Phorboxazole compounds and methods of their preparation

1. A compound of formula XIX:

wherein:

R 1 is alkyl, alkenyl, haloalkenyl, or alkynyl;

each R 2 is independently H, alkyl, aralkyl, or aryl;

each dotted line indicates independently the presence of a single or double bond; and

each Z is H or taken together form an exocyclic methylene moiety;

provided that when the compound of formula XIX has the structure:

R 2 is H or methyl;

then R 1 is other than:

wherein said alkyl, alkenyl, alkynyl and aryl groups are optionally substituted with one or more of halo, alkyl, cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl, oxo, nitro, cyano, amino, —N-substituted amino (—NHR″), —N,N-disubstituted amino (—N(R″)R″), carboxy, —O—C(═O)R″, —C(═O)R″, —OR″, —C(═O)OR″, —NHC(═O)R″, aminocarbonyl, —N-substituted aminocarbonyl (—C(═O)NHR″), —N,N-disubstituted aminocarbonyl (—C(═O)N(R″)R″), thiol, thiolato (—SR″), sulfonic acid (—SO 3 H), phosphonic acid (—PO 3 H), —P(═O)(OR″)OR″, S(═O)R″, —S(═O) 2 R″, —S(═O) 2 NH 2 , —S(═O) 2 NHR″, —S(═O) 2 NR″R″, —NHS(═O) 2 R″, —NR″S(═O) 2 R″, —CF 3 , —CF 2 CF 3 , —NHC(═O)NHR″, —NHC(═O)NR″R″, —NR″C(═O)NHR″, —NR″C(═O)NR″R″, or —NR″C(═O)R″ where each R″ is, independently, H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, or two R″ groups that are attached to the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocycloalkyl ring, wherein one or two of the heterocycloalkyl ring carbon atoms independently may be optionally replaced by —O—, —S—, —SO, —SO 2 —, —NH—, —N(alkyl)-, —N(acyl)-, N(aryl)-, or —N(aroyl)-groups.

2. A compound of claim 1 of the following formula:

3. A compound of claim 1 of the following formula:

4. A compound of claim 3 wherein R 1 is:

5. A process for preparing a compound of formula XIX:

wherein:

R 1 is alkyl, alkenyl, haloalkenyl, or alkynyl;

each R 2 is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group;

each dotted line indicates independently the presence of a single or double bond; and

each Z is H or taken together form an exocyclic methylene moiety,

comprising the steps of:

contacting a compound of formula XX:

with a compound of formula XXI:

wherein:

R 1 is alkyl, alkenyl, haloalkenyl, or alkynyl; and

each R 2 is independently H, alkyl, aralkyl, aryl, or hydroxyl protecting group;

for a time and under conditions effective to provide a compound of formula XIX;

wherein said alkyl, alkenyl, alkynyl and aryl groups are optionally substituted with one or more of halo, alkyl, cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl, oxo, nitro, cyano, amino, —N-substituted amino (—NHR″), —N,N-disubstituted amino (—N(R″)R″), carboxy, —O—C(═O)R″, —C(═O)R″, —OR″, —C(═O)OR″, —NHC(═O)R″, aminocarbonyl, —N-substituted aminocarbonyl (—C(═O)NHR″), —N,N-disubstituted aminocarbonyl (—C(═O)N(R″)R″), thiol, thiolato (—SR″), sulfonic acid (—SO 3 H), phosphonic acid (—PO 3 H), —P(═O)(OR″)OR″, S(═O)R″, —S(═O)) 2 R″, —S(═O) 2 NH 2 , —S(═O) 2 NHR″, —S(═O)NR″R″, —NHS(═O) 2 R″, —NR″S(═O) 2 R″, —CF 3 , —CF 2 CF 3 , —NHC(═O)NHR″, —NHC(═O)NR″R″, —NR″C(═O)NHR″, —NR″C(═O)NR″R″, or —NR″C(═O)R″ where each R″ is, independently, H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, or two R″ groups that are attached to the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocycloalkyl ring, wherein one or two of the heterocycloalkyl ring carbon atoms independently may be optionally replaced by —O—, —S—, —SO, —SO 2 —, —NH—, —N(alkyl)-, —N(acyl)-, N(aryl)-, or —N(aroyl)-groups.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 4 .

8. A method for treating cancer in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a compound of claim 1 , wherein the cancer treated is selected from the group consisting of pancreatic, breast, non-small lung, colon, and prostate cancers.

