FIG. 9 .

17 . The method of any one of claims 1 - 15 , wherein the bryostatin compound or precursor thereof is bryostatin 1.

18 . A bryostatin analog having the formula (XXXI):

wherein:
R 4 is an alkyl or a substituted alkyl;
Z 2 is CR 5 R 6 or NR 7 when the covalent bond designated “b” is a double bond;
Z 2 is OR 8 or N(R 7 ) 2 when the covalent bond designated “b” is a single bond;
R 5 , R 6 , R 7 and R 8 are each independently H, alkyloxycarbonyl, substituted alkyloxycarbonyl, alkyl or substituted alkyl;
R 11 is an acyl, a substituted acyl, an alkyl or a substituted alkyl;
R 12 is H, an alkyl or a substituted alkyl;
R 13 is H, an alkyl or a substituted alkyl; and
R 14 and R 15 are independently H, a hydroxyl protecting group or a promoiety;
or a solvate, hydrate or prodrug form thereof and/or a salt thereof.

19 . The bryostatin analog of claim 18 , wherein R 14 is a promoiety.

20 . A pharmaceutical composition comprising a therapeutically effective amount of a bryostatin analog of any one of cl

Assignees

• Univ Leland Stanford Junior

Inventors

• Wender Paul
• Quiroz Ryan
• Ho Stephen
• Shimizu Akira
• Ryckbosch Steven
• Stevens Matthew C
• Jeffreys Matthew S
• Hardman Clayton
• Sloane Jack

Classifications

• C07D407/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/351

  not condensed with another ring · CPC title

• A61P31/18

  for HIV · CPC title

• A61K31/365

  Lactones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title