Byrostatin analogues, synthetic methods and uses

• US 20070270485A1
• Filed: 07/03/2007
• Published: 11/22/2007
• Est. Priority Date: 11/30/1999
• Status: Abandoned Application

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Park, Cheol-Min, Wender, Paul, Lippa, Blaise, Hinkle, Kevin
• Application Number:
  US11/825,092
• Publication Number:
  US 20070270485A1
• Time in Patent Office: Days
• US Class Current: 514/450
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 309/06 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 309/10 Oxygen atoms
• CPC Class Codes: C07D 319/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 319/16 condensed with one six-membered ring
• CPC Class Codes: C07D 407/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 493/08 Bridged systems
• CPC Class Codes: C07D 493/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

Biologically active compounds related to the bryostatin family of compounds, having simplified spacer domains and/or improved recognition domains are disclosed, including methods of preparing and utilizing the same.

Claims

1. A compound having the structure represented by a formula of the group:

wherein;

R³ is H, OH or a protecting group;

R⁶ is H, H or ═

O;

R⁸ is H, OH, ═

O, R′

, —

(CH₂)_nO(O)CR′

or (CH₂)_nCO₂-haloalkyl where n is 0, 1, 2, 3, 4 or 5, provided that R⁶ and R⁸ are not both ═

O;

R⁹ is H, OH or is absent;

R²⁰ is H, OH, or -T-U—

V—

R′

where;

T is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

;

U is absent or is —

C(O)—

, —

C(S)—

, —

S(O)—

or —

S(O)₂—

; and

V is absent or is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

, provided that V is absent when U is absent;

R²¹ is ═

CR^aR^b or R²¹ represents independent moieties R^c and R^d where;

R^a and R^b are independently H, CO₂R′

, CONR^cR^d or R′

;

R^c and R^d are independently H, alkyl, alkenyl, alkynyl or (CH₂)_pCO₂R′

where p is 1, 2 or 3;

R′

is independently selected from;

H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

R″

is OH, OTBS or OBn; and

X is —

CH₂—

, —

O—

, —

S—

or —

N(R^e)—

where R′

is COH, CO₂R′

or SO₂R′

,

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 having one or more of the stereochemical configurations represented by the corresponding formula of the group:

3. The compound or salt of any of claims 1 to 3 where:

R⁸ is H, alkyl, aralkyl, or —

O₂C-lower alkyl, provided that for Formula C26 des-methyl 705 R⁸ is other than —

O₂C-t-butyl;

R⁹ is H;

R²⁰ is H, OH, —

O₂C-lower alkyl or —

O₂C-alkenyl;

R²¹ is ═

C—

CO₂-lower alkyl; and

X is —

CH₂—

or —

O—

.

4. The compound or salt of claim 3 where:

R³ is OH;

R⁸ is H, t-butyl, —

O₂C—

CH₃, —

O₂C—

C(CH₃)₃ or —

O₂C—

CH₂—

CH₂—

CH₃; and

R²⁰ is H, OH, —

O₂C—

CH₃, —

O₂C—

CH₂—

CH₂—

CH₃ or —

O₂C—

CH═

CH—

CH═

CH—

CH₂—

CH₂—

CH₃.

5. A compound having the structure represented by a formula of the group:

wherein;

R⁷ is absent or represents from 1 to 4 substituents on the ring to which it is attached, independently selected from;

lower alkyl, hydroxyl, amino, alkoxyl, alkylamino, ═

O, acylamino and acyloxy;

R²⁰ is H, OH, or -T-U—

V—

R′

where;

T is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

;

U is absent or is —

C(O)—

, —

C(S)—

, —

S(O)—

or —

S(O)₂—

; and

V is absent or is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

, provided that V is absent when U is absent;

R²⁶ is H, OH or R′

;

R′

is independently selected from;

H, alkyl alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

R* is independently selected from;

H and lower alkyl;

q is 0 or 1;

E is an aldehyde, hydroxymethyl, carboxyl, or a protected form thereof;

P is H or a protecting group; and

G is absent or represents P,

or a pharmaceutically acceptable salt thereof.

6. A compound of claim 5 having one or more of the stereochemical configurations represented by the corresponding formula of the group:

7. The compound of any of claims 5 or 6 wherein:

R* is independently selected from;

H, methyl and ethyl;

E is an aldehyde, hydroxymethyl, carboxyl, CHO, CH₂OP, CH(OP)₂ or CO₂P; and

P is independently H or a protecting group selected from;

allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl, and protecting groups wherein two occurrences of P, taken together with the atoms through which they are connected, form a ring having 5-7 members.

8. The compound or salt of claim 7 where:

R²⁰ is H, OH, —

O₂C-lower alkyl or —

O₂C-alkenyl;

R²⁶ is H or CH₃;

R′

is independently selected from;

H and methyl;

q is 1;

E is OPMB, TBSO—

CH₂—

or —

C(O)H; and

/or

P is H, benzyl, OPMB or TBSO.

9. The compound or salt of claim 8 where:

R²⁰ is H, OH, —

O₂C—

CH₃, —

O₂C—

CH₂—

CH₂—

CH₃ or —

O₂C—

CH═

CH—

CH═

CH—

CH₂—

CH₂—

CH₃.

10. The compound of salt of claim 7 where:

R⁷ is absent;

R²⁶ is H or C₁-C₆ alky; and

q is zero in Formula 15 F.

