Oligocycloalkanoid compounds and methods of use

Details Oligocycloalkanoid compounds and methods of use Oligocycloalkanoid compounds and methods of use

2000-05-10

2003-05-13

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S414000, C514S419000, C514S533000, C514S548000, C514S563000, C514S572000, C514S573000, C514S574000, C514S601000, C514S619000, C514S623000, C514S691000, C514S715000, C514S729000, C530S300000, C548S455000, C548S496000, C560S040000, C560S173000, C562S499000, C564S082000, C564S084000, C564S098000, C564S152000, C564S153000, C564S155000, C564S159000, C564S188000, C568S367000, C568S664000, C568S816000

Reexamination Certificate

active

06562782

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel oligocycloalkanoid compounds, the synthesis thereof, and their methods of use.
BACKGROUND OF THE INVENTION
The design and synthesis of small, nonpeptide mimetics of polypeptide structure is a profoundly active field of research (Giannis et al.,
Chem. Int. Ed. Engl.
32:1244-1267 (1993). Peptidomimetics are of interest both from fundamental and applied perspectives (for therapeutic uses and the study of protein-protein interactions). From a practical perspective, nonpeptide compounds have several distinct advantages over their isostructural polypeptides. Firstly, polypeptides are readily recognized by peptidases and, therefore, have an extremely short lifetime in the digestive tract. Secondly, polypeptides often carry a significant number of charged moieties and, therefore, are limited in their ability to cross the blood/brain barrier. Finally, peptidomimetics are generally designed with conformational restraint in mind, allowing functional groups making up pharmacophoric moieties to be precisely positioned and gaining increased affinity for target proteins through structural rigidity.
Natural products have provided synthetic chemists with a variety of structurally novel and biologically interesting molecules. Two such natural products, which possess a repeating array of cyclopropanes, have been recently isolated. The first compound, denoted (−)-FR-900848, is a nucleoside containing natural product obtained from the fermentation broth of
Streptoverticillum fervens
HP-891, which displays potent and selective antifungal activity against
Aspergillus niger
(Yoshida et al.,
J. Antiboitics
43:748-754 (1990)). The second compound, denoted (−)-U-106305, is a potent inhibitor of cholesteryl ester transfer protein (“CETP”) (Kuo et al.,
J. Am. Chem. Soc.
117:10629-10634 (1995)). Because CETP catalyzes the transformation of high-density lipoproteins to low-density lipoproteins, CETP represents an interesting target to combat atheriosclerosis.
The propensity of cyclopropanes to impart rigidification into otherwise conformational mobile molecules has been used in the synthesis of constrained protease inhibitors (Lim et al.,
J. Org. Chem.
62:9382-9384 (1997)). Concurrently, methodology has been developed that uses these cyclopropanes as scaffolds for displaying functionality (Taylor et al.,
Org. Lett.
1:1257-1260 (1999); Theberge et al.,
J. Org. Chem.
61:8792-8798 (1996); and Taylor et al.,
Org. Lett.
2:601-603 (2000)). One example of the conformational bias afforded by cyclopropane moieties is the cyclopropanyl-containing molecule synthesized by Martin et al. (
J. Med. Chem.
41:1581-1597 (1998)), which demonstrated activity as an HIV-1 protease inhibitor.
Oligocyclopropanes may serve as powerful scaffolds for the recognition of a variety of biological targets. Yet oligocycloalkanes possessing larger cyclic rings (i.e., cyclobutane, cyclopentane, cyclohexane, etc.) are virtually unmnown. Dilkamural, a naturally-occurring compound that has been identified, contains two contiguous cyclopentane ring systems (Ninomiya et al.,
J. Org. Chem.
64:5436-5440 (1999)). While a simple, non-substituted ter-cyclopentane ring system is known (Goheen,
J. Am. Chem. Soc.
63:744-748 (1941)), no highly-substituted ter-cycloalkane ring systems are known, let alone therapeutic uses thereof.
The present invention is directed to overcoming these deficiencies in the art.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to an oligocycloalkanoid compound of formula (I)
wherein m, n, and o are independently an integer from 0 to 2; A
1
through A
10
