JP2002080490A - New nucleoside - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound to be administered in a dose unit preparation containing an ordinary nontoxic pharmaceutically acceptable carrier, adjuvant and excipient by oral, parenteral(including subcutaneous, intravenous, intramuscular, sternal injection or intravenous drip method) administration, inhalation spray, rectal or topical administration. SOLUTION: This new nucleoside has a structure of formula (1) or formula (2). This control release administration form is provided as one aspect. This substitute administration route of the nucleoside having the structure of formula (1) or formula (2) is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present application relates to (1) provisional application No. 60 / 028,586 filed on April 23, 1997, and (2) 1997.
Provisional Application No. 60 / 043,974, filed on April 23, 2004,
(3) Provisional application No. 60/05 filed on Aug. 12, 1997
No. 5,487, and (4) Provisional Application No. 60 / 036,094, filed Jan. 14, 1997.

[0002]Field of the invention  The present invention relates to the field of nucleosides.

[0003]Background of the Invention  The mammalian immune system contains two main types of lymphocytes: bone
B lymphocytes (B cells) originating in the marrow; and originating in the thymus
Source T lymphocytes (T cells). B cells are mainly body fluids
Involved in sexual immunity (ie, antibody production), T cells are primarily
Involved in cell-mediated immunity.

[0004] T cells are generally considered to be classified into two types: helper T cells and cytotoxic T cells. Helper T cells activate B cells and other lymphocytes, including cytotoxic T cells, and macrophages by releasing soluble protein mediators called cytokines that are involved in cell-mediated immunity. Lymphokines, as used herein, are a subset of cytokines.

[0005] Helper T cells are also generally classified into two types, Th1 and Th2. Th1 cells (also known as type 1 cells) contain interleukin 2 (IL-
2), produces tumor necrosis factor (TNFα) and interferon gamma (IFNγ) and is primarily involved in cell-mediated immunity such as delayed-type hypersensitivity and antiviral immunity. In contrast, Th2 cells (also known as type 2 cells) use interleukins (IL4, IL-
5, IL-6, IL-9, IL-10 and IL-1
3) and assists in the humoral immune response as seen in response to allergens, such as IgE and I
gG4 antibody isotype switch (Mosmann, 1989, Annu Rev Im).
Munol, 7: 145-173).

Th1 and Th2 used herein
The term "response" is meant to encompass the full range of effects each resulting from the induction of Th1 and Th2 lymphocytes. In particular, such reactions are altered by transcription, translation, secretion, and other mechanisms in the production of the corresponding cytokines, increase the proliferation of the corresponding lymphocytes, and exercise effects (motility effects).
ts), and other effects associated with increased production of cytokines.

[0007] Nucleosides and other compounds are Th1
The mechanisms that selectively regulate Th2 and Th2 responses relative to each other have not yet been elucidated. One possibility conceived by the inventors is that effective nucleosides alter the storage of guanosine triphosphate (GTP),
This in turn affects the rate at which cytokines are produced. In this theory, relatively large changes in available GTP are required to affect the concentration of both Th1 and Th2 cytokines, while relatively small changes in available GTP are necessary to affect Th1 and Th2 cytokines. Tend to affect the degree to different degrees.

[0008] These findings are of particular importance, as current therapies for many of the aforementioned diseases have limited efficacy, significant side effects, or both. For example,
Treatment of autoimmune diseases includes temporary relief, elimination of toxic antibodies (eg, in myasthenia gravis), and cyclosporine, which targets corticosteroids, chloroquine derivatives, antimetabolic or antitumor agents, and immune system cells Harmful drugs, including drugs such as

[0009]Summary of the Invention  The present application relates to novel nucleosides. Intended nuku
Reoside is a nucleoside corresponding to Formulas 1 and 2.
You.

[0010]Detailed description of the invention Definition  When the following terms are used herein, they
Is used as defined below.

The terms “α” and “β” refer to the specific stereochemical configuration of a substituent at an asymmetric carbon atom in the chemical formulas described.

The term "aryl" has one ring (eg, phenyl) or two fused rings (eg, naphthyl) optionally substituted with hydroxyl, lower alkyl, chloro, and / or cyano. It means a monounsaturated aromatic carbocyclic radical.

The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of one another. A mixture of a pair of enantiomers in a 1: 1 ratio is
A "racemic" mixture.

The term "heterocycle" refers to N, O or S
Means a monovalent saturated or unsaturated carbocyclic radical having at least one heteroatom such that each possible position of the ring is, for example, hydroxy, oxo, amino, imino, lower alkyl, bromo, Chloro,
And / or optionally substituted with cyano.

The term "isomers" refers to different compounds that have the same formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.

The term "L-configuration" is used throughout this specification to describe the chemical configuration of the ribofuranosyl component of a compound bound to nucleobases. L- of the sugar component of the compound of the present invention
The configuration is in contrast to the D-configuration of the ribose sugar component of natural nucleosides such as cytidine, adenosine, thymidine, guanosine, and uridine.

The term "lower alkyl" refers to methyl,
Ethyl, n-propyl, isopropyl, n-butyl, t
-Butyl, I-butyl or n-hexyl.
The term further refers to cyclic, branched or straight chain 1 to 6 carbon atoms.

The term "monocyclic" refers to O, N, S, S
means a monovalent saturated carbocyclic radical having at least one heteroatom such as e or P, wherein each possible position of the ring is, for example, a sugar moiety or a moiety such as bromo, chloro and / or cyano It may be optionally substituted with other moieties, thereby ultimately aromatizing the monocyclic system.

The term "nucleoside" refers to a particular position on a heterocycle, or a purine (position 9) or a pyrimidine (1
A) a compound comprising a pentose or modified pentose moiety attached in its natural position.

