Tricyclic and tetracyclic pyrones

Details Tricyclic and tetracyclic pyrones Tricyclic and tetracyclic pyrones

1999-06-24

2002-05-07

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S224500, C514S229800, C514S267000, C514S287000, C514S292000, C514S293000, C514S338000, C514S432000, C514S434000, C514S437000, C514S452000, C514S453000, C514S454000, C514S455000, C544S032000, C544S034000, C544S095000, C544S250000, C544S251000, C546S064000, C546S065000, C546S080000, C546S081000, C546S082000, C546S083000, C546S089000, C546S090000, C546S092000, C546S280100, C546S282400, C546S282700, C546S283100, C549S016000, C549S017000, C549S024000, C549S025000, C549S026000, C549S027000, C549S276000, C549S

Reexamination Certificate

active

06384045

ABSTRACT:

BACKGROUND OF THE INVENTION
It was recently discovered that arisugacin, a natural product isolated from a culture of Penicillium, is an inhibitor of acetylcholinesterase (AChE), and on this basis arisugacin has been predicted to be effective in the treatment of Alzheimer's disease. Related compounds also showed inhibitory activity. Omura, S., et al. (1995), “Arisugacin, a Novel and Selective Inhibitor of Acetylcholinesterase from Penicillium sp. FO-4259,” J. Antibiotics 48:745-746. Arisugacin and the related compounds are tetracyclic pyrones (having four fused rings). Other tetracyclic pyrones, certain pyripyropenes, have been shown to be inhibitors of cholesterol acyltransferase (ACAT), and therefore have been predicted to be effective in the treatment of atherosclerosis and hypercholesterolemia. Omura, S., et al. (1993), “Pyripyropenes, Highly Potent Inhibitors of Acyl-CoA; Cholesterol Acyltransferase Produced by
Aspergillus fumigatus,”
J. Antibiotics 46:1168-1169; and “Kim, Y. K. et al. (1994), “Pyripyropenes, Novel Inhibitors of Acyl-CoA:Cholesterol Acyltransferase Produced by
Aspergillus fumigatus,”
J. Antibiotics 47:154-162. Pyripyropene A, one such inhibitor, is further characterized in Tomoda, H., et al. (1994), “Relative and Absolute Stereochemistry of Pyripyropene A, A Potent, Bioavailable Inhibitor of Acyl-CoA:Cholesterol Acyltransferase (ACAT),” J. Am. Chem. Soc. 116:12097-12098.
A number of multicyclic pyrones are known to the art and described in Chemical Abstracts; however, tricyclic and tetracyclic pyrones as disclosed and claimed herein, appear not to have been previously described.
There is a need for simpler inhibitors of AchE and ACAT that are useful as treatments for Alzheimer's disease, atherosclerosis and hypercholesterolemia.
SUMMARY OF THE INVENTION
The tricyclic and tetracyclic pyrones of this invention are useful as inhibitors of AChE and ACAT, and can be used in the treatment of Alzheimer's disease, atherosclerosis and Kit hypercholesterolemia. The tricyclic compounds are also potent inhibitors of cancer cell growth and macromolecule synthesis (e.g., DNA, RNA and protein synthesis) and can be used in the treatment of various forms of cancers including leukemia, ascites, and solid tumors. Further, their short-term inhibition of macromolecule synthesis is reversible following removal, but their long-term inhibition of tumor cell growth is not. Importantly, the tricyclic compounds are also powerful inhibitors of tubulin polymerization and may be useful as cell cycle-specific anticancer drugs. As hereinafter described, certain of these pyrones are useful intermediates in the synthesis of other pyrones of this invention. The tricyclic compounds are cytostatic but not overly cytotoxic.
The tricyclic pyrones of this invention include compounds selected from the group of compounds of the formula:
wherein:
T is independently CH, N, S or O;
X is independently O, NH or S;
Y is independently O, NH or S;
Z is independently CH, N, S or O;
R
1
is independently Formula I; or
R
1
and R
3
and R
4
and R
5
are, independently, H, OH, alkyl, alkenyl, alkynyl, an aromatic ring system,
 wherein R and M are independently H, alkyl, alkenyl or alkynyl, an aromatic ring system, amino, amido, sulfhydryl, or sulfonyl, W is Cl, F, Br or OCI, and A is an aromatic ring system;
R
2
and R
9
are independently H or R where R is as defined above.
