JP2001213783A - Medocal treatment agent for animals - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine which is effective to animal cancer and viral diseases. SOLUTION: A trifluorothymidine derivative of formula (I) as medical agent. In the formula (I), R1 indicates H, a lower alkyl, a lower alkanoil, etc.; R2 is H, a lower alkyl substituted sylil, a lower alkylphenyl substituted sylil, etc.; R3 is H, acetyl, or benzoyl, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent containing a trifluorothymidine derivative. For more information,
The present invention relates to a therapeutic agent for animal cancer and viral diseases using a trifluorothymidine derivative.

[0002]

2. Description of the Related Art In recent years, the position of pets in a home has changed with the change in lifestyle, and it has become as important as a family especially in a household living alone or without children. Therefore, living in a sanitary environment like humans, getting enough meals, and being treated if sick, the life of pets is extended like humans. For this reason, many diseases have been reduced, and there is a need for treatment of diseases that have not been a serious problem. For example, as the life expectancy increases and the death rate due to cancer increases, a new and effective method is required for treating cancer.

For the treatment of animal diseases, the application of drugs used in humans can be considered first, but it is not always effective for animals, and therapeutic agents more suitable for animals are required. Trifluorothymidine is a nucleic acid antimetabolite synthesized by Heidelberger in 1962 (J. Med. Che.
m, 84, P3597, 1962), and various studies have been made as anticancer agents and antiviral agents. However, it is not useful as a pharmaceutical because it has poor oral absorbability and is rapidly metabolized by human metabolic enzymes even after intravenous administration and loses its activity. Therefore, various studies were made to improve the oral absorbability and maintain the effect.
Above all, the synthesis of various mask compounds is described in
52898, JP-A-59-36696, JP-A-60-5
6996, Japanese Patent Application Laid-Open No. 62-187482, etc., and attempts have been made to use it as an anticancer drug, but no compound has yet been found which completely achieves its purpose.

[0004]

An object of the present invention is to provide a veterinary therapeutic agent suitable for treating animals.

[0005]

In the treatment of animal cancer, the application of drugs used in humans can be considered. However, it is not always effective for animals, and drugs more suitable for animals are required. Accordingly, the present inventors have conducted intensive studies on therapeutic agents more suitable for animals, and as a result, have found that trifluorothymidine derivatives are very suitable for treating cancer and viral diseases in animals. Was completed. That is,
Trifluorothymidine derivatives were expected to have a therapeutic effect on human cancer, but are known to rapidly lose their activity by human metabolic enzymes, and are still effective as pharmaceuticals even after various improvements. It has not been. However, as a result of a detailed study of the metabolism between humans and animals, it has been found that metabolism is slow in animals and that effective blood levels can be maintained for a long period of time. Completed.

That is, the present invention relates to the following [1]:

[0007]

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Wherein R1 is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a substituted benzoyl group, a nicotinoyl group, a substituted nicotinoyl group, a methoxymethyl group, a tetrahydrofuranyl group, a benzyl group, a substituted benzyl group, a propargyl group; R2 represents a hydrogen atom, a lower alkyl-substituted silyl group, a lower alkylphenyl-substituted silyl group, a trityl group, a lower alkyloxycarbonyl group, a dimethylaminoethyloxycarbonyl group, a lower alkyl group, a substituted propargyl group, an allyl group or a substituted allyl group; Alkyloxythiocarbonyl group, dimethylaminoethyloxythiocarbonyl group, lower alkylthiocarbonyl group, lower alkyl group, lower alkanoyl group, benzoyl group, substituted benzoyl group, nicotinoyl group, substituted nicotinoyl group, methoxymethyl Group, tetrahydrofuranyl group,
A benzyl group, a substituted benzyl group, a propargyl group, a substituted propargyl group, an allyl group or a substituted allyl group,
3 represents a hydrogen atom, an acetyl group, a benzoyl group, a nicotinoyl group, a methoxymethyl group or a tetrahydrofuranyl group. An animal therapeutic agent containing a trifluorothymidine derivative represented by the formula:

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

The term "lower" as used in the present invention refers to a lower alkyl group or a lower alkanoyl group having 1 to 4 carbon atoms, and a substituent such as a substituted benzoyl group, a substituted benzyl group or a substituted propargyl group is a complex group. It means a substituent such as a ring, a halogen atom, a lower alkyl group, an optionally substituted lower alkyl group, an optionally substituted amino group, an acyl group or an alkoxy group.

