Inositol derivatives for inhibiting superoxide anion production

Details Inositol derivatives for inhibiting superoxide anion production Inositol derivatives for inhibiting superoxide anion production

1999-02-03

2001-04-24

Carr, Deborah (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S102000, C514S110000, C554S078000, C554S229000

Reexamination Certificate

active

06221856

ABSTRACT:

TABLE OF CONTENTS
Page
1.
FIELD OF THE INVENTION
 1
2.
BACKGROUND OF THE INVENTION
 1
3.
SUMMARY OF THE INVENTION
 4
4.
DESCRIPTION OF THE FIGS.
13
5.
DETAILED DESCRIPTION OF THE INVENTION
13
 5.1. INOSITOL DERIVATIVES
13
 5.2. SYNTHESIS OF THE INOSITOL DERIVATIVES
16
  5.2.1. THE COMPOUNDS OF FORMULA (I)
16
  5.2.2. THE COMPOUNDS OF FORMULA (II)
19
6.
METHODS FOR USE OF THE INOSITOL DERIVATIVES
20
7.
EXAMPLE: INHIBITION OF f-METHIONINE-LEUCINE-
28
PHENYLALANINE-STIMULATED SUPEROXIDE ANION
PRODUCTION IN HUMAN NEUTROPHILS BY
D-2,3-DI-O-BUTYRYL-MYO-INOSITOL 1,4,5,6-
TETRAKISPHOSPHATE OCTAKIS(ACETOXY-
METHYL)ESTER
8.
EXAMPLE: INHIBITION OF f-METHIONINE-LEUCINE-
29
PHENYLALANINE-STIMULATED SUPEROXIDE ANION
PRODUCTION IN HUMAN NEUTROPHILS BY SN-DI-O-
PALMITOYL-D,L-6-O-BUTYRYL-PHOSPHATIDYLINO-
SITOL 3,4,5,-TRISPHOSPHATE HEPTAKIS(ACETOXY-
METHYL)ESTER
9.
EXAMPLE: INHIBITION OF f-METHIONINE-LEUCINE-
30
PHENYLALANINE-STIMULATED SUPEROXIDE ANION
PRODUCTION IN HUMAN NEUTROPHILS BY
D-2,3-DI-O-BUTYRYL-MYO-INOSITOL 1,4,5,6-
TETRAKISPHOSPHATE OCTAKIS(ACETOXY-
METHYL)ESTER AND D-2,3-DI-O-BUTYRYL-MYO-
INOSITOL 1,4,5,6-TETRAKISPHOSPHATE
OCTAKIS(ACETOXYMETHYL)ESTER + SN-DI-O-
PALMITOL-D,L,6,O-BUTYRYL-PHOSPHATIDYLINO-
SITOL 3,4,5-TRISPHOSPHATE HEPTAKIS(ACETOXY-
METHYL)ESTER
10.
EXAMPLE: INHIBITION OF f-METHIONINE-LEUCINE-
32
PHENYLALANINE- OR PHORBOL ESTER-STIMULATED
SUPEROXIDE ANION PRODUCTION IN HUMAN
NEUTROPHILS BY SN-DI-O-PALMITOL-D,L-6-O-
BUTYRYL-PHOSPHATIDYLINOSITOL 3,4,5-
TRISPHOSPHATE HEPTAKIS(ACETOXY-
METHYL)ESTER
11.
EXAMPLE: PRODUCTION OF PHOSPHATIDYLINO-
33
SITOL 3,4,5-TRISPHOSPHATE BY f-METHIONINE-
LEUCINE-PHENYLALANINE-STIMULATED
NEUTROPHILS OF A CROHN'S DISEASE PATIENT
ABSTRACT
50
1. FIELD OF THE INVENTION
The present invention was made with government support under grant no.
1RO1-DK47240-01A1 awarded by the National Institutes of Health. The government has certain rights in the invention.
The present invention relates to inositol derivatives that inhibit the production of superoxde anion, which can result from inflammation and from non-inflammatory conditions and which can lead to oxidative damage of tissues and pathological conditions. The present invention also relates to compositions comprising the inositol derivatives and methods for their use for preventing or treating in mammals conditions such as inflammation that cause superoxide anion production, oxidative damage of tissues, and pathological conditions caused by superoxide anion production.
2. BACKGROUND OF THE INVENTION
Superoxide anion is formed by macrophages and polymorphonuclear leukocytes, also known as neutrophils as a byproduct of oxygen metabolism. Macrophages and neutrophils are distributed throughout most tissues and play a role in inflammation, in host defense, and in reactions against a number of autologous and foreign substances. As major players in the inflammatory response, they are attracted to sites of injury or disease by cytokines released at these sites. While superoxide anion can function as a microbicidal agent that helps degrade tissue damaged from external or internal trauma, it can also have destructive effects. The presence of superoxide anion can lead to the formation of other reactive and tissue-damaging species such as HOCl and H
2
O
2
. In the presence of Fe
2+
, H
2
O
2
can proceed to form hydroxyl radical which can be highly destructive to surrounding tissue.
Superoxide anion is produced in response to inflammation or of non-inflammatory conditions, such as adult respiratory distress syndrome, and can lead to significant tissue injury (S. L. Leib et al.,
J. Clin. Invest.
98(1 1):2632-2639 (1996); R. A. Miller et al.,
J. Invest. Med.
43(1):39 (1995); and J. Jackson et al.,
Hematology/Oncology Clinics of North America