As used herein, the term “aromatic ring system” includes five and six-membered rings, fused rings, heterocyclic rings having oxygen, sulfur or nitrogen as a ring member, OR-substituted and R-substituted aromatic rings where R is defined as above. Preferably the substituents have one to five carbons. As used herein, the terms “alkyl,” “alkenyl,” an “alkynyl” include C1-C6 straight or branched chains. Unless otherwise specified, a general formula includes all stereoisomers.
Compounds of this invention also include compounds of the formula:
wherein:
X, Y and R
2
-R
3
are as set forth for Formula I;
R
1
is independently Formula II or as set forth for Formula I;
R
15
is independently NH
2
, OH, or OCOR′ where R′ is H, or alkyl;
R
16
is independently OH or H; and
R
15
and R
16
taken together are O;
compounds of the formula:
wherein:
X, Y, T, Z and R
2
and R
3
are as set forth in Formula I:
R
1
is independently Formula III or as set forth for Formula I; and
R
6
is H when R
7
is OH, or R
6
is OH when R
7
is H, or R
6
and R
7
taken together are ═O;
compounds of the formula:
wherein R
1
is independently Formula IV or as set forth for Formula I, and R
3
is as set forth for Formula I above; and R
2
, R
4
R
3
for Formula I above;
and compounds of the formula:
wherein R
1
is Formula V or independently is as set forth for Formula I above.
The tetracyclic pyrones of this invention include compounds selected from the group of compounds of the formula:
wherein:
R
1
and R
2
are independently as defined as R
3
as set forth for Formula I above;
R
10
and R
11
and R
13
and R
14
are independently defined as R
3
as set forth for Formula I above; and
R
12
is H, alkyl, alkenyl or alkynyl, an aromatic ring system, amino, amido, sulfhydryl, or sulfonyl.
A preferable class of compounds of this invention useful as macromolecule synthesis inhibitors in cancer cells are compounds selected from compounds of the formula:
wherein:
R
1
is independently selected from the group consisting of H, R, 3-pyridyl, R-substituted 3-pyridyl, phenyl, R-substituted, di-substituted and tri-substituted phenyl, O—R-substituted, di-substituted and tri-substituted phenyl where R is as defined above; and preferably comprises an aromatic ring;
R
2
and R
9
are independently selected from the group consisting of H and R, where R is as defined above;
R
3
, R
4
and R
5
are independently selected from the group H, R, OH, OCHO, and OR where R is as defined above; and
T and Z are independently selected from the group consisting of CH, N, S or O.
Most preferably, the compounds are selected from the group consisting of compounds of Formula 1 wherein:
R
1
is independently selected from the group consisting of alkyl, 3-pyridyl and 3,4-dimethoxyphenyl; preferably 3-pyridyl or 3,4-dimethoxyphenyl;
R
2
is independently selected from the group consisting of H and CH
3
;
R
3
is independently selected from the group of H, OH, and OCHO;
R
4
and R
5
are independently H;
R
9
is independently selected from the group of H and isopropenyl; and
T and Z are independently CH.
Throughout the specification hereof, chemical structures are depicted and numerically labelled. The names of the numbered structures are set forth in Table 1 and indicated in boldface in the text.
TABLE 1
Names of Structures
1A
3-methyl-1H-5a,6,7,8,9-pentahydro-1-oxopyrano[4,3-b]-
[i]benzopyran
1B
cis-3-5a-dimethyl-6-hydroxy-1H-5a,6,7,8,9-pentahydro-1-
oxopyrano[4,3-b][1]benzopyran
1C
trans-3-5a-dimethyl-6-hydroxy-1H-5a,6,7,8,9-pentahydro-1-
oxopyrano[4,3-b][1]benzopyran
1D
cis-3-5-a-dimethyl-6-formyloxy-1H-5a,6,7,8,9-pentahydro-1-
oxopyrano[4,3-b][1]benzopyran
1E
trans-3-5a-dimethyl-6-formyloxy-1H-5a,6,7,8,9-pentahydro-1-
oxopyrano[4,3-b][1]benzopyran
2A
3-(3-pyridyl)-1H-5a,6,7,8,9-pentahydro-1-oxopyrano[4,3-
b][1]benzopyran
2B
cis-3-(3-pyridyl)-5a-methyl-6-hydroxy-1H-5a,6,7,8,9-pentahydro-
1-oxopyrano[4,3-b][1]benzopyran
2C
trans-3-(3-pyridyl)-5a-methyl-6-hydroxy-1H-5a,6,7,8,9-
pentahydro-1-oxopyrano[4,3-b][1]benzopyran
2D
cis-3-(3-pyridyl)-5a-methyl-6-formyloxy-1H-5a,6,7,8,9-
pentahydro-1-oxopyrano[4,3-b][1]benzopyran
2E
trans-3-(3-pyridyl)-5a-methyl-6-formyloxy-1H-5a,6,7,8,9-
pentahydro-1-oxopyrano[4,3-b][1]benzopyran
3A
3-(3,4-dimethoxyphenyl)-1H-5a,6,7,8,9-pentahydro-1-
oxopyrano[4,3-b][1]benzopyran
3B
cis-3-(3,4-dimethoxyphenyl)-5a-methyl-6-hydroxy-1H-5a,6,7,8,9-
pentahydro-1-oxopyrano[4,3-b][1]benzopyran
3C
trans-3-(

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