The term "C1-4" represents the number of carbon atoms per unit substituent. That is, for example, in the case of dialkyl substitution, it means having 2 to 8 carbon atoms.

The term "heterocycle" as used herein means a monocyclic heterocyclic ring or a bicyclic fused heterocyclic ring composed of a 5- or 6-membered ring containing 1 to 4 nitrogen, oxygen or sulfur atoms. For example, as a monocyclic heterocycle, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine, tetrahydrofuran, morpholine, thiol Such as morpholine
Examples of the cyclic condensed heterocycle include quinoline, isoquinoline, naphthyridine, furopyridine, thienopyridine, pyrrolopyridine, oxazolopyridine, imidazolopyridine, condensed pyridine rings such as thiazolopyridine, benzofuran, benzothiophene, and benzimidazole. .

[0013] The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The alkyl group having 1 to 4 carbon atoms includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, te
An rt-butyl group and the like can be mentioned.

The alkoxy group having 1 to 4 carbon atoms includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. And the like. Examples of the aminoalkyl group having 1 to 4 carbon atoms include an aminomethyl group, a 1-aminoethyl group, and a 2-aminopropyl group.

The alkylamino group having 1 to 4 carbon atoms includes, for example, N-methylamino group, N, N-dimethylamino group,
N, N-diethylamino group, N-methyl-N-ethylamino group, N, N-diisopropylamino group and the like can be mentioned.

The acyl group having 1 to 4 carbon atoms includes, for example, an acetyl group, a propanoyl group and a butanoyl group.

The acylamino group having 1 to 4 carbon atoms includes, for example, an acetylamino group, a propanoylamino group and a butanoylamino group.

The alkylthio group having 1 to 4 carbon atoms includes a methylthio group, an ethylthio group and a propylthio group.

The alkoxycarbonyl group having 1 to 4 carbon atoms includes, for example, a methoxycarbonyl group and an ethoxycarbonyl group. Examples of the optionally substituted alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Isobutyl group, sec-butyl group, tert-butyl group and the like, and a substituent selected from a group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a phenyl group and a heterocyclic ring; Those having four can be cited.

The trifluorothymidine derivatives used in the present invention are disclosed in JP-A-5-17496 and JP-A-5-1788.
82, JP-A-7-82294 or JP-A-8-596
88 and the like. The representative compounds of the present invention are described in Table 1 below, but the present invention is not limited to these examples.

[0022]

[Table 1]

The therapeutic agent for animals containing the trifluorothymidine derivative of the present invention is useful as a therapeutic and / or ameliorating agent for diseases related to animal cell proliferation or viral diseases.

Here, the diseases relating to cell proliferation include malignant tumors, autoimmune diseases, skin diseases, infectious diseases, vascular diseases,
Allergic diseases, gastrointestinal tract injury, hormonal diseases, diabetes and the like. The target disease of the present invention is not limited to these.

Also, the trifluorothymidine derivative-containing preparations are useful as veterinary drugs, and they are used in the form of general preparations similar to humans. Animal preparations are prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants. This preparation can be selected from various forms depending on the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions, suspensions). Preparations) and suppositories.

In molding into tablets, various carriers well-known in the art can be widely used. Examples thereof include lactose, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, Shellac,
Binders such as methylcellulose and polyvinylpyrrolidone,
Disintegrating agents such as dried starch, sodium alginate, agar powder, carmellose calcium, starch, lactose, disintegrating inhibitors such as sucrose, cocoa butter, hydrogenated oil, quaternary ammonium bases, and absorption promoters such as sodium lauryl sulfate; It is possible to use humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as talc, stearate and polyethylene glycol. Furthermore, tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.

In molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples include crystalline cellulose, lactose, starch,
Excipients such as hardened vegetable oil, kaolin, talc, etc., binders such as gum arabic powder, tragacanth powder, gelatin and the like, disintegrants such as carmellose calcium, agar and the like can be mentioned.

Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like in accordance with a conventional method.

