Bryostatin compounds and methods of preparing the same

Patent metadata

Field	Value
Publication number	US-10947221-B2
Application number	US-201716337221-A
Country	US
Kind code	B2
Filing date	Sep 28, 2017
Priority date	Oct 5, 2016
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

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 bryostatin compound is of formula (XXIV)

wherein
W 1 is an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an allenyl, a substituted allenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, an alkyl, a substituted alkyl; or
W 1 is a carbon chain comprising oxygen atoms, nitrogen atoms, rings, substituted rings, or a combination thereof;
Z 2 is ═CR 5 R 6 or ═NR 7 when the covalent bond “b” is a double bond;
Z 2 is —OR 8 or —N(R 7 ) 2 when the covalent bond “b” is a single bond;
X 1 is H or OR 11 ;
Y 1 is H or OR 12 ;
R 5 , R 6 , R 7 and R 8 are each independently H, halogen, alkyloxycarbonyl, substituted alkyloxycarbonyl, alkyl or substituted alkyl;
R 11 is H, an acyl, a substituted acyl, an alkyl, a substituted alkyl, —CO(substituted aryl), CO-aryl, CO-heteroaryl or —CO(substituted heteroaryl);
R 12 is H, an alkyl or a substituted alkyl;
R 13 is H, an alkyl or a substituted alkyl;
R 14 and R 15 are independently H, a hydroxyl protecting group or a promoiety; and
R 16 is H, an alkyl, a substituted alkyl, —CO(substituted aryl), CO-aryl, CO-heteroaryl or CO(substituted heteroaryl),

wherein the method comprises:
(a) preparing a compound of formula (X) from a starting material of formula (I):

through the use of intermediates of generic formulae (II)-(IX)

wherein:
P 1 and P 2 are independently H or a hydroxyl protecting group or synthetic equivalent thereof;
each R and R 1 —R 4 is independently H, an alkyl or a substituted alkyl;
R 12 is H, 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 each X is a leaving group;

(b) preparing a compound of formula (XX) from a starting material of formula (XI):

through the use of intermediates of generic formulae (XII)-(XIII), (XIVa), (XIVb), and (XIV)-(XIX)

wherein:
Z 1 is an alkynyl, a substituted alkynyl, an allenyl, a substituted allenyl an alkyl or a substituted alkyl;
R 3 , R 12 , R 13 and R 16 are independently H, an alkyl or a substituted alkyl; and
P 3 is H or a hydroxyl protecting group; and

(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.

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 claim 1 , wherein Z 1 comprises 4-10 carbons.

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

5. The method of claim 1 , further comprising:
(d) preparing a compound of formula (XXII) from the macrocyclic compound:

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 7 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 claim 5 , 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 claim 5 , 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 claim 1 , 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 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 claim 1 , 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 claim 1 , 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 claim 1 , wherein step (b) comprises preparing a compound of formula (XIVb) from compounds of formula (XII) and (XIII) via intermediate (XIVa):

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

wherein R 13 is an alkyl comprising at least two carbons or a substituted alkyl.

16. The method of claim 1 , wherein the bryostatin compound is bryostatin 1.

Assignees

• Univ Leland Stanford Junior
• The Board Of The Leland Stanford Junior Univ

Inventors

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

Classifications

• C07D493/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• C07D407/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/365

  Lactones · CPC title

• A61K31/351

  not condensed with another ring · CPC title

• A61P35/00

  Antineoplastic agents · CPC title