Triptycene analogs

Details Triptycene analogs Triptycene analogs

2001-10-09

2004-12-07

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclohexadiene having atoms double bonded directly at the 1-...

C552S267000, C552S299000, C552S301000, C552S303000, C552S307000, C552S308000

Reexamination Certificate

active

06828450

ABSTRACT:

BACKGROUND OF THE INVENTION
As precursors of reactive quinone methides, many natural and synthetic quinones function as bioreductive alkylating agents and have antitumor activity. (See for example, Thomson R H, Naturally occuring quinones III: recent advances. New York: Chapman and Hall 1987; Moore H W, Science 1977, 197: 527-32; Lin A J, et al, J Med Chem 1972, 15: 1247-52; Lin A J, et al, J Med Chem 1973, 16: 1268-71; Lin A J, et al, J Med Chem 1974, 17: 558-61; Lin A J, et al, J Med Chem 1975, 18: 917-21). The cytotoxicity of quinones may be due to two competing mechanisms: soft electrophilic arylation and redox cycling oxidation. (See for example, Brunmark A, Cadenas E, Free Radical Biol Med 1989, 7:435-77; O'Brien P J, Chem-Biol Interact 1991, 80: 1-41; Monks T J, et al, Toxicol Appl Pharmacol 1992, 112: 2-16). While complete two-electron reduction of the quinone ring by DT diaphorase produces a stable hydroquinone, partial one-electron reduction of the quinone ring by NADPH-oxidizing enzymes yields an unstable semiquinone free radical (FR) that can spontaneously autoxidize at the expense of molecular O
2
to generate a cascade of reactive O
2
species (ROS) and FRs, which can induce DNA damage, lipid peroxidation and cytotoxicity. However, most quinone antitumor agents used clinically, such as anthracycline antibiotics, mitomycin C and benzoquinone derivatives, have a complex chemical structure with a number of active functional groups and the exact contribution of the quinone group to their antitumor activity remains uncertain. (See for example, Myers C E, Chabner B A, Anthracyclines. In: Chabner B A, Collins J M, eds. Cancer chemotherapy: principles and practice. Philadelphia: Lippincott 1990: 356-81; Rossi L, et al, Arch Biochem Biophys 1986, 251: 25-35; Begleiter A, et al, Cancer Res 1988, 48: 1727-35; Qiu X B, et al, Free Radical Biol Med 1998, 24: 848-54). The anthracycline quinone antibiotics adriamycin (ADR) and daunomycin (DAU) covalently bind to and intercalate into DNA, inhibit DNA replication and RNA transcription, are DNA topoisomerase (Topo) II poisons, produce oxidative stress and damage biomembranes, induce DNA breakage and chromosomal aberrations, trigger apoptosis and have a wide spectrum of anticancer activity. (See for example, Cadenas E, Free Radical Biol Med 1998, 24: 848-54; Liu L F, Annu Rev Biochem 1989, 58: 351-75; Mimnaugh E G, et al, Cancer Res 1985, 45: 3296-304; Ganapathi R, et al, Biochem Pharmacol 1990, 40: 1657-62; Ling Y-H, et al, Cancer Res 1993, 53: 1845-52; Ramachandran C, et al, Anticancer Res 1997, 17: 3369-76). However, the clinical effectiveness of DOX and DAU is severely limited by their cumulative cardiotoxicity and ability to induce multi-drug resistance, so it is important to develop drugs with improved bioactivity.
SUMMARY OF THE INVENTION
This invention provides analogs of triptycene which are useful as anticancer drugs, as well as for other uses. The potency of these compounds is in a similar magnitude as daunomycin, a currently used anticancer drug. Each compound of the invention produces one or more desired effects (blocking nucleoside transport, inhibiting nucleic acid or protein syntheses, decreasing the proliferation and viability of cancer cells, inducing DNA fragmentation or retaining their effectiveness against multidrug-resistant tumor cells).
More specifically, the invention provides triptycene analogs having the following formula:
wherein X is selected from the group consisting of: H, R, SR and NR
2
;
Y is selected from the group consisting of: halogen (preferably Cl, Br, I), R, NR
2
, SR and H;
R and R
1-2
are independently selected from the group consisting of: H, halogen, OR, and hydrocarbyl (preferably lower alkyl, allyl, phenyl, aryl, substituted alkyl, substituted allyl, substituted phenyl, —CH