are independently a direct link, alkylene, alkylene-O—, carbonyl, oxygen, or sulfur; X and Y are independently hydrogen, hydroxy, alkyl, or in combination an electrophilic group; and R
1
through R
10
are independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, N-, S-, or O-heterocycles, fused or multi-ring aryl with or without hetero ring members, arylalkyl, arylalkenyl, arylalkynyl, alkylphenyl, alkenylphenyl, alkynylphenyl, alkoxy, alkenyloxy, alkynyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, alkylacyl, alkenylacyl, alkynylacyl, arylacyl, aroyl, alkylaroyl, aminoaroyl, aminoakylacyl, aminoalkyl, aminoalkenyl, aminoalkynyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, dialkylamino, dialkenylamino, dialkynylamino, arylalkylamino, arylalkenylamino, imino, alkylimino, alkenylimino, alkynylimino, arylimino, thiol, sulfoxide, alkyl sulfonamide, alkenyl sulfonamide, alkynyl sulfonamide, aryl sulfonamide, alkyl sulfonate ester, alkenyl sulfonate ester, alkynyl sulfonate ester, aryl sulfonate ester, amino acid, or polypeptide, with at least one of R
1
through R
4
and at least one of R
7
through R
10
being other than hydrogen. A pharmaceutical composition including the oligocycloalkanoid compound of formula (I) in a pharmaceutically acceptable carrier is also disclosed.
Another aspect of the present invention relates to methods of making oligocycloalkanoid compounds of the present invention, by reacting a compound selected from the group of an R
1
to R
10
precursor, an oxidizing agent, a reducing agent, or a deprotecting agent with a compound of formula (II) under conditions effective to prepare an oligocycloalkanoid compound of the present invention
wherein m, n, and o are independently an integer from 0 to 2; A
11
-A
20
are independently alkylene, alkylene-O—, carbonyl, oxygen, or sulfur; X and Y are independently hydrogen, hydroxy, alkyl, or in combination an electrophilic group; and R
11
-R
20
are independenly hydrogen, hydroxy, alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, N-, S-, or O-heterocycles, fused or multi-ring aryl with or without hetero ring members, arylalkyl, arylalkenyl, arylalkynyl, alkylphenyl, alkenylphenyl, alkynylphenyl, alkoxy, alkenyloxy, alkynyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, alkylacyl, alkenylacyl, alkynylacyl, arylacyl, aroyl, alkylaroyl, aminoaroyl, aminoakylacyl, aminoalkyl, aminoalkenyl, aminoalkynyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, dialkylamino, dialkenylamino, dialkynylamino, arylalkylamino, arylalkenylamino, imino, alkylimino, alkenylimino, alkynylimino, arylimino, thiol, sulfoxide, alkyl sulfonamide, alkenyl sulfonamide, alkynyl sulfonamide, aryl sulfonamide, alkyl sulfonate ester, alkenyl sulfonate ester, alkynyl sulfonate ester, aryl sulfonate ester, amino acid, polypeptide, leaving group, or protecting group, with at least one of R
11
through R
14
and at least one of R
17
through R
20
being other than hydrogen.
A further aspect of the present invention relates to a method of treating a bacterial infection. This treatment method is carried out by providing an oligocycloalkanoid compound of the present invention and then administering a bacteriacidally effective amount of the oligocycloalkanoid compound to a patient having a bacterial infection, under conditions effective to treat the bacterial infection.
Another aspect of the present invention relates to a method of inhibiting or treating septic shock. This treatment method is carried out by providing an oligocycloalkanoid compound of the present invention and then administering an effective amount of the oligocycloalkanoid compound to a patient having a bacterial infection, under conditions effective to inhibit or treat septic shock resulting from the bacterial infection.
Still another aspect of the present invention relateds to a method of treating a disease caused by bacterial endotoxin. This treatment method is carried out by providing an oligocycloalkanoid compound of the present invention and then administering an effective amount of the oligocycloalkanoid compound to a patient having a bacterial infection, under conditions effective to neutralize bacterial endotoxin and thereby treat the disease caused bacterial endotoxin.
A further aspect of the present invention relates to a meth

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