2(2):317-34 (1988)). Inflammation accompanies a variety of disorders, including eczema, inflammatory bowel disease, rheumatoid arthritis, asthma, psoriasis, ischemia/reperfusion injury, ulcerative colitis and acute respiratory distress syndrome. These disorders can be chronic and, in severe cases, life-threatening. In addition, acute inflammation can follow a heart attack or stroke and often results in irreparable damage to surrounding tissue.
Exposure of tissues to superoxide anion radical can lead to oxidative stress and tissue damage, which can contribute to the development of pathological conditions. Superoxide anion can act as a carcinogen causing oxidant-induced DNA sequence changes that affect the activities of proto-oncogenes and supressor genes and activating cellular kinases to promote cell growth (Cerutti and Trump,
Cancer Cells
3:1-7 (1991)). The production of superoxide anion and other free radicals can lead to demyelination or neuronal death and conditions such as multiple sclerosis, the deterioration of cognitive function with aging, dementia, amyotropic lateral sclerosis (“ALS”), Alzheimer's disease, Parkinson's disease, and other degenerative neuropathies. (Keller and Mattson,
Rev. Neurosci.
9:105-116 (1998); McGeer and McGeer,
J. Neural. Transm. Suppl.
54: 159-166 (1998); Markesbery,
Free Radic. Biol. Med.
23:13447 (1997); Jenner and Olanow,
Neurology
47(6Suppl 3):S161-70 (1996); Evans,
Br. Med. Bull.
49:577-87 (1993); Joseph,
Integr. Physiol. Behav. Sci.
27:216-27 (1992)).
Current therapies for conditions that result from oxidative tissue damage are either non-existent or fraught with drawbacks. First, while these therapies may act to reduce the degree of tissue swelling that accompanies inflammation, these therapies do not inhibit the formation of tissue-damaging superoxide anion, H
2
O
2
or HOCl. Second, therapies involving the administration of anti-inflammatory steroids can cause undesirable immunosuppression and, in fact, premature atrophy of the thymus gland. Third, therapies involving a prolonged use of salicylates or other non-steroidal anti-inflammatory drugs can result in gastrointestinal bleeding. Fourth, therapies used for the treatment of asthma that involve repeated and frequent use of bronchiodialators can result in drug tolerance and a need for increased dosages and/or alternative drugs. Therapies for cancer are far fewer in number, have serious drawbacks, and have limited efficacy. Chemotherapy can be highly toxic, resulting in fatigue, vomiting, hair loss, and immunosuppression. Radiation therapy can lead to burns and localized immunosuppression. Excision of cancerous lesions can be highly invasive. Therapies for degenerative neuropathies are virtually non-existent. Although it is possible to use chemicals to slow nerve degeneration, methods for completely halting or reversing the damage have not yet been elucidated.
Thus, there is a clear need for agents that inhibit superoxide anion production, thereby treating or preventing conditions resulting from oxidative tissue damage without causing the above-mentioned, undesirable side-effects.
Phosphatidylinositol 3,4,5-trisphosphate has been isolated from FLPEP-stimulated human neutrophils (A. E. Traynor-Kaplan et al.,
J. Biol. Chem.
264(26):15668-15673 (1989) and A. E. Traynor-Kaplan et al.,
Nature
334(6180):353-56 (1988)). It has recently been shown that certain inositol phosphate derivatives including D-myoinositol 3,4,5,6-tetrakisphosphate (A. Vajanaphanich et al.,
Nature
371:711 (1994); J. M. Uribe et al.,
J. Biol. Chem.
271(43):26588 (1996); M. T. Rudolf et al.,
J. Med. Chem.
41 (19):3635-3644 (1998)), and sn-di-O-pahmitoyl-D,L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis(acetoxymethyl)ester (C. Schultz et al.,
Membrane
-
penneant
, Bioactivatable Derivatives of Inositol Polyphosphates andphosphoinositides, in Phosphoinositides: Chemistry, Biochemistry and Biomedical Applications, K. S. Bruzik, Ed.
Am. Chem. Soc., Symp. Ser.,
718, 232-243 (1998)) inhibit calcium-mediated chloride secretion. D-myo-Inositol 1,4,5,6-tetrakisphosphate has been shown to inhibit a phosphatidylinositol PI-3 kinase (“PI-3 kinase”) signaling pathway in colonic epithelia (Eckmann et al.,
Proc. N

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