Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-17
2002-09-03
Riley, Jezia (Department: 1656)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S001000, C514S023000, C514S025000, C514S183000
Reexamination Certificate
active
06444648
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field to Which the Invention Belongs
The present invention relates to a leishmaniasis preventing and/or treating agent having 2-deoxy-2-[(3S)-(9-phenylnonanoyloxy)tetradecanoyl]amino-3-O -(9-phenylnonanoyl)-4-O-sulfo-&agr;-D-glucopyranose represented by a formula (I) or a non-toxic salt thereof as an effective ingredient.
2. Prior Art
The leishmaniasis is a parasite disease common to human beings and animals, which is induced by leishmaniasis parasites via Phlebotomus flies as blood-sucking insects. At present, the disease is widely spread, mainly in developing countries, in old world such as India, China and Mediterranean Sea and new world such as the Middle and South American areas, and is a infectious disease that is estimated to have about 12,000,000 to 14,000,000 patients all over the world. This disease is designated as one of the six greatest diseases with which WHO should grapple. The leishmaniasis is clinically classified into three types: visceral type, cutaneous type and mucocutanaous type. Among them, the visceral leishmaniasis is a serious disease that results in death if it is left without treatment.
When a person is infected with a leishmaniasis infectious species, the leishmaniasis appears after a latent period from one or two weeks to several months. The symptom, which depends on the respective types, includes fever, lassitude, weight loss, anemia, hepatosplenomegray, swelling of lymph node, etc. for the visceral leishmaniasis. The number of leukocytes decreases, which makes the patient weak against other infectious diseases and becomes systemic weak. The cutaneous leishmaniasis spreads from boundaries between mucous membrane and skins, and gradually destroys surrounding cartilages. The face and the looks are conspicuously destroyed, and occasionally the nasal septum is infected, finally a nose is sometimes taken off. The cutaneous leishmaniasis causes a nodule on an exposed portion of the human body and may causes occasionally an ulcer. Although spots and swellings never seen occur on the skin, they are accompanied by no pain.
As therapeutic agents for such leishmaniases, various medicines such as Amphotericin B, Bleomycin, Interleukin 2, Interferon &ggr; and Pentamidine have been used. (See Koff A. B. etal., J. Ame. Acad. Dermatol, 31, 639 (1994)). Among them, it is known that an antimony-based medicine is a specific. Further, it is reported that a lipopolysaccaride (LPS) is effective for cellular death resulting from the leishmaniasis infectious species (See Jacques, M. Eur. J. Immunol., 17, 203 (1987)).
DISCLOSURE OF THE INVENTION
However, since these medicines all have strong side effects, doctors need to pay their meticulous attentions to their use. Therefore, development of more effective and safer medicine by selectively acting upon leishmaniasis is desired.
In JP-B 4-74359 In JP-B 4-74359, it is disclosed that a compound used in the present invention, 2-deoxy-2-[(3S)-(9-phenylnonanoyloxy)tetradecanoyl]-amino-3-O-(9-phenylnonanoyl)-4-O-sulfo-&agr;-D-glucopyranose, which is represented by the formula (I) and a non-toxic salt thereof (hereinafter abbreviated as “the compound in the present invention”) have lipid A-like activity and exhibit immuno-enhancing activity (macrophages activating effect, B cell mitogenic activity, non-specific antibody producing activity, cellular immunity enhancing activity, etc.) and antitumor activity (interferon inducing activity, interferon producing activity, TNF inducing activity, etc.). Various kinds of non- non-toxic salts of the compound of the present invention are disclosed in JP-A 6-41175.
However, the activity of the compound in the present invention upon the leishmaniasis has not been reported at all.
Having streneously made investigations to discover a compound that acts upon prevention and/or therapy of the leishmaniasis and is highly safe, the present inventors discovered that 2-deoxy-2-[(3S)-(9-phenylnonanoyloxy)-tetradecanoyl]amino-3-O-(9-phenylnonanoyl)-4-O-sulfo-&agr;-D-glucopyranose having the formula (I) and a non-toxic salt thereof accomplish the object.
GIST OF THE INVENTION
A leishmaniasis preventing and/or treating agent having 2-deoxy-2-[(3S)-(9-phenylnonanoyloxy)tetradecanoyl]amino-3-O-(9-phenylnonanoyl)-4-O-sulfo-&agr;-D-glucopyranose represented by a formula (I) or a non-toxic salt thereof as an effective ingredient.
The 2-deoxy-2-[(3S)-(9-phenylnonanoyloxy)tetradecanoyl]amino-3-O-(9-phenylnonanoyl)-4-O-sulfo-&agr;-D-glucopyranose represented by a formula (I) or the non-toxic salts are effective to prevent and/or treat leishmaniasis, and is a highly safe compound.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a leishmaniasis preventing and/or treating agent having 2-deoxy-2-[(3S)-(9-phenylnonanoyloxy)tetradecanoyl]-amino-3-O-(9-phenylnonanoyl)-4-O-sulfo-&agr;-D-glucopyranose represented by the formula (I) or a non-toxic salt thereof as an effective ingredient.
1. Salts
The compound in the present invention represented by the formula (1) is converted to corresponding salts according to known methods. The salts which are non-toxic and water-soluble are preferred. Appropriate salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline-earth metals (calcium, magnesium, etc.), ammonium salts and salts of pharmaceutically-acceptable organic amines (tetramethyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine, arginine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, etc.).
The compounds in the present invention represented by the formula (I) or its salts may be converted to their hydrates according to known methods.
2. Methods for producing the compound in the present invention
As regards various kinds of non-toxic salts of the compound in the present invention represented by the formula 1, in JP-A 6-41175, methods for producing sodium salts thereof are described in detail in the Examples 2, 3, 5 and 6 and methods for producing tris(hydroxymethyl)methylammonium salt thereof in the Example 4.
3. Toxicity
The toxicity of the compound in the present invention is very low, and can be judged to be enough safe as to be used as a medicine. For example, a sodium salt of 2-deoxy-2-[(3S)-(9-phenylnonanoyloxy)tetradecanoyl]amino-3-O-(9-phenylnonanoyl)-4-O-sulfo-&agr;-D-glucopyranose exhibits an LD
50
value of 60 to 70 mg/kg in a case of intraveneous administration to SD-series male and female rats.
4. Application to medicine
The compounds in the present invention is effective for preventing and/or treating the leishmaniasis in animals including human beings, especially in the human beings.
In order to use the compound in the present invention represented by the formula (1), its non-toxic salt or their hydrate for the above purpose, it is usually administered systemically or topically and orally or parenterally.
Each of them is administered at a dosage, which depends upon ages, weights, symptoms, therapeutic effects, administrating ways, treatment periods, etc., ordinarily orally in a range of 1 mg to 1000 mg/one administration for an adult once to several times a day, or parenterally (preferably intravenously) in a range of 1 mg to 100 mg/one administration for an adult once to several times a day or continuously intravenously in a range of 1 to 24 hours a day.
As mentioned above, since the dosage depends upon various conditions, an amount smaller than the above dosage may be sufficient, or an amount beyond the above range may be necessary.
When the compound in the present invention is administrated, it is used in the form of solid compositions, liquid compositions and other compositions for the oral administrations, and in the form of injection solutions, medicines for external applications, suppositories, etc. for the parenteral administrations.
The solid compositions for the oral administrations include tablets, pills, capsules, powders, gran
Knobbe Martens Olson & Bear LLP
Riley Jezia
University of the Ryukyu
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