The term "C-nucleoside" is used throughout this specification to describe the type of bond formed between a ribose sugar moiety and a heterocyclic base. In C-nucleosides, the linkage occurs from the C-1 position of the ribose sugar component and binds to the carbon of the heterocyclic base. The bond formed in the C-nucleoside is of the carbon-carbon type.

The term "D-nucleoside" refers to D-nucleoside.
A nucleoside compound having a ribose sugar component (eg, adenosine) is meant.

The term "L-nucleoside" refers to L-nucleoside.
It means a nucleoside compound having a ribose sugar component.

The term "N-nucleoside" is used throughout this specification to describe the type of linkage formed between a ribose sugar component and a heterobase.
In N-nucleosides, the linkage occurs from the C-1 position of the ribose sugar component and binds to the heterocyclic base nitrogen. N
The bond formed in the nucleoside is of the carbon-nitrogen type;

The term "nucleotide" refers to a phosphate ester substituted at the 5 'position of a nucleoside.

The term "purine" is defined by the formula 1, 1-A ~
It means the nitrogen bicyclic heterocycle shown in 1-F.

Examples of compounds expected to be effective in the present invention are shown in Formulas 1 and 2.

Equation 1 has the following structure:

[0028]

Embedded image Equation 2 has the following structure:

[0029]

Embedded image

[0030]Administration  The compounds of the present invention can be used in appropriate pharmaceutical
It is intended to be administered under a protocol. Like that
Monotherapy Dosage and Protocol for Different Drugs
Is described in the PDR or at least manufactured
Available from distributors or sellers.

It will be appreciated that the therapeutically effective amount will vary depending on the infection or condition being treated, its severity, the treatment used, the pharmacokinetics of the drug used, and the patient being treated (animal or human). ) Will be understood by those skilled in the art. Therefore, the effective dose is 1 mg /
It ranges from kg body weight or less to 25 mg / kg body weight or more. This dosage range is generally about 0,1.
It produces an effective blood level concentration of the active compound ranging from 04 to about 100 micrograms / cc of patient blood. However, by administering a small amount and then increasing the amount until the side effects are unduly detrimental or achieve the intended effect, an appropriate patient-specific therapy will be developed.

The compounds of the present invention can be administered orally, parenterally (including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion), by inhalation spray, or rectally, topically, and the like. It can be done in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients.

It is contemplated that the compounds of the present invention can be formulated in admixture with a pharmaceutically acceptable carrier. For example, the compounds of the present invention can be administered orally as a pharmaceutically acceptable salt. Since the compounds of the present invention are primarily water soluble, they may be in physiological saline (eg, at a pH of about 7.2).
緩衝 7.5 buffered) for intravenous administration. Conventional buffers such as phosphate, bicarbonate, or citrate can be used for this purpose. It will be appreciated that those skilled in the art will recognize that within the scope of the disclosure herein, the formulation may be modified to provide a particular dosage without destabilizing the compositions of the invention or impairing their therapeutic activity. Various formulations for the route can be provided. In particular,
Modification of the compounds of the present invention to make them more soluble in water or other excipients can be readily effected, for example, by slight modifications (eg salting, esterification, etc.) known to those skilled in the art. It is also within the purview of those skilled in the art to modify the route and manner of administration of a particular compound so as to manage the pharmacokinetics of the compound of the present invention for maximal beneficial effects in the patient.

Furthermore, the compounds included in the combination of the present invention can be administered separately or together, and if administered separately, can be administered in any order. The amounts of active ingredient and pharmaceutically active agent, as well as the relative timing of administration, are selected to achieve the desired combined therapeutic effect.

The administration route of the compound of the present invention may be continuous (intravenous drip), orally several times a day (for example, Q.I.
I. D. ), Including oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal, and suppository administration.

To prepare a therapy of the present invention, a therapeutically effective amount of a compound is thoroughly mixed with a pharmaceutically acceptable carrier by conventional pharmaceutical compounding techniques to produce dosages. Is preferred. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, such as oral or parenteral. In preparing the pharmaceutical compositions for oral dosage form, the usual pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, it is possible to use suitable carriers and additives including water, glycols, oils, alcohols, flavorings, preservatives, colorings and the like. it can. For solid oral preparations, such as powders, tablets, capsules, and solid preparations, such as suppositories, starches, sugar carriers, such as glucose, mannitol, lactose, and related carriers, diluents, granulating agents,
Suitable carriers and additives can be used, including lubricants, binders, disintegrants, and the like. If desired, tablets or capsules can be enterically coated or sustained release by standard methods.

For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, but may also contain other ingredients which aid in dispersion. Of course, if sterile water is used and is maintained in a sterile condition, the composition and carrier must be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed.

In general, the most preferred use of the present invention is such that the active compound has relatively low cytotoxicity against non-target host cells and relatively high activity against the target. It is also understood.

While specific embodiments have been disclosed herein, the scope of the invention is not limited except by the interpretation of the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07H 19/24 C07H 19/24 (31) Priority claim number 60 / 055,487 (32) Priority date Heisei 9 August 12, 1997 (August 12, 1997) (33) Countries claiming priority United States (US) (72) Inventor Kowani Wan United States, Calif. (72) Inventor Debron Averett United States of America, California 92653, Irvin, Trinity 26 (72) Inventor Kanda Sammy Ramasamy United States of America, California 92653, Laguna Hills, Rotsky Creek Lane 5F Term (Reference) 4C057 BB02 DD01 LL41 LL51 4C08 6 AA03 EA16 EA18 NA14 ZB01 ZB02 ZB05 ZC02

Claims (2)

[Claims] 1. A nucleoside having the structure of Formula 1. Embedded image 2. A nucleoside having a second structure. Embedded image