11. The compound or salt of claim 7 where R²⁶ is H.

12. A compound having the structure represented by a formula of the group:

wherein;

R³ is H, OH or a protecting group;

R⁶ is H, H or ═

O;

R⁷ is absent or represents from 1 to 4 substituents on the ring to which it is attached, independently selected from;

lower alkyl, hydroxyl, amino, alkoxyl, alkylamino, ═

O, acylamino and acyloxy;

R⁸ is H, OH, ═

O, R′

, —

(CH₂)_nO(O)CR′

or (CH₂)_nCO₂-haloalkyl,

provided that R⁶ and R⁸ are not both ═

O;

R⁹ is H, OH or is absent;

R¹² and R^12a are independently H, OH, lower alkyl, lower alkoxyl, or lower acyloxy, or R¹² and R^12a taken together represent ═

O;

R²⁰ is H, OH, or -T-U—

V—

R′

where;

T is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

;

U is absent or is —

C(O)—

, —

C(S)—

, —

S(O)—

or —

S(O)₂—

; and

V is absent or is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

, provided that V is absent when U is absent;

R²¹ is ═

CR^aR^b or R²¹ represents independent moieties R^c and R^d where;

R^a and R^b are independently H, CO₂R′

, CONR^cR^d or R′

;

R^c and R^d are independently H, alkyl, alkenyl, alkynyl or (CH₂)_pCO₂R′

;

R²⁶ is H, OH or R′

;

R′

is independently selected from;

H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

L is a straight or branched linear, cyclic or polycyclic moiety, containing a continuous chain of preferably from 6 to 14 chain atoms, which substantially maintains the relative distance d of about 2.5 to 5.0 angstroms between the C1 and C17 atoms and the directionality, represented by the bold arrows, of the C1C2 and C16C17 bonds of naturally-occurring bryostatin;

X is —

CH₂—

, —

O—

, —

S—

or —

N(R^e)—

where R′

is COH, CO₂R′

or SO₂R′

,

Y is CH₂, —

O—

or —

N(H)—

;

Z is —

O—

or —

N(H)—

;

n is 0, 1, 2, 3, 4 or 5; and

p is 1, 2 or 3,

or a pharmaceutically acceptable salt thereof,

excluding the compounds of Formula 1998a where R³ is H or OH and where R²⁰ is —

O—

C(O)—

CH₃ or —

O—

C(O)—

(CH₂)₆—

CH₃, and the compounds of Formula 1998b where R⁸ is H or t-Bu;

13. A compound of claim 12 having one or more of the stereochemical configurations represented by the corresponding formula of the group:

14. A compound of claim 12 having the stereochemical configurations represented by the corresponding formula of the group:

15. The compound or salt of any of claims 12 to 14 where:

R⁷ is absent;

R⁸ is H, alkyl, aralkyl or —

O₂C-lower alkyl;

R²⁰ is H, OH, —

O₂C-lower alkyl or —

O₂C-alkenyl;

R²¹ is ═

C—

CO₂-lower alkyl;

R²⁶ is H or C₁-C₆ alky; and

X is —

CH₂—

or —

O—

.

16. The compound or salt of claim 15 where:

R³ is OH;

R⁸ is H, t-butyl, —

O₂C—

CH₃, —

O₂C—

C(CH₃)₃ or —

O₂C—

CH₂—

CH₂—

CH₃; and

R²⁰ is H, OH, —

O₂C—

CH₃, —

O₂C—

CH₂—

CH₂—

CH₃ or —

O₂C—

CH═

CH—

CH═

CH—

CH₂—

CH₂—

CH₃.

17. The compound or salt of claim 16 where R²⁶ is H.

18. A method for preparing a bryostatin analog, comprising a step selected from the group:

wherein;

R⁷ is absent or represents from 1 to 4 substituents on the ring to which it is attached, independently selected from;

lower alkyl, hydroxyl, amino, alkoxyl, alkylamino, ═

O, acylamino and acyloxy;

R²⁰ is H, OH, or -T-U—

V—

R′

where;

T is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

;

U is absent or is —

C(O)—

, —

C(S)—

, —

S(O)—

or —

S(O)₂—

; and

V is absent or is —

O—

, —

S—

, —

N(H)—

or —

N(Me)—

, provided that V is absent when U is absent;

R²⁶ is H, OH or R′

;

R′

is independently selected from;

H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

R* is independently selected from;

H and lower alkyl;

q is 0 or 1;

E is an aldehyde, hydroxymethyl, carboxyl, or a protected form thereof; and

P is H or a protecting group.

19. The method of claim 18 comprising a stereospecific synthesis wherein the starting material for Step 13a, 14a, 15c, 15d or 16d has one or more of the stereochemical configurations represented by formulae 12F, 12F, 15C, 15D or 16D, respectively:

20. The method of any of claims 18 or 19 wherein:

Step 13a takes place under reaction conditions including the presence of an acid;

Step 14a takes place under reaction conditions including the presence of an acid and an alcohol of the formula R*—

OH, where R* is lower alkyl;

Step 15c takes place under reaction conditions including the presence of an acid;

Step 15d takes place under reaction conditions including the presence of an alkyl glutarate ester; and

/or

Step 16d takes place under reaction conditions including the presence of a dienolate of an ester of acetoacetate.

21. The method of claim 20 wherein:

R⁷ is absent;

R²⁰ is R²⁰ is H, OH, —

O₂C-lower alkyl or —

O₂C-alkenyl;

R²⁶ is H or OH;

R′

is independently selected from;

H and methyl;

R* is independently selected from;

H, methyl and ethyl;

q is 1;

E is OPMB, TBSO—

CH₂—

or —

C(O)H; and

/or

P is H, benzyl, OPMB or TBSO.