Therapeutic compounds and methods of use

Details Therapeutic compounds and methods of use Therapeutic compounds and methods of use

1999-06-17

2001-12-04

Higel, Floyd D. (Department: 1613)

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

Organic compounds

Nitriles

C558S423000, C514S519000

Reexamination Certificate

active

06326507

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to compounds which have been found to be useful for prevention or treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, rheumatoid arthritis, and other inflammatory diseases.
One of the major needs in cancer prevention is the development of effective and safe new agents for chemoprevention. In particular, there is a need for chemopreventative agents targeted at mechanisms known to be involved in the process of carcinogenesis. In recent years, there has been a resurgence of interest in the study of mechanisms of inflammation that relate to carcinogenesis and in the use of such mechanisms as the basis for development of new chemopreventative agents.
The concept that inflammation and carcinogenesis are related phenomena has been the subject of many studies that have attempted to link these two processes in a mechanistic fashion (Sporn and Roberts, 1986; Ohshima and Bartsch, 1994). The enzymes that mediate the constitutive synthesis of NO and prostaglandins from arginine and arachidonate, respectively, have relative little significance for either inflammation or carcinogenesis. In contrast, inducible nitric oxide synthase (iNOS) and inducible cycloxygenase (COX-2) both have critical roles in the response of tissues to injury or infectious agents (Moncada et al., 1991; Nathan and Xie, 1994; Siebert and Masferrer, 1994; Tamir and Tannebaum, 1996). These inducible enzymes are essential components of the inflammatory process, the ultimate repair of injury, and carcinogenesis. While physiological activity of iNOS and COX-2 may provide a definite benefit to the organism, aberrant or excessive expression of either iNOS or COX-2 has been implicated in the pathogenesis of many disease processes, particularly in chronic degeneration of the central nervous system, carcinogenesis, septic shock, cardiomyopathy, and rheumatoid arthritis.
Triterpenoids, biosynthesized in plants by the cyclization of squalene, are used for medicinal purposes in many Asian countries; and some, like ursolic and oleanolic acids, are known to be anti-inflammatory and anti-carcinogenic (Huang et al., 1994; Nishino et al., 1988). However, the biological activity of these naturally occurring molecules is relatively weak, and therefore the synthesis of new analogs to enhance their potency was undertaken (Honda et al., 1997; Honda et al., 1998). It was previously reported that several such synthetic analogs can suppress the de novo formation of iNOS and COX-2 in macrophages that have been stimulated by IFN-&ggr; or LPS (Suh et al., 1998). The role of both iNOS and COX-2 as enhancers of carcinogenesis in many organs is receiving increasing attention (Ohshima et al., 1994; Tamir et al., 1996; Takahashi et al., 1997; Ambs et al., 1998; Tsujii et al., 1998; Oshima et al., 1996; Hida et al., 1998; Huang et al, 1998); suppression of either the synthesis or the activity of these enzymes is therefore a target for chemoprevention (Oshima et al., 1998; Kawamori et al., 1998). Agents which induce differentiation or suppress proliferation of premalignant or malignant cells represent yet another mechanistic approach to chemoprevention, as well as to chemotherapy, of cancer.
SUMMARY OF THE INVENTION
The present invention provides methods and compositions for the prevention or treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The methods of the invention involve administering to a subject a therapeutic compound of the formula:
wherein A or B is a single or double bond and C
11
or C
12
have substituted thereon ═X which is an organic or inorganic moiety; R
1
is an organic or inorganic moiety which may be substituted anywhere on the six-membered ring denoted by positions 1 through 10; R
2
and R
3
are hydrogen or organic or inorganic moieties, wherein an R
2
group may be substituted anywhere on the structure represented in the formula; and n is a number from 0 to 100.
The invention further relates to therapeutic compositions and methods of their use having the formula
wherein either A or B is a double bond such that when A is a double bond, C
11
has substituted thereon ═X which is an organic or inorganic moiety and when B is a double bond, C
12
has substituted thereon ═X; R
1
is an organic or inorganic moiety which may be substituted anywhere on the six-membered ring denoted by positions 1 through 10; R
2
and R
3
are hydrogen or organic or inorganic moieties, wherein an R
2
group may be substituted anywhere on the structure represented in formula (I); and n is a number from 0 to 100).
Accordingly, in an embodiment the compositions and methods of the invention are useful for prevention or treatment of disorders such as cancer; neurodegenerative diseases (NDDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS); inflammatory diseases, e.g., inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; and rheumatoid arthritis (RA). The methods of the invention can be used therapeutically to prevent or treat such conditions in a subject. The methods are based, at least in part, on the discovery that the presently disclosed compounds have been found to suppress transcription or translation of iNOS and COX-2 genes, the overexpression of which is linked with excess NO and/or prostaglandin formation.
In a further aspect the invention relates to triterpenoid compositions effective for modulating interferon-&ggr; (IFN-&ggr;)-induced NO production in macrophages, said composition having an IC
50
value of at least less than 0.6 &mgr;M, preferably less than 0.001 &mgr;M.
In another aspect a method of preventing or treating a disorder characterized by overexpression of iNOS or COX-2 genes is presented, comprising administering to a subject a pharmaceutically effective amount of a composition of formula (I), such that the disorder is prevented or treated. Such disorders include cancer; neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis; and rheumatoid arthritis.
In a further aspect a method of modulating transcription or translation of iNOS or COX-2 genes in a subject comprises administering to a subject a pharmaceutically effective amount of a composition of formula (I), such that the transcription or translation of iNOS or COX-2 genes is modulated.
In yet another aspect a method of modulating excessive nitric oxide or prostaglandin formation in a subject is presented, comprising administering to a subject a pharmaceutically effective amount of a composition of formula (I), such that nitric oxide or prostaglandin formation is modulated.


REFERENCES:
patent: 4395423 (1983-07-01), Neumann
Bogdan, C. et al., “Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10,”J. Biol. Chem. (1992), 267:23301-23308.
Clinton, R.O. et al., “Steroidal[3,2-c]pyrazoles. II. Androstanes, 19-norandrostanes and their unsaturated analogs,”J. Am. Chem. Soc. (1961), 83:1478-1491.
Dean, PDG. et al., “Halogenolysis of methyl glycyrrhetate with lithium iodidedimethylformamide,”J. Chem. Soc. (1965), 6655-6659.
Ding, A. et al., “Macrophage deactivating factor and transforming growth factors-beta1, beta2, and beta3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma,”J. Immunol. (1990), 940-944.
Honda, T. et al., “New enone derivatives of oleanolic acid and ursolic acid as inhibitors of nitric oxide production in mouse macrophages,”Bioorg. Med. Chem. Lett., 7:1623-1628 (1997).
Johnson, W.S. et al., “A plan for distinguishing between some five- and six-membered ring ketones,”J. Am. Chem. Soc. (1945), 67:1745-1754.
Picard, C.W. et al., “The triterpene resinols and related acids, part VI,”J. Chem. Soc. (1939), 1045-1048.
Sharpless, K.B. et al., “Electrophilic and nucleophilic organoselenium reagent

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