9. A compound of formula XXII:

wherein:

G is —O— or —CH 2 —;

Q is H or OR 2 , provided that when G is —O—, then Q is H;

R 1 is alkyl, alkenyl, haloalkenyl, or alkynyl;

each R 2 is independently H, alkyl, aralkyl, or aryl;

each dotted line indicates independently the presence of a single or double bond; and

each Z is H or taken together form an exocyclic methylene moiety;

provided that when the compound of formula XXII has the structure:

R 2 is H or methyl;

then R 1 is other than:

wherein said alkyl, alkenyl, alkynyl and aryl groups are optionally substituted with one or more of halo, alkyl, cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl, oxo, nitro, cyano, amino, —N-substituted amino (—NHR″), —N,N-disubstituted amino (—N(R″)R″), carboxy, —O—C(═O )R″, —C(═O)R″, —OR″, —C(═O)OR″, —NHC(═O)R″, aminocarbonyl, —N-substituted aminocarbonyl (—C(═O)NHR″), —N,N-disubstituted aminocarbonyl (—C(═O)N(R″)R″), thiol, thiolato (—SR″), sulfonic acid (—SO 3 H), phosphonic acid (—PO 3 H), —P(═O)(OR″)OR″, S(═O)R″, —S(═O) 2 R″, —S(═O) 2 NH 2 , —S(═O) 2 NHR″, —S(═O) 2 NR″R″, —NHS(═O) 2 R″, —NR″S(═O) 2 R″, —CF 3 , —CF 2 CF 3 , —NHC(═O)NHR″, —NHC(═O)NR″R″, —NR″C(═O)NHR″, —NR″C(═O)NR″R″, or —NR″C(═O)R″ where each R″ is, independently, H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, or two R″ groups that are attached to the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocycloalkyl ring, wherein one or two of the heterocycloalkyl ring carbon atoms independently may be optionally replaced by —O—, —S—, —SO, —SO 2 —, —NH—, —N(alkyl)-, —N(acyl)-, N(aryl)-, or —N(aroyl)-groups.

10. A compound of claim 9 of the following formula:

11. A compound of claim 9 of the following formula:

12. A compound of claim 11 wherein R 1 is ethyl, ethenyl, or ethynyl.

13. A compound of claim 12 wherein the ethenyl is optionally substituted with halo.

14. A compound of claim 13 wherein the halo is bromo or chloro.

15. A compound of claim 12 wherein R 1 is:

16. A compound of claim 12 wherein R 1 is:

17. A process for preparing a compound of formula XXII:

wherein:

G is —O— or —CH 2 —;

Q is H or OR 2 , provided that when G is —O—, then Q is H;

R 1 is alkyl, alkenyl, haloalkenyl, or alkynyl;

each R 2 is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group;

each dotted line indicates independently the presence of a single or double bond; and

each Z is H or taken together form an exocyclic methylene moiety, comprising the steps of:

contacting a compound of formula XXIII:

with a compound of formula XXIV:

wherein:

R 1 is alkyl, alkenyl, haloalkenyl, or alkynyl; and

each R 2 is independently H, alkyl, aralkyl, aryl, or hydroxyl protecting group;

for a time and under conditions effective to provide a compound of formula XXIII;

wherein said alkyl, alkenyl, alkynyl and aryl groups are optionally substituted with one or more of halo, alkyl, cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl, oxo, nitro, cyano, amino, —N-substituted amino (—NHR″), —N,N-disubstituted amino (—N(R″)R″), carboxy, —O—C(═O)R″, —C(═O)R″, —OR″, —C(═O)OR″, —NHC(═O)R″, aminocarbonyl, —N-substituted aminocarbonyl (—C(═O)NHR″), —N,N-disubstituted aminocarbonyl (—C(═O)N(R″)R″), thiol, thiolato (—SR″), sulfonic acid (—SO 3 H), phosphonic acid (—PO 3 H), —P(═O)(OR″)OR″, S(═O)R″, —S(═O) 2 R, —S(═O) 2 NH 2 , —S(═O) 2 NHR″, —S(═O) 2 NR″R″, —NHS(═O) 2 R″, —NR″S(═O) 2 R″, —CF 3 , —CF 2 CF 3 , —NHC(═O)NHR″, —NHC(═O)NR″R″, —NR″C(═O)NHR″, —NR″C(═O)NR″R″, or —NR″C(═O)R″ where each R″ is, independently, H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, or two R″ groups that are attached to the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a 3- to 8- membered heterocycloalkyl ring, wherein one or two of the heterocycloalkyl ring carbon atoms independently may be optionally replaced by —O—, —S—, —SO, —SO 2 —, —NH—, —N(alkyl-, —N(acyl)-, N(aryl)-, or —N(aroyl)-groups.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 9 .

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 16 .

20. A method of inducing apoptosis in malignant cells in vitro, comprising the step of:

contacting said cells with an effective amount of a compound according to claim 9 .

21. A method for treating cancer in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a compound of claim 9 , wherein the cancer treated is selected from the group consisting of pancreatic, breast, non-small lung, colon, and prostate cancers.