When prepared as an injection, the liquid preparation, emulsion and suspension are preferably sterilized and isotonic with blood. When formed into these forms, they are commonly used as diluents in this field. Things, such as water,
Ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, an amount of salt, glucose or glycerin necessary for preparing an isotonic solution may be contained in the preparation for animals, and ordinary dissolution aids, buffers, soothing agents and the like may be added. You may.

In shaping into a suppository, a wide variety of conventionally known carriers can be used. Examples thereof include semi-synthetic glycerides, cocoa butter, higher alcohols, esters of higher alcohols, polyethylene glycol and the like.

Further, if necessary, a coloring agent, a preservative, a fragrance, a flavor, a sweetener and other pharmaceuticals can be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in these veterinary preparations of the present invention is not particularly limited and may be appropriately selected from a wide range.
%, Preferably about 5 to 50% by weight.

The administration method of these animal preparations of the present invention is not particularly limited, and they are administered in accordance with various preparation forms, the age, sex, degree of disease and other conditions of patients.
For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered. Injections are used alone or mixed with normal replenishers such as glucose and amino acids. It is administered intramuscularly and, if necessary, alone, intramuscularly, subcutaneously or intraperitoneally. Suppositories are administered rectally.

[0034]

EXAMPLES The effects of the present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Results of Monkey Blood Concentration Measurement Three cynomolgus monkeys (male, 4 to 5 kg) were treated with 15.2 mg of trifluorothymidine PEG40 per kg.
0, 1.25 ml solution was administered intravenously. Blood was collected over time and the plasma concentration of the drug was measured by HPLC.
The results are shown in Table 2 [Table 2].

[Table 2]

Example 2 Results of Intravenous Administration of Blood Levels in Rats Three male SD rats were given 60 mg / kg of Table 1
A 1.25 ml solution of Exemplified Compound 1 in PEG 400 was administered intravenously. Blood was collected over time, and the plasma concentration of trifluorothymidine, which is the active substance, was measured by HPLC. The results are shown in Table 3 [Table 3].

[Table 3]

Example 3 Results of Oral Administration of Blood Concentration in Rats Three male SD rats (7 weeks old) were given 5 kg / kg.
8.5 mg of a 0.5% methylcellulose solution of Exemplified Compound 1 of Table 1 in 10 ml was orally administered. Blood was collected over time and the plasma concentration of the drug was measured by HPLC. The results are shown in Table 4 [Table 4].

[Table 4]

Example 4 Results of Measurement of Blood Concentration in Orally Administered Mice in Mice Three male CDF1 mice (22 weeks old) were administered with 40 mg / kg of 20% Tween 80 of Exemplified Compound 1 in Table 1
A 10 ml solution was administered orally. Blood is collected over time,
The plasma concentration of the drug was measured by HPLC. Table 5 shows the results
It is shown in [Table 5].

[Table 5]

[0039]

According to the present invention, it has been found that the therapeutic agent containing a trifluorothymidine derivative has high blood persistence in animals and exerts a very high effect based on the difference in metabolism between humans and animals. That is, they have found that the drug is very suitable for treating cancers such as hematopoietic tumors and solid cancers in animals and for treating viral diseases.

Claims (1)

[Claims] 1. A compound represented by the formula (1): [Wherein, R1 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a substituted benzoyl group, a nicotinoyl group, a substituted nicotinoyl group, a methoxymethyl group, a tetrahydrofuranyl group, a benzyl group, a substituted benzyl group, a propargyl group, R2 represents a hydrogen atom, a lower alkyl-substituted silyl group, a lower alkylphenyl-substituted silyl group, a trityl group, a lower alkyloxycarbonyl group, a dimethylaminoethyloxycarbonyl group, a lower alkyloxythio group; Carbonyl group, dimethylaminoethyloxythiocarbonyl group, lower alkylthiocarbonyl group, lower alkyl group, lower alkanoyl group, benzoyl group, substituted benzoyl group, nicotinoyl group, substituted nicotinoyl group, methoxymethyl group, tetra Dorofuraniru group, a benzyl group, substituted benzyl group, a propargyl group, a substituted propargyl group, an allyl group or a substituted aryl group, R3 represents a hydrogen atom, an acetyl group, a benzoyl group, a nicotinoyl group, a methoxymethyl group or a tetrahydrofuranyl group. ] The therapeutic agent for animals containing the trifluorothymidine derivative represented by these.