2
—(CH
2
)
n
CO
2
H, —CH
2
—(CH
2
)
n
CH(NH
2
)CO
2
H, carboxylic acid, substituted carboxylic acid, amine, substituted amine, NHR, NR
2
, amino acid, RCO
2
(CH
2
)
n
NH, where one or both of the hydrogen atoms on CH
2
can be substituted with alkyl, allyl, phenyl, aryl, substituted allyl, substituted phenyl, substituted carboxylic acid, amine, or substituted amine, and where n is an integer from 0 to 8); R
3-4
, independently of one another, are selected from the group consisting of: H, halogen (preferably bromine), OR, R, SR and NR
2
; R
5
, independently of other R
5
s, is selected from the group consisting of: ═O, ═N—OH, and ═CHR; and reduced forms thereof; wherein in reduced forms, either ring A or ring C or both is replaced with
and wherein in reduced forms, each R
5
is independently H, C1-C8 alkyl or —OR;
and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
The numbering scheme used herein is shown in the example structure below:
Other compounds of the invention include those with formula:
wherein
R
5
is selected from the group consisting of: R, halogen, NR
2
, SR and H; R
6
is selected from the group consisting of: H, R, SR and NR
2
; R
7
and R
8
are independently selected from the group consisting of: H, halogen, OR and hydrocarbyl; R
17
and R
18
are independently selected from the group consisting of: H, halogen, (preferably bromine), R, SR and NR
2
; R
19
and R
20
are, independently of one another, H, R, or OR; (R
9
and R
10
) and (R
11
and R
12
) and (R
13
and R
14
) and (R
15
and R
16
) are together ═O or are independently H or —OR; R is selected from the group consisting of H, halogen, OR and hydrocarbyl; reduced forms thereof and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
Other compounds of the invention include those with formula:
wherein X is —NW(CW
2
)
n
Z, where the Ws are independently selected from the group consisting of: H, C1-C8 alkyl, and C1-C8 alkenyl and Z is selected from the group consisting of: R, COR, COOR, CONR
2
, OOCR and NRCOR;
Y is selected from the group consisting of: halogen, C1-C8 alkyl, C1-C8 alkenyl, OR, NR
2
, SR, H, COR, OCOR and NRCOR;
R and R
1-2
, are independently selected from the group consisting of: H, OR, and hydrocarbyl;
R
3-4
, independently of one another, are selected from the group consisting of: H, OR, SR, and NR
2
;
R
5
, independently of other R
5
s, is selected from the group consisting of: ═O, —H and —OT, where T is H or C1-C8 alkyl or alkenyl; and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
Other compounds of the invention include those with formula:
wherein X is selected from the group consisting of: H, R; SR and NR
2
;
Y is selected from the group consisting of: halogen, NR
2
, SR, H, and R;
R and R
1-2
, are independently selected from the group consisting of: H, halogen, OR, and hydrocarbyl;
R
3-4
, independently of one another, are selected from the group consisting of: H, halogen (preferably bromine), R, SR, and NR
2
;
R
5
, independently of other R
5
s, is selected from the group consisting of: ═O, ═NOH, ═C HR and reduced forms thereof;
R
21
and R
22
are independently selected from the group consisting of: H, R, and OR; and reduced forms thereof and pharmaceutically acceptable salts of the foregoing, as well as optical isomers thereof.
Also provided are compounds of the formula:
and the reduced forms thereof, wherein in said reduced forms, either ring A or ring C or both is reduced to
wherein all but one of X, Y, R1 and R2 is independently H, C1-C6 alkyl, C1-C6 alkenyl, OR, SR or NR2 wherein each R is independently H or C1-C6 alkyl and the other R1 or R2 is a solubilzing group; and each R5 is independently H, C1-C6 alkyl or OR. The solubilizing group may be of the formula: NR(CR
2
)
n
X wherein X is a sugar, R, COR, COOR, CONR
2
, OOCR and NRCOR; R is independently selected from the group consisting of: H, C1-C8 alkyl and C1-C8 alkenyl; n is an integer from 1 to 8.
Scheme 1 shows some of the compounds of the invention and abbreviations used herein.
Currently, the most preferred compounds include those compounds of the formulas listed above